1. health and fitness
2. disease

PHARMA, BIOTECH & LIFE SCIENCE
WHAT’S INSIDE
DISCOVERY
6
RESEARCH & DEVELOPMENT
12
PRECLINICAL
18
CLINICAL TRIALS
27
DIAGNOSTICS
35
BUSINESS & GOVERNMENT POLICY
39
TOOLS & TECHNOLOGY
A high-tech Angie’s List .......................................................8
A resource for cellular metabolism .................................14
Matching drug and trial options to patients ..................30
On the cutting edge.............................................................40
FINANCE/MARKETS
EDITORIAL/COMMENTARY
PRODUCTS & SERVICES
Q&A
3
10
45
46
SPECIAL REPORT
22
Disease Modeling
So life-like
After decades of questionable results,
are disease models turning a corner?
32
SHOW PREVIEW:
54th ASCB Annual
Meeting, Philadelphia
A new universality
in cell biology
Recognizing potential in RSV
Johnson & Johnson deals
out $1.75B for respiratory
disease company Alios
BY KELSEY KAUSTINEN
NEW BRUNSWICK, N.J.—Pharma giant John-
son & Johnson isn’t interested in closing 2014
quietly, marking the last quarter of the year
instead with the $1.75-billion acquisition
of privately held Alios BioPharma Inc. The
South San Francisco, Calif.-based clinicalstage biopharmaceutical firm is focused on
the development of antiviral therapies for
respiratory diseases, so the deal nabs Johnson
& Johnson a portfolio of drug candidates in
a variety of indications, including influenza,
rhinovirus and respiratory syncytial virus
(RSV). Both companies’ boards of directors
unanimously approved the transaction.
“We are so pleased to be joining the Janssen Pharmaceutical companies of Johnson
& Johnson, who have an impressive track
record of bringing breakthrough drugs for
viral diseases to market,” Dr. Lawrence M.
Blatt, president and CEO of Alios BioPharma,
said in a news release. “Our portfolio of novel
medications targets a diverse range of viral
infections, including respiratory syncytial
virus, which complements ongoing efforts by
Janssen to develop innovative treatments for
important and life-threatening infections.”
The transaction, which is subject to customary closing conditions including the
Hart-Scott-Rodino Act, is expected to close
Johnson & Johnson will pay $1.75 billion to acquire privately held Alios BioPharma Inc., based in
the Bay Area of California. J&J particularly has its eye on a promising candidate for treating
respiratory syncytial virus, though the deal brings with it other antiviral pipeline products as well.
in the fourth quarter of this year.
“We are excited that this acquisition will
enable us to explore treatment options for a
number of viral infections, including RSV,
the last of the major pediatric diseases with
no available preventive therapy,” commented
Dr. William N. Hait, global head of research
and development at Janssen. “AL-8176 complements our existing early-stage portfolio
for RSV, which aims to prevent and treat
this disease, the leading cause of acute lower
respiratory infection in children under the
age of five.”
AL-8176 is a nucleoside analog under
development as an oral antiviral therapy
against RSV. The compound inhibits RSV’s
replication by acting on the viral polymerase,
ALIOS CONTINUED ON PAGE 31
CREDIT: ENDO INTERNATIONAL
Engineering, physics,
computational modeling and
quantitative methods are all part of
this year’s ASCB special sessions
NOVEMBER 2014 : VOLUME 10 : NUMBER 11
Endo International intends to leverage its resources to optimize and drive increased
adoption of three key drugs—Xiaflex, Testopel and Testim—that are part of the portfolio
of Auxilium, which Endo is in the process of acquiring.
A new UC San Diego-led resource funded by the NIH will make it easier for pharmaceutical
companies to share data for drug design. Pictured here is UC San Diego’s Atkinson Hall.
Expanding the pipeline Mining pharma’s data
Endo to acquire Auxilium
Pharmaceuticals in a cashand-stock transaction for
approximately $2.6 billion
BY JEFFREY BOULEY
DUBLIN, Ireland—Seeking in part to gain
a broader offering of urology and orthopedic products that are natural complements to its current men’s health and pain
products, Irish company Endo International plc announced in early October a
definitive agreement with Auxilium Pharmaceuticals Inc. to acquire the Chesterbrook, Pa.-based company for $2.6 billion.
Under the terms of the deal, Endo will
acquire all of the outstanding shares of
common stock of Auxilium for a per-share
consideration of $33.25 in a cash-andstock transaction. The boards of directors of both companies have unanimously
approved the transaction, including the
repayment and assumption of debt. The
ENDO CONTINUED ON PAGE 42
Pharmaceutical companies to share data for
drug design via new UC San Diego-led resource
BY LLOYD DUNLAP
SAN DIEGO—Pharmaceutical companies will
collaborate with researchers at the University
of California, San Diego to provide previously
unreleased proprietary data for drug discovery through a new $3.7-million effort.
The project, led by UC San Diego princi-
pal investigators Drs. Rommie Amaro, Victoria Feher and Michael K. Gilson, includes
a major subcontract to Rutgers University,
directed by Dr. Stephen K. Burley of the
Research Collaboratory for Structural Bioinformatics Protein Data Bank.
DATA CONTINUED ON PAGE 8
Modeling neurodegenerative disease
Stem cells help develop cellular models for
understanding Parkinson’s disease
From modeling diseases to discovering therapies, stem cells have the potential to change the way we think about medicine.
Our researchers have partnered with The Parkinson’s Institute to build a path to more physiologically relevant cellular
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Access the free white papers at lifetechnologies.com/pdmodels
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FINANCE
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NOVEMBER 2014 | | DDNEWS 3
Selecta nets more than $20M in equity funding
WATERTOWN, Mass.—Selecta Bio-
sciences Inc., a clinical-stage biotechnology company developing a
novel class of targeted antigen-specific immune therapies, announced
Oct. 15 that it has secured equity
funding of more than $20 million
from a combination of new and
existing investors.
“With strong financial support from both our current and
new investors, we are now well
positioned to rapidly advance our
immune tolerance pipeline, including the lead program SEL-212, the
first non-immunogenic treatment
for refractory and tophaceous gout,”
said Dr. Werner Cautreels, president
and CEO at Selecta. “Severe gout is
a highly debilitating disease and
just one of the potential therapeutic applications of our proprietary
Synthetic Vaccine Particle (SVP)
platform. With a well-established
development path and favorable proforma economics, SEL-212 is a great
opportunity. SEL-212 is just the
beginning for us, as we have identified many biopharmaceuticals,
including existing and new classes
of biologics such as gene therapy,
where the effects of antidrug antibodies (ADAs) are deleterious.”
Selecta reports that it has established strong research and develop-
ment and manufacturing expertise
to enable the company to readily
adapt its proprietary SVP platform to
other applications developed internally or in collaboration with partners. In addition to its lead program
for severe gout (SEL-212), Selecta is
advancing immune tolerance programs to prevent ADAs against Factor VIII (SEL-201), anti-TNF alpha
antibodies and vectors used for gene
therapy, as well as candidates for
allergies and autoimmune diseases.
Including the funding just
secured, Selecta has obtained a
total of $78.6 million in private
equity funding to date from such
investors as Polaris Venture Partners, Flagship Ventures, OrbiMed
Advisors, NanoDimension, Rusnano, I2BF, Eminent Venture Capital
and Leukon Investments.
Selecta’s immunomodulatory
SVPs can induce antigen-specific
immune tolerance, enabling them
to be applied in a variety of therapeutic areas with large unmet medical need. The company is focused
on three key near-term applications: inhibition of immunogenicity for biologic therapies, treatment
of allergies and treatment of autoimmune diseases. ■
Rigontec raises
€9.45M in
first closing of
Series A round
BONN, Germany—Mid-October saw
Rigontec GmbH, a privately held
biopharmaceutical company developing RNA-based immunotherapeutics for the treatment of cancer
and viral diseases, announce the
first closing of its Series A financing round, raising €9.45 million,
or about $12 million. The round
was co-led by Wellington Partners
and Boehringer Ingelheim Venture
Fund, and it included NRW Bank
and High-Tech Gründerfonds.
Rigontec is developing synthetic ligands of a novel receptor
of the innate immune system, retinoic acid inducible gene I (RIG-I),
which recognizes viral RNA. RNA
motifs that activate RIG-I promote
the destruction of diseased cells and
the induction of a lasting immune
memory, thereby treating and preventing recurrence of disease.
Rigontec’s lead compound
ImOl100, a proprietary first-in-class
product targeting RIG-I, is currently being evaluated for development
in several cancer types, including
melanoma and prostate cancer.
ImOl100 is a chemically synthesized mimic of the natural ligand
of RIG-I with improved safety and
drug-like properties. In various
preclinical models, ImOl100 has
demonstrated substantial tumor
regression and systemic antitumor
activity, including long-term protection against tumor rechallenge.
Rigontec’s technology also allows
the design of pipeline candidates
with additional gene silencing and
inhibitory activities, further broadening the applicability of this new
class of drugs in the area of oncology and viral infections. ■
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MARKETS
4 DDNEWS | | NOVEMBER 2014
For more information, visit www.DDN-News.com
Pharmaceutical and biotech market indices
F
Amex Pharmaceutical Index
or the month of september, the
Dow Jones Industrial Average fell
0.32 percent, the S&P 500 dropped
1.55 percent and the NASDAQ
Composite Index sank 1.9 percent.
Despite the weak month, the Burrill Select
Index is up 20.03 percent for the year, strongly
outpacing all of the major indices.
460
461
465
15/Nov
06/Dec
03/Jan
492
495
14/Feb
14/Mar
481
11/Apr
505
512
522
09/May
13/Jun
11/Jul
506
15/Aug
524
533
29/Aug
30/Sep
1151
1144
29/Aug
30/Sep
SOURCE: YAHOO FINANCE
Burrill Select
Burrill Mid-Cap Biotech and Small-Cap Biotech
503
513
533
586
497
257
122
135
15/Nov
06/Dec
576
14/Feb
552
553
567
1105
610
903
945
946
06/Dec
03/Jan
1090
941
963
1036
1076
1116
300
207
145
03/Jan
505
621
14/Mar
11/Apr
MID-CA P
184
09/May
215
13/Jun
197
11/Jul
220
225
218
15/Aug 29/Aug 30/Sep
15/Nov
14/Feb
14/Mar
11/Apr 09/May
13/Jun
11/Jul
15/Aug
S MALL-CAP
SOURCE: BURRILL & CO.
SOURCE: BURRILL & CO.
U.S. Treasury efforts to fend off inversions could quell M&As
BY BURRILL MEDIA
SAN FRANCISCO—Seeking to discourage com-
panies from acquiring or merging with offshore
companies in so-called inversions in order to
avoid U.S. taxation, the U.S. Treasury Department in September announced new rules that
eliminate the ability of U.S. companies to use
earnings of their foreign subsidiaries to fund
acquisitions without paying U.S. taxes on that
capital. The rules also make it more difficult
for companies to invert by strengthening the
requirement that the former owners of the U.S.
entity own less than 80 percent of the new
combined entity. The rules apply to deals that
have not closed as of Sept. 22, 2014.
The result of these rules, not surprisingly,
may be to suppress that rate of mergers and
acquisitions (M&As), given that inversions
have, so far, been a substantial driver of M&A
activity in the life sciences in 2014. In fact, of
the $286.2 billion in life-sciences M&A transactions announced so far this year, 44 percent
involved inversions. That includes AbbVie’s
$54.7-billion acquisition of Shire—which
AbbVie now plans to abort—and Mylan’s purchase of Abbott Lab’s European-branded generics division for $5.3 billion.
“The actions by the Treasury Department
will diminish the attractiveness of inversions, but will fall short of putting an end to
them. They will need to be justified by more
than their tax benefits alone,” says G. Steven
Burrill, CEO of Burrill Media. “It will take
legislative action to put a halt to these transactions. When the new session of Congress
begins, the controversy over inversions represents an opportunity for comprehensive tax
reform and the opportunity to address sub-
stantive tax issues of concern to the industry
from the effects of tax policy on investment
to its ability to incentivize R&D spending.”
While inversions may be cooling, at least in
the short run, initial public offerings (IPOs)
are still taking place at a fairly heated pace. As
Burrill notes, the “brisk pace of life- sciences
initial public offerings continued in September with a total of seven IPOs completed on
global markets, six of which occurred on U.S.
exchanges. The activity raised the total number
P
U
B
L
I
Illumina reports record
financial results for Q3 2014
C
SAN DIEGO—Illumina Inc. recently announced its
financial results for the third quarter of fiscal year
2014, noting that revenue was $481 million, a
35-percent increase compared to $357 million in
Q3 2013, and that GAAP net income for the quarter
was $93 million, or 63 cents per diluted share,
compared to $31 million, or 22 cents per diluted
share, for the same period last year. Non-GAAP net
income for the quarter was $114 million, or 77
cents per diluted share, compared to $63 million,
or 45 cents per diluted share in 2013.
“Illumina experienced tremendous momentum
in the third quarter, with strong shipments in HiSeq
X, NextSeq and MiSeq, as well as the associated
consumables, resulting in record financial results,”
stated Jay Flatley, CEO. “With the most extensive
sequencing portfolio available, we are well positioned for continued long-term growth as we
develop and address the large and untapped market opportunities ahead of us.”
The gross margin for the quarter was 69.5 percent
completed globally in 2014 as of the end of
September 2014, raising a total of $7.8 billion.
That compares to 46 IPOs globally that raised
nearly $6.2 billion in the same period last year.
In September, four of the six IPOs on U.S.
exchanges involved companies based overseas, indicating that companies are finding an
easier time raising capital in the U.S. These
included Affirmed Therapeutics (Germany),
ReWalk Robotics (Israel), ProQR Therapeutics (Netherlands) and Foamix (Israel). ■
of U.S. IPOs to 82 for the first nine months of
the year for a total of $6.3 billion. That compared to 39 IPOs on U.S. exchanges during the
first nine months of 2013, in which companies
raised a total of $6 billion.”
The 82 IPOs so far in 2014 are already the
most to be completed in a single year. Though
these new issues are up an average of 8.3 percent, 40 are above their initial offering price
while 42 are below.
Overall, a total of 102 IPOs have been
C O
M
P A
N
compared to 58.8 percent in the prior year period; the
prior year period included impairment charges of $25.2
million related to the discontinuation of a non-core
product line. Excluding the effect of non-cash charges
associated with stock compensation, amortization of
acquired intangible assets, legal contingencies and
impairments, non-GAAP gross margin was 73.2 percent compared to 70.2 percent in the prior year period.
Trinity Biotech announces
third-quarter results
DUBLIN, Ireland—Trinity Biotech plc, a leading devel-
oper and manufacturer of diagnostic products for
the point-of-care and clinical laboratory markets,
recently announced results for the quarter ended
Sept. 30, 2014. In addition, it announced that it was
temporarily suspending its FDA trials for its Meritas
Troponin test. Total revenues for Q3 were $27.2 million, which compares to $24.1 million in Q3 2013,
an increase of 12.6 percent. Gross profit for Q3 of
this year amounted to $13 million, representing a
gross margin of 47.9 percent, which is lower than
the 49.7 percent achieved in the same period last
Y
N
E
W
S
year. Research and development expenses have
increased to $1.1 million from $900,000 when compared to last year. Operating profit has decreased
from $4.8 million to $4.6 million for the quarter.
However, if U.K.-related closure costs and Meritas
sales and marketing expenses are excluded, operating profit would have increased from $4.8 million in
Q3 2013 to $5 million this quarter.
ADOCIA reports Q3 financials
LYON, France—ADOCIA,
a biotechnology company
specializing in the development of medicines from
already-approved therapeutic proteins, announced
its revenues for the third quarter of 2014, which
were €100,000 (roughly $127,100), generated
from research contracts on the formulation of
monoclonal antibodies. For the same period last
year, revenues were €4.7 million (nearly $6 million), principally as the result of the amortization
of the upfront payment regarding the licensing
contract signed with Eli Lilly. The non-amortized
part of the upfront payment was totally recognized
in revenues over the third quarter 2013.
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6 DDNEWS | | NOVEMBER 2014
DISCOVERY
LONDON—Researchers from the Institute of Psychiatry at King’s College London and the University of Exeter have released new evidence that
epigenetic changes in the brain contribute to
Alzheimer’s disease. A recent study discovered
that chemical modifications to DNA in the ANK1
gene have a strong association with measures of
neuropathology in the brain, and individuals with
more Alzheimer’s disease-related neuropathology
had more DNA modifications to the ANK1 gene,
particularly in the entorhinal cortex and other
cortical regions that are traditionally affected.
“It’s intriguing that we find changes specifically
in the regions of the brain involved in Alzheimer’s
disease. Future studies will focus on isolating different cell types from the brain to see whether
these changes are neuron-specific,” said first
author Dr. Katie Lunnon of the University of Exeter
Medical School.
CHDI extends
collaboration with Evotec
HAMBURG, Germany—Evotec AG has announced that
its collaboration with CHDI Foundation Inc., established in 2006, has been extended and restated. As
a result, CHDI will fund up to 52 full-time scientists
at Evotec over the next three years. The partnership is focused on discovering new treatments for
Huntington’s disease, and this extension expands
the agreement to include the use of Evotec’s highthroughput screening and proteomics platforms.
“Evotec represents one of our largest and
longest-standing relationships and continues to
be an important strategic partner in our search for
effective treatments for Huntington’s disease,” Dr.
Robert Pacifici, CHDI’s chief scientific officer, commented. “Their integrated drug discovery capabilities are helping us to discover novel targets and
to advance drug candidates towards the clinic,
and we look forward to continuing to work with
Evotec over the coming years.”
IN THIS SECTION
Alzheimer’s disease
A high-tech Angie’s List............................ 8
ANK1 gene modifications
linked to Alzheimer’s disease ................... 6
Antibiotics/Microbiome
Micriobiome to the rescue ....................... 6
Data sharing
Mining pharma’s data
(DATA from cover)..................................... 8
HIV/AIDS
Computational combat ............................. 6
Huntington’s disease
CHDI extends collaboration with Evotec.. 6
Oncology
Creating realistic systems ........................ 6
Microbiome to the rescue
Vaginal bacteria reveals
untapped medical potential
of the human microbiome
BY ZACK ANCHORS
SAN FRANCISCO—One of the most common
bacterial organisms found in the vagina has
helped scientists at the University of California, San Francisco (USCF) reveal the extent
to which the human microbe could serve as
a rich source for antibiotic compounds. The
researchers found that Lactobacillus gasseri, a
common species in the microbe community
of the vagina, produces a compound, lactocillin, which closely resembles an antibiotic
compound that the pharmaceutical company
Novartis is currently testing in a Phase 2 clinical trial. The discovery, along with other key
finding of UCSF’s study, suggests there could
be many other small molecules produced by
microbes in or on the human body that possess therapeutic potential.
Dr. Mohamed Donia, who drafted the new
study as a postdoctoral fellow at UCSF, tells
DDNews that the ability of organisms like Lactobacillus gasseri to produce antibiotic compounds turns the typical drug development
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
ANK1 gene modifications
linked to Alzheimer’s disease
Researchers at the University of California, San Francisco have discovered that the human
microbiome could serve as a rich source of potential therapeutics. Pictured here is the UCSF
Mission Bay campus.
process on its head. “We’re used to developing drugs by discovering natural products or
using synthetic chemistry, and then spending
years modifying these compounds to achieve
the best biological activity and the least toxicity,” says Donia, who is currently an assistant
professor of molecular biology at Princeton
UCSF CONTINUED ON PAGE 7
Computational Creating
combat
realistic
systems
Researchers combine molecular, quantum
mechanics to screen for HIV compounds
Models are designed to show growth
of tumor cells and effectiveness of
drugs outside of the body
BY KELSEY KAUSTINEN
ODENSE, Denmark— The HIV
virus remains a difficult one to
treat due to its ability to constantly mutate and to protect
vulnerable binding sites. In
light of this tendency, drugs
that have proven effective in the
past can lose their potency, leading to a constant need for new
drugs targeting new facets of
the virus. Given the complexity
of the virus, however, identifying
compounds with the potential
to target it effectively is a timeconsuming process—one that
researchers from the University
of Southern Denmark have been
able to speed up through a new
screening model.
The researchers in question
included postdoc Vasanthanathan
Poongavanam, from the Department of Physics, Chemistry and
UNIVERSITY OF SOUTHERN DENMARK
BR IEFS
BY ILENE SCHNEIDER
CHARLOTTESVILLE, Va.—“Researchers can take primary cells
Pharmacy at the University of
Southern Denmark, and Jacob
Kongsted, an associate professor
from specific human organs, but they die in the Petri dish, and
trying to get a drug response is unrealistic,” explains Dr. Brian
Wamhoff, vice president of research and development and cofounder of HemoShear, adding, “Drug discovery with cells on
the bench is not meaningful in a human context. Tumor cells
grow faster in a Petri dish than they do in humans, and other
parameters are not the same as they are in the human body.
Experimenting on mice is not the same as using the same
drugs on humans.”
HemoShear, Wamhoff says, can create human responsiveness on the bench by taking multiple cell types that require
each other in vivo, bringing them together in the right context
and exposing them to physiological parameters that they experience in the human body. “The cells stay alive, wake up and
respond, leading to better drug discovery,” he explains.
Funded by a contract with the National Cancer Institute
(NCI), HemoShear is developing a series of tumor models that
recreate a wide variety of cancers for discovery of new drugs.
HIV CONTINUED ON PAGE 8
MODEL CONTINUED ON PAGE 9
Postdoc Vasanthanathan
Poongavanam, from the
Department of Physics, Chemistry
and Pharmacy at the University of
Southern Denmark (pictured here),
and Associate Professor Jacob
Kongsted have combined
molecular and quantum mechanics
in a new, rapid screening model for
HIV compounds.
DISCOVERY
For more information, visit www.DDN-News.com
UCSF
CONTINUED FROM PAGE 6
University. “This particular compound has bypassed that whole
process, and there could be many
molecules in other parts of the
human microbiota with the same
potential.”
The UCSF study, which was published in Cell in September, found
that lactocillan serves to kill common vaginal bacterial pathogens
while sparing other bacteria known
to dwell harmlessly in the vagina.
“This bacteria actually produced
the right drug in the right place,
with the exact biological activity
that is needed, and probably at the
time,” says Donia.
While many medicines are
derived from microbes and plants,
few efforts have been made to use
host and interact with other bacteria,” says Donia.
Researchers created a machinelearning algorithm that enabled
a computer to identify known
genes that produce small molecules with potential as drugs.
When they used this algorithm
to systematically analyze genes
in the human microbiome, they
identified 3,000 BGCs at different
body sites. “We were surprised to
find so many BGCs producing
every small molecule type, and we
were also surprised to find that so
many of them were very common
within a population of healthy
humans,” says Donia. One of the
compounds that researchers identified and then studied in greater
detail was the molecule produced
within the vaginal microbe community, lactocillin, which belongs
to a class of antibiotics called
thiopeptides.
The approach taken by the UCSF
researchers differed in significant
ways from that of other studies car-
NOVEMBER 2014 | | DDNEWS 7
ried out under the umbrella of the
Human Microbiome Project. “Most
studies have been focused on continuing to sequence and document
just which microbes are part of the
microbiome,” says Donia. “We took
a functional approach and tried to
find out what these microbes are
actually doing.”
The most common method of
identifying bacteria residing in
humans involves genus-level analysis, but UCSF researchers found
that this method is not detailed
enough to predict which drug-like
molecules bacteria will produce.
Individual species, and different
strains within each species, produce different molecules. “We
need to learn what these molecules
are and what they are doing,” said
Dr. Michael Fischbach, an assistant professor of bioengineering
at UCSF and senior author of the
study. “This could represent a pool
of molecules with many tantalizing
candidates for drug therapy.” ■
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“We’re used to developing
drugs by discovering natural
products or using synthetic
chemistry, and then spending
years modifying these
compounds to achieve the
best biological activity and the
least toxicity,” says Dr.
Mohamed Donia, formerly a
postdoctoral fellow at the
University of California, San
Francisco and now an
assistant professor of
molecular biology at Princeton
University. “This particular
compound has bypassed that
whole process, and there could
be many molecules in other
parts of the human microbiota
with the same potential.”
bacteria within the human body
as a source for new drug molecules. But recent efforts to better
understand the human mirobiome
has created new opportunities to
explore this therapeutic potential.
Scientists have made significant
progress toward mapping the bacterial ecosystems found in the gut,
skin, nasal passages, mouth, vagina
and other parts of the human body
through research funded by the
NIH’s Human Microbiome Project.
However, much less is known
about the small molecules that govern interactions between microbes
and their human hosts. A primary
purpose of the UCSF study was
to identify the biosynthetic gene
clusters (BGCs) that contain the
genetic blueprints for creating such
molecules. “Small molecules are
the common language that almost
every living cell can understand,
so we wanted to interrogate what
small molecules are being produced by these bacteria and find
out how they interact with their
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HD_AD_DDN_Portrait(Oct2014).indd 1
10/13/2014 9:57:48 AM
DISCOVERY
8 DDNEWS | | NOVEMBER 2014
A high-tech Angie’s List
Platform links
researchers with drug
discovery expertise
BY LLOYD DUNLAP
JERSEY CITY, N.J.—The Alzheimer’s Drug Discovery Foundation
(ADDF) and OnDeckBiotech have
announced the launch of ADDF
ACCESS, a new and improved openaccess platform to connect scientists
with a virtual network of contract
research organizations (CROs),
drug development experts and educational resources. By leveraging
OnDeckBiotech’s digital technology,
the enhanced ADDF ACCESS platform will streamline links between
researchers and CROs specializing
in diseases of the central nervous
system (CNS) to expedite drug discovery research and development.
ADDF ACCESS users will see
improved functionalities across the
ADDF ACCESS platform, including
direct communication with CROs
and consultants, a suite of project
management tools and educational
resources focused on drug development for CNS diseases. The new
ADDF ACCESS platform powered
by OnDeckBiotech went live in early
September right after the ADDF’s
15th International Conference on
Alzheimer’s Drug Discovery, held
Sept. 8-9, in Jersey City, N.J.
“This is an exciting opportunity
to leverage the OnDeck technology and a dedicated development
team to improve the functionality
of ADDF ACCESS,” said Dr. Howard
Fillit, executive director and chief
science officer of ADDF, in a statement announcing the collaboration.
“The new platform will streamline
the process of identifying and contracting with
CROs that have pharmaceutical development
expertise for challenging
CNS diseases. This type
of expertise is critical
to the success of translational CNS
research programs in academia and
small biotechnology companies.”
“It’s not uncommon for a study
director to spend weeks searching
for and evaluating vendors experienced with a particular model.
These costly delays are an unnecessary distraction for scientific teams,
and any misstep can compromise
an otherwise promising program,”
said Cliff Culver, CEO and founder of OnDeckBiotech. “We have
seen significant savings of time
and reduced administrative cost
for both sponsors and vendors on
the platform, and we are confident
these improvements have a positive
impact on research efficiency.”
Culver notes that his company
and ADDF were “working on similar things independently of each
other.” ADDF realized that vendors
were having trouble sourcing quality CROs, and the partnership with
OnDeck was the result. OnDeck provides a cloud-based platform, which
has now been customized for the
Alzheimer’s community, to improve
functionality, with enhanced search
TOOLS &
TECHNOLOGY
DATA
CONTINUED FROM PAGE 1
The data provide atomic details
of drug mechanisms and will be
used to improve computer-aided
drug-design methods with the aim
of accelerating drug discovery.
“One of the challenges in medical research is the paucity of realworld data available to academic
researchers and other interested parties to develop new and
improved methods for computeraided drug discovery,” says Amaro,
associate professor of chemistry
and biochemistry at UC San Diego.
“Pharmaceutical companies generate lots of data in-house as they conduct drug research, but often have
difficulty sharing these datasets,
due to legal and technical barriers.”
“This project is all about helping
companies release the high-quality
data they have generated, which has
incredible value to researchers working to improve methods of computer-aided drug discovery,” she adds.
“Companies want to help, because
everyone stands to benefit from the
ability to develop new medications
more quickly and inexpensively.”
The new Drug Design Data
Resource (D3R) will span UC San
capabilities to help researchers identify companies that provide specific,
relevant services.
The service includes detailed profiles of featured CROs,
including information
on platform technologies relevant to CNS
indications, opportunities to rate and review
CROs and directly communicate with consultants and key
personnel at participating CROs.
Project management tools enable
users to easily distribute requests
for proposals (RFPs) to multiple
vendors and ensure robust, competitive bids, including an RFP
template, contracting templates and
relationship history-tracking data.
Educational material to support
CRO selection and program design,
including recommendations for
selecting and managing CRO contracts, and access to webinars from
the ADDF’s Annual Drug Discovery
for Neurodegeneration Conference
are all part of the package.
By facilitating quality connections between scientists and toptier drug discovery experts, ADDF
ACCESS removes an enormous
hurdle to undertaking drug discovery and development in academia
and small biotechnology companies, Culver notes. In addition, it’s
provided as a free service to users.
Vendors pay for the privilege of
being listed and profit when new
business is directed their way. ■
“One of the challenges in medical
research is the paucity of real-world
data available to academic
researchers and other interested
parties to develop new and
improved methods for computeraided drug discovery,” says Dr.
Rommie Amaro, an associate
professor at UC San Diego.
Diego’s Skaggs School of Pharmacy
and Pharmaceutical Sciences, Department of Chemistry and Biochemistry,
Center for Research in Biological
Systems, Center for Drug Discovery
Innovation (CDDI) and the San Diego
Supercomputer Center. The D3R is
being administered through the Center for Research in Biological Systems,
which is based at the UC San Diego
Qualcomm Institute.
D3R researchers will act as “data
brokers,” collaborating with scien-
EDITCONNECT: E111407
tists and attorneys in the pharmaceutical industry to identify, evaluate, release and enhance useful
industrial datasets. The data will
then be made available to the drug
discovery research community in
a manner designed to maximize
value, longevity and impact.
A dataset will ideally be comprised of approximately 50 or more
compound structures provided in
smiles (simplified molecular-input
line-entry system) or sdf format,
Feher notes, along with the associated Kd, Ka, Ki or IC50 assay values, and at least five target co-crystal structures in pdb format. “There
are likely to be cases where crystal
structures will be further refined by
Dr. Stephen Burley’s group at Rutgers,” Feher adds, “in which case,
crystallographic structure factors
for electron density mapping may
also be provided by the company.”
The UC San Diego team members are developing a webpage,
drugdiscoverydata.org, that will
provide a portal to search and
download the datasets collected
and connect to related resources
such as PDB, PubChem, BindingDB, MOAD and ChEMBL. This
webpage will also provide information, participation instructions and
For more information, visit www.DDN-News.com
HIV
CONTINUED FROM PAGE 6
in the same department.
“HIV is a retrovirus that contains enzymes which make it able
to copy itself with the help of host
genetic material and thus reproduce,” Poongavanam explains.
“If you can block these enzymes’
ability to replicate itself, the virus
cannot reproduce.”
The researchers’ new method is
detailed in a pair of papers: “Binding free energy based structural
dynamics analysis of HIV-1 RT
RNase H-inhibitor complexes,”
which appeared in Integrative
Biology, and “Inhibitor Ranking
through QM Based Chelation Calculations for Virtual Screening of
HIV-1 RNase H Inhibition,” which
appeared in PLOS ONE.
So far, Poongavanam and Kongsted have used the new methods to
screen half a million compounds,
reveraling 25 compounds of interest that were tested in a conventional laboratory experiment,
showing 14 of them were capable
of inhibiting the HIV virus’ ability
to reproduce. The promising candidates are now being explored by
Italian researchers at the University of Cagliari to see if they could
be advanced as HIV drugs.
“Our approaches are not new,
but we use a combination of
existing approaches for this problem in a new way,” Poongavanam
explains. “Methods that use
molecular mechanics principles
are often used to screen millions
of chemical compounds in drug
discovery because these methods
challenge dataset downloads.
Multiple industrial partners are
currently being recruited to the
project. Gilson, a professor of pharmacy and co-director of the CDDI,
notes that the D3R will work closely
with pharmaceutical companies
to publicly release data for use by
researchers developing new software to speed the discovery of new
medicines for a variety of diseases.
“Negotiations have begun, and
we have found several companies
[which] are very enthusiastic about
the project,” Feher states. “Three
companies expressed their support when we initiated our grant
submission, and we are looking to
them for our initial datasets. Members of the computational community, whether in pharmaceutical
companies or academia, recognize
the value in having these datasets
publicly available.”
“The drug companies, for example, might provide the structure of
a protein and 50 molecules created
during a drug discovery project, as
well as how well those drugs and
drug candidates bind to their protein targets,” adds Gilson. “Researchers worldwide will use these data as
benchmarks to test their methods
and improve their accuracy.”
are fast. But in our study, we used
quantum mechanics in addition
to molecular mechanics methods in order to put more effort
in accuracy of the prediction.”
“These methods are very different in principle, but combining these methods solves many
mysteries in understanding complex molecular recognition,” he
continues. “Quantum mechanics
is primarily used to study in detail
how a compound binds to a protein at the atomic level; therefore,
this method is very accurate, but
slow. On the other hand, molecular mechanics-based methods
are primarily used to understand
large, complex structures at the
molecular scale, and they are fast.
In our study, we used a ‘hybrid’
in order to achieve more accuracy
and speed. This approach is very
powerful, and indeed became
internationally recognized after
the Nobel Prize (2013) was awarded to Prof. Martin Karplus, Prof.
Michael Levitt and Prof. Arieh
Warshel, who are considered pioneers in this growing field.”
Poongavanam adds that
“These approaches could be
applicable to other diseases, but
it needs to be tested thoroughly,
as we have only validated the
models for this enzyme.” He
expects to see approaches such
as this, utilizing computer-based
predictions and screening models, become more prevalent, noting that they are areas of interest
for pharmaceutical and biotech
companies. ■
EDITCONNECT: E111405
Feher, a project scientist in the
UC San Diego Department of
Chemistry and Biochemistry and
lead for discovery resources at the
CDDI, says these types of real-world
challenges represent a powerful
way to test and improve computational methods and thereby speed
drug discovery and reduce costs.
“Unfortunately drug discovery is
still to a large extent trial and error,”
says Feher, who spent a decade working in the pharma industry before
coming to UC San Diego. “What
computational chemists globally are
trying to do is to make faster, more
accurate, more predictive programs
to speed up the process. Part of our
mission is to engage the community in these challenges to test newly
developed predictive algorithms.”
Adds Gilson: “There’s a sense
that, although computational drug
discovery is already useful, it hasn’t
fulfilled its potential, and that the
calculations are not as accurate as
they could be. We want to help the
research community objectively
identify the strengths and weaknesses of existing methods, so the
results can be fed back into a process of continuous improvement
and thus advance the field.” ■
EDITCONNECT: E111403
DISCOVERY
For more information, visit www.DDN-News.com
MODEL
CONTINUED FROM PAGE 6
The company recently announced
that it has completed the first phase
of development of a novel cancer
drug discovery platform that replicates human tumor biology and
responds to clinically relevant
drug concentrations. Using its new
platform, HemoShear was able to
successfully replicate human therapeutic response to cisplatin, a drug
approved to treat non-small cell
lung cancer (NSCLC), at a therapeutically relevant concentration.
Similarly, HemoShear evaluated
two other drugs currently in clinical studies and confirmed a therapeutic response.
When evaluated in traditional
cell culture systems and mouse
studies, the same dose of cisplatin
does not show a response. HemoShear’s findings reinforce the need
to test cancer drug candidates
under more human-relevant tumor
conditions.
“Nearly 95 percent of all cancer
drugs entering clinical trials fail
because of toxicity or lack of efficacy,” Wamhoff says. “A major contributor to this dismal failure rate
can be attributed to the inability
of traditional models to uncover
the underlying disease biology
and predict efficacy and safety of
cancer drug candidates. With our
novel approach to recreating the
tumor microenvironment, we have
demonstrated a major step toward
understanding human response to
cancer drug treatments.”
Wamhoff adds, “There are a lot
of 3D tumor systems available, but
ours can separate cell types to see
how a drug targets each one. It’s a
depth of biology not available on
other systems.”
HemoShear started in 2008
with the goal of validating human
responses to 200 drugs in order to
enter drug discovery collaborations
with select pharmaceutical and biotechnology companies to identify
novel therapeutic approaches. By
bringing together cancer cells,
stromal cells and vasculature
under the right conditions, the
company hopes to improve the success of drug candidates when they
enter the clinic and bring them to
patients faster.
Two years ago the NCI approached
HemoShear to create its tumor
microenvironment. The company
has received more than $10 million in
Small Business Innovation Research
funding from the government.
HemoShear’s translational tissue
systems apply physiological blood
flow characteristics to human tissue to restore its in-vivo biology,
using material from HemoShear’s
biorepository and interpreting
data with cutting-edge computational analytics. In Phase 1 of the
NCI-funded program, HemoShear
demonstrated that NSCLC tumor
structure, biology and molecular
signaling pathways are restored in
the HemoShear platform.
“Now the company is about a
half-year away from more robustly
establishing a model for NSCLC
and developing one for pancreatic
cancer, then one for prostate cancer
and, eventually, one for any solid
tumor,” says Dr. Dan Gioeli, director of tumor studies at HemoShear.
“We also want to create a model to
analyze the mechanism of liver
cancer, the most common site for
metastasis of lung and pancreatic
cancer. We’re trying to understand
the biology of metastasis, so we
can develop drugs to target it. We
want to determine how drugs affect
metastasis, how metastasis affects
the site and how drugs interdict
those processes.”
He concludes, “HemoShear’s
goal is to enter drug discovery collaborations with select pharmaceutical and biotechnology companies to identify novel therapeutic
approaches. We need to have the
right partners, and we’re cautiously
optimistic.” ■
EDITCONNECT: E111406
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instrument that is ideal for use in pairwise comparison assays,
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Applications Scientist,
Seahorse Bioscience
The XFp Extracellular Flux Analyzer
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NOVEMBER 2014 | | DDNEWS 9
“Now the company is
about a half-year
away from more
robustly establishing
a model for NSCLC
and developing one
for pancreatic cancer,
then one for prostate
cancer and,
eventually, one for
any solid tumor,” says
Dr. Dan Gioeli, director
of tumor studies at
HemoShear.
10 DDNEWS | | NOVEMBER 2014
EDITORIAL
For more information, visit www.DDN-News.com
Clinical trials and tribulations
S
pay more. Or cancel. And so it is with clinical
EVERAL MONTHS AGO, some folks trials and the push in recent years for pharma
I follow online were raving about a and biotech companies to do clinical trials well
new anime series available through outside one’s national borders. The lure has been
a steaming video website dedicated lower costs and often easier patient recruitment.
But the bill may be coming due, and
to that genre, and I got
the value proposition—though it
sucked in. To get quicker, uninterprobably won’t be entirely elimirupted access to the episodes, I paid
nated—will likely drop noticeably.
for a membership. However, since
By the way, I’m going to avoid the
I’m not into anime overall as much
popular term “overseas trials.” Ceras when I was younger, I canceled
tainly, Central America is not overthat membership after a few maraseas from Canadian and U.S. pharthon sessions to plow through the
mas. Asia is not overseas from Euroseries.
pean pharmas. And India—both a
I’ve done this kind of thing before.
major player in pharma and a popular
Enjoy the benefits of a free trial offer Jeffrey Bouley,
DDNews Chief Editor
clinical trial locale for pharmas based
and cancel before the first payment
is due. Pay for access to a site only long enough elsewhere—certainly isn’t overseas from itself.
Ah, India. The real impetus for this month’s
to get all the materials I need from it. Join a
movie/music service to get my first dozen or editorial.
Let me quote from an article in The Hindu,
so DVDs and/or CDs for a penny plus shipping
and handling, and then fulfill my membership titled “A steel frame for clinical trials,” that
requirements as quickly and cheaply as possible caught my eye in October: “In recent months,
to ensure that my discs overall still cost me less the quest for a safer, more transparent clinical
trials regime has found new momentum. Fourthan going to a store…
…wait, that last one probably dated me a bit. teen notifications in July 2014, governing variEgads, I’m getting old fast (though not quite old ous aspects pertaining to a clinical trial—ranging
enough yet to enjoy AARP benefits and discounts). from placebo-controlled trials to compensation
My point is that many of us like to enjoy these awards—have been notified. Further, the Central
free or reduced-cost benefits, but in the vast Drugs Standard Control Organization (CDSCO)
majority of cases, eventually we need to pay. Or has proposed a forward-looking IT-enabled inforBY JEFFREY BOULEY
mation system that will ensure transparency and
protect the interests of trial subjects.”
And just a month earlier, on Hindu Business
Online, this excerpt: “Pharmaceutical companies, research labs and others looking to conduct clinical trials will now have to justify the
research. India is seen as a cheap destination for
clinical trials and companies often test products
meant for overseas markets here. A new order
issued [by CDSCO] makes it compulsory for
these entities to prove why the research needs
to be conducted in India.”
Interest in clamping down a bit on trials by
outside nations inside India has been brewing for
years. That might have been spurred sharply by the
news in April that 254 Indian women from modest
backgrounds died in the course of a 15-year U.S.funded clinical trial—a trial for a cervical cancer
screening method in which the women who died
were part of a control group denied screening,
raising ethical concerns among Indians.
Ethical concerns and missteps are not uncommon in the world of clinical trials. But they may
be put in a more stark light if missteps or corner-cutting take place in parts of the world that
offer “budget trial costs.” Without minimizing
the need for ethicality, though, let me be blunt:
The bill is coming due for those cheaper trial
locales. Pharmas and biotechs should probably
be thinking now about better ways to streamline
costs and increase efficiencies. ■
OUT OF ORDER: REGULATOR, GO TO HEAL
A
BY RANDALL C WILLIS
S I ALLUDED IN MY last commen-
tary, life has not been good for the
last few months for Health Canada, the governmental department
that, among other things, serves
the healthcare functions covered in the United
States by the FDA. And much of the difficulty
has been prompted by one of Canada’s national
newspapers, The Toronto Star.
First, the Star did an exposé series highlighting the lack of transparency at Health Canada
with regard to post-marketing adverse events,
citing the lack of a centralized database that
healthcare workers could access and no mechanism (or apparent will) to warn the population
about problems as they arise. To support their
position, the Star reporters cited information
gleaned from an FDA site designed specifically
for that purpose, information that was completely hidden in Canada.
More recently, the Star published another
series on the ineffectiveness of Health Canada
in stopping pharmaceutical companies from
importing contaminated drug compounds
or excipients from other countries for use in
Canadian patients. Again, as a comparator and
offender-identification resource, the reporters
turned to the FDA web site, which highlighted
several cases where the U.S. organization fined
drug manufacturers for shoddy practices and
banned some products from the U.S. market.
The Canadian government has slowly
responded to the issues raised, but by late September, one commentator had had enough.
“We should, in part, abolish Health Canada
and harmonize our drug regulation with those
foreign agencies that are more competent than
our own government,” proclaimed University
of Ottawa professor Amir Attaran in a Toronto
Star commentary.
can guidelines, literally referencing
His demand is not unique, as he
their counterpart and adjusting for
quickly points out, citing the Eurolocal factors such as drug availability
pean Medicines Agency and discusand treatment infrastructure. And
sions within Africa, Asia and South
in some cases, there is no Canadian
America to regionally harmonize
guidance and clinicians simply work
drug and medical device regulations.
with U.S.-produced guidance.
So, is it time for Health Canada
I can hear the Canadian mob
to stick to its HHS-equivalent duties
marching down the street. (Excuse
and divest drug and medical device
us, but we are here to flog you. Hope
regulations to the FDA?
it’s not a bad time. We can come back.)
As I have joked with several AmerRandall C Willis
“What about our national autonoican friends, we Canadians look just
like you. If you give us too much anticoagulant, my?” they might cry.
The science is the science; the medicine
do we not bleed?
Our regulatory approvals are based on the is the medicine. As in all other jurisdictions,
same clinical trials data as yours, so why should the true autonomy comes in drug prices and
drug companies have to double-up every time formulary coverage, which are handled regionthey submit an NDA? And because of the dra- ally, and there is nothing to suggest that this
matically smaller potential patient populations would have to change in a merged North
in Canada, a drug company may find itself American system.
Ultimately, the question (at least north of the
spending ungodly amounts of money applying
for approval of a drug targeting 400 people or border) should come down to what’s in the best
fewer. I have no numbers, but I wonder how interest of Canadians, and as I believe Attaran
many drugs do not come across the border rightly points out: “The FDA is more transparbecause there is no economic model for profit. ent, better resourced and scientifically better
Likewise, the practical reality is that neither equipped than Health Canada will ever be.”
As for what would be in it for the FDA to
country lives within a geographic bubble. What
happens in one jurisdiction (with the possible accept such a merger: possibly nothing. But
exception of Las Vegas) ultimately ripples then, I really don’t foresee the FDA’s practices
needing to change, and other than expanding
through the other one.
If FDA officials learn of unforeseen post- its mailing lists to include Canadian addresses,
marketing adverse events and decide to add a I don’t foresee any increased burdens, financial
black box warning to a drug’s monograph, that or otherwise.
And who knows, perhaps the FDA can follow
same black box often becomes reflected in the
Canadian monograph. I leave it to The Star to Health Canada’s lead on pharmaceutical mardetermine when and why the black box is added keting, which is dramatically more conservative than the United States’ relative Wild West
in Canada.
A merger of the two agencies (or engulfment) approach of forgiveness, not permission.
In any event, if you don’t hear from me after
would also reflect current Canadian clinical
practices. Very often, in my experience, Canadi- this is published, it is probably because the pitchan practice guidelines are adaptations of Ameri- forked, hockey-sticked mob has had its way. ■
www.DDN-News.com
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EDITORIAL
For more information, visit www.DDN-News.com
NOVEMBER 2014 | | DDNEWS 11
COMMENTARY: Success of new-generation
metabolo-therapies in personalized medicine
depends on measuring bioenergetic health
BY DAVID A. FERRICK OF SEAHORSE
I
BIOSCIENCE & VICTOR DARLEY-USMAR OF THE
UNIVERSITY OF ALABAMA AT BIRMINGHAM
T IS NOW WIDELY ACCEPTED that com-
plex diseases associated with aging
involve dysfunctional metabolism. This
growing healthcare problem includes
obesity/diabetes, neurodegeneration,
cancer and cardiovascular disease.1-3
The major driver of age-related, metabolic dysfunction is the availability of low-cost, highcalorie foods, in combination with a contemporary sedentary lifestyle. This modern-era
health epidemic is creating a “perfect storm”
of risk factors that is
increasingly manifesting as multiple
diseases within the
human body and is
straining, if not overwhelming, the capabilities and resources
of healthcare systems
worldwide. Defining
Victor Darley-Usmar,
metabolic health, Ph.D., professor of
particularly the way pathology at
cells use energy, or University of
bioenergetics, has Alabama at
become a necessity Birmingham
for healthcare in the 21st century, and at the
present time, there is no clinical test available
to assess this critical parameter.
At the crossroads of understanding cell
physiology, disease pathology and etiology
is cell metabolism, which is widely known
to be a common feature of these costly, debilitating and lethal diseases. This association
is in large part due to its central role in the
life-sustaining and biosynthetic processes of
the cell, specifically energy in the form of
ATP, sensing and reacting to cellular stress
and providing the building blocks that make
up the cells, tissues and organs of the body.
A new class of drugs
The next decade will witness the release of
a new class of drugs, known as “metabolotherapeutics,” which will target metabolic
pathways and the individual metabolites
that are required for the maintenance of normal health. Finally clinicians will be able to
address the long-overlooked area of metabolic liabilities in complex diseases. Establishing
metabolic phenotypes and their interdependency with specific signaling pathways has
enabled researchers to reprogram them to
affect disease states, and the result is a new
generation of discoveries and metabolotherapeutic approaches across the entire
spectrum of age-related diseases.
Like many other classes of treatment,
metabolo-therapies will probably be best
utilized and result in better outcomes by
employing a personalized, targeted therapeutic approach for each patient. Chronic diseases have a complex interplay of genetic and
environmental factors and can take decades
to cause harm. When they do, the resulting
disease may take just
as long to significantly disrupt a patient’s
l i f e s t y l e a n d /o r
threaten his or her
life. Until now, the
ability to determine
a true indication
of a patient’s metabolic health (the key
David A. Ferrick,
integrator of envi- Ph.D., chief scientific
ronmental factors officer of Seahorse
involved in disease Bioscience
etiology and progression) has not been possible. This is a huge
gap that needs to be addressed as we start to
target the metabolic basis of diseases and as a
result prescribe a new class of therapies that
target metabolic pathways. We are, in fact,
already behind, as many existing therapies
are dose-limited due to the off-target effects
on bioenergetics.
Clinical tests aimed at bioenergetic status
should play a critical role in the selection and
monitoring of those metabolo-therapies that
have the greatest efficacy and safety profile.
Additionally, healthcare economics will more
than likely favor approaches that identify the
best therapeutics first and not the current
“trial and error” process that often results in
patients going through a gauntlet of therapies
until one is found that works.
The answer in our cells
To develop an index of bioenergetic function,
one has to look no further than the mitochondria. Mitochondria are the central organelle
in cell metabolism that, along with producing the majority of energy for the cell, are
also the biosynthetic hub for manufacturing
cellular building blocks. Based on this metabolic role, mitochondria are fundamental in
determining whether a cell will grow, mature
or die. This explains why the study of cell
metabolism has become so important in agerelated diseases. Valuable insight into mitochondrial function can be gained through
measuring the rate of oxygen consumed by
cells, as virtually all the oxygen is directed
to the mitochondria. Oxygen metabolism is
the key step that enables mitochondria to
perform many tasks, and therefore, measurement of the oxygen consumption rate (OCR)
can be used as a direct measure of mitochondrial activity. This realization provided the
compelling rationale for exploring translational bioenergetics several decades ago.
However, expansion into the clinical arena
is only now possible due to breakthrough
advances in oxygen sensor chemistry, assay
throughput, workflow, ease-of-use and reliability of measuring OCR.
Using a well-validated test of mitochondrial function, the Cell Mito Stress Test
being an example, the OCR of a cell can be
apportioned between the key factors that
define bioenergetic health. The first factor is the basal condition that reflects the
patient’s current status, based on when
the blood sample was drawn and is used to
calculate various changes from this “base”
state. The second factor is the rate of energy
production in the form of ATP, the energy
currency of the cell. The third factor is the
proportion of the mitochondrial OCR that,
rather than being used to make ATP, instead
“leaks” through the system as its energy is
released as heat. This leak of mitochondrial
energy can provide indications of metabolic
efficiency. The fourth factor is the capacity of
the mitochondria to respond to an energetic,
or stress-induced, demand. This is achieved
by determining the maximal OCR rate of
the cells and is analogous to revving a car
engine to its maximum rpm. The difference
between basal and maximum OCR reveals
the energetic capacity of the mitochondria
and is perhaps the most sensitive and earliest indication of impairment and/or metabolic stress. And lastly, the amount of oxygen
consumed outside of the mitochondria often
correlates with negative aspects of cellular
health, such as inflammation, that contribute to the progression of many age-related
diseases.
Canary in the coal mine
In one test, a comprehensive measure of
energetic health, or its disease-related deterioration, can now be made. The prognostic
and diagnostic value of bioenergetic measurements in patients is still unknown, but
recent findings support an emerging concept
that circulating leukocytes and platelets can
serve as the “canary in the coal mine” by acting as early sensors or predictive biomarkers of metabolic function under conditions
of chronic stress and disease.4-8 These studies prompted researchers at the University
of Alabama at Birmingham (UAB) to begin
an integrated approach using cells isolated
from human blood, to establish a quantitative assay of bioenergetic function that they
expect will have the power to predict disease
progression and response to treatment.9
The two main challenges to achieving this
goal are: 1) the establishment of an index of
bioenergetic activity that accounts for the
complexity of metabolic function and can
be appropriately weighted, based on the
impairment(s) of a particular indication; and
2) the adaptation of a technology platform
and an assay that can directly measure metabolic activity. To address these challenges,
UAB established the Mitochondrial Medicine
Laboratory to develop the clinical tests that
can measure bioenergetics and partnered
with Seahorse Bioscience to provide the
technology platform and informatics. The
goal of the Mitochondrial Medicine Lab is
to develop a mitochondrial biomarker-based
approach to assessing health, called the bioenergetic health index (BHI).
To facilitate development of the BHI,
Seahorse Bioscience addressed both the
difficulty of obtaining functional metabolic
measurements and the ability to interpret
those results. This was accomplished by standardizing the direct measures of metabolic
flux using a proprietary technology called
extracellular flux. Early translational studies
suggest that this platform may be amenable
for defining metabolic status and that assays
may be developed to pinpoint metabolic liabilities in diseases that can instruct which
drug is most likely to be effective.
An early finding by the group at UAB is
that the mitochondrial parameters generated in the test of mitochondrial function
are interactive. If integrated appropriately
into a single value, they can serve as a sensitive indicator of the response of cells to
environmental stress and chronic disease
progression.9 This is accomplished in the
BHI equation by quantifying positive aspects
of bioenergetic function (reserve capacity
and ATP-linked respiration) and contrasting these with potentially deleterious ones
(non-mitochondrial oxygen consumption
and proton leak). For example, the larger the
value for reserve capacity, which raises BHI,
the more effectively mitochondria can meet
both the normal energy needs of the cell and
the increased metabolic demand caused by
stress and disease.10
Preliminary studies in several indications
are in progress at the Mitochondrial Medicine Laboratory at UAB and other institutions around the world. The overall goal is
to determine if BHI can be deployed as the
first clinical test for assessing bioenergetic
dysfunction. Can it be predictive early in disease progression before significant pathology and/or acutely prior to life-threatening
conditions? If successful, the BHI test could
become an important approach to integrating personalized medicine with state-of-theart translational bioenergetics. ■
David Ferrick, Ph.D., is chief scientific
officer at Seahorse Bioscience, a privately
held Boston-area biotechnology company
that designs and manufactures metabolic
analyzers and assay kits for measuring cell
metabolism in living cells.
Victor Darley-Usmar, Ph.D., is the director
of the Mitochondrial Medicine Laboratory
at University of Alabama at Birmingham
and has pioneered the application of the
mitochondrial stress test to analysis of patient
bioenergetic health.
REFERENCES
If you’d like to check out
the 10 references for this
commentary, just go to
the online version of the
commentary, which appears
unabridged at:
http://ddn-news.com/
news?newsarticle=8956
The opinions expressed in guest commentaries do not necessarily represent those of DDNews and/or its owners, editors or other staff.
For more information, visit www.DDN-News.com
12 DDNEWS | | NOVEMBER 2014
RESEARCH & DEVELOPMENT
LEIDEN, the Netherlands—MIMETAS has announced
receipt of $1.6 million in funding to develop a kidney-on-a-chip for toxicological use and will collaborate in a consortium with Radboudumc and
FHNW. This funding stems from the NephroTube
CRACK IT Challenge, which is organized by the
U.K.’s National Centre for the Replacement, Refinement and Reduction of Animals in Research and
supports the development of a microfluidic renal
model that can predict renal toxicity in preclinical
development. The funds will allow the consortium
to develop, analyze and validate a high-throughput
kidney-on-a-chip model through the combination
of MIMETAS’ OrganoPlate 3D-culturing technology
and the human renal cell line ciPTEC. This model
will aid in the detection of renal tubular injury seen
in drug-induced nephrotoxicity and allow for fewer
animal experiments.
Ario boosts portfolio
with TRPA1 acquisition
CAMBRIDGE, U.K.—Ario Pharma Ltd. has announced
the acquisition of a TRPA1 antagonist research program from PharmEste, a program that includes a
series of small-molecule TRPA1 antagonists, patents and related data. Ario Pharma, which has its
own TRPA1 chemistry portfolio as well, plans to
initiate a TRPA1 lead optimization project with a
focus on orally available TRPA1 antagonist small
molecules for asthma. The TRPA1 target has
shown potential in inflammatory diseases and
plays a key role in the pathophysiology of asthma.
“This asset acquisition significantly strengthens Ario Pharma’s chemistry portfolio in the TRPA1
field, and we plan to select one or more development candidates within the next 18 months,” said
John Ford, CEO of Ario Pharma. “We are overcoming solubility and pharmacokinetic issues associated with historical TRPA1 modulators developed
by other companies and are excited by the level
of target validation of TRPA1 in respiratory, pain
and other inflammatory diseases.”
IN THIS SECTION
Asthma
Ario boosts portfolio
with TRPA1 acquisition .......................... 12
Metabolomics
A resource for cellular metabolism ........ 14
Non-coding RNA
Centralizing research.............................. 12
Obesity/Liver disease
Hickory dickory dock… .......................... 12
Renal toxicity
MIMETAS to pursue
kidney-on-a-chip model with $1.6M ...... 12
Stem cells
Hitting the stem cell ‘reset’.................... 12
Hitting the stem cell ‘reset’
Scientists return human
stem cells to earliest
developmental state
BY LLOYD DUNLAP
CAMBRIDGE, U.K.—Scientists have managed
to “reset” human pluripotent stem cells to
their earliest developmental state, equivalent
to cells found in an embryo before it implants
in the womb (seven to nine days old). These
“pristine” cells could be the true starting point
for human development, but have until now
been impossible to recreate in the lab.
The findings, published in Cell, are expected to lead to a better understanding of human
development and could eventually enable the
production of more reproducible starting
materials for a wide range of applications,
including cell therapies.
In the article, authors Dr. Yasuhiro Takashima, Prof. Austin Smith, et. al., note that, “Our
findings suggest that authentic ground-state
pluripotent stem cells may be attainable in
CREDIT: CHRISTIAN RICHARDT
MIMETAS to pursue kidneyon-a-chip model with $1.6M
Researchers at the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute at the
University of Cambridge (the university’s Clare College and King’s College Chapel pictured here)
report that they have found a way to return stem cells to their earliest developmental state.
human, lending support to the notion of a
generic naive state of pluripotency in mammals. In human, the naive-state transcription
factor circuitry appears in large part to be conserved but requires greater reinforcement to
be stably propagated. Disposition to collapse
reflects the transient nature of naive pluripotency in the embryo (Nichols and Smith,
CREDIT: MIKE PEEL
BRIEFS
“The growth in non-coding RNA sequence and functional information
is phenomenal and shows no signs of slowing. There has never been a
greater demand for a universal resource for these data. The
collaboration of RNAcentral consortium members to produce this
resource represents an enormous step forward for the RNA field,” says
Sam Griffiths-Jones of the University of Manchester (pictured here).
tral, reportedly the first unified
resource for all types of non-coding
RNA data, was launched in September by the RNAcentral Consortium. RNAcentral brings together
information from a federation of
Hickory
dickory dock…
Using a novel biological aging clock and
tissue samples, UCLA researchers find
that obesity accelerates aging of the liver
BY LORI LESKO
LOS ANGELES—Armed with a recently developed biomarker of
expert databases and provides tools
for easy browsing. The RNAcentral
consortium currently includes 24
RNA database resources.
The initial release of RNAcentral contains about 8 million
sequences. Using funding from
RNA CONTINUED ON PAGE 15
UCLA CONTINUED ON PAGE 16
RNAcentral launched in September
to provide unified resource for noncoding RNA data
CAMBRIDGE , U.K.— RNAcen-
STEM CONTINUED ON PAGE 17
aging known as an epigenetic clock, University of California, Los
Angeles (UCLA) researchers and German investigators have discovered that obesity accelerates aging of the liver and increases
odds of liver cancer. This finding was published Oct. 13 in the early
online edition of Proceedings of the National Academy of Sciences.
Although it had long been suspected that obesity ages a person
faster, it wasn’t possible to prove the theory until first author
Steve Horvath, a UCLA professor of human genetics and biostatistics, developed an epigenetic clock last year. A team headed by
Horvath and Prof. Jochen Hampe of the University of Dresden in
Germany were then able to show that carrying excessive weight
can negatively impact select human tissues.
“This is the first study that evaluated the effect of body weight
on the biological ages of a variety of human tissues,” Horvath said
in a news release. “Given the obesity epidemic in the Western
world, the results of this study are highly relevant for public
health.” The idea for the study actually began in 2003 when Horvath downloaded a freely available liver DNA methylation data
set from Gene Expression Omnibus, an online repository of data.
“I found a very strong correlation between body mass index
(BMI) and epigenetic age acceleration in liver tissue,” Horvath
tells DDNews. “I immediately contacted Prof. Jochen Hample
Centralizing
research
BY ILENE SCHNEIDER
2009). The imperative for developmental
progression may be intrinsically stronger in
primates that, unlike rodents, have not evolved
the facility for embryonic diapause (Nichols
and Smith, 2012).”
In conclusion, the authors state that,
“Human genetic variation notwithstanding,
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RESEARCH & DEVELOPMENT
14 DDNEWS | | NOVEMBER 2014
A resource for cellular metabolism
Agilent teams with
University of Toronto on
metabolomics library
BY ZACK ANCHORS
SANTA CLARA, Calif.— Scientists at the Univer-
sity of Toronto’s main biomedical research laboratory will soon have a sophisticated new resource to support their
studies of cellular metabolism. Agilent Technologies has announced
that it is entering a collaboration
with the university that will result
in the creation of a comprehensive
metabolomics multiple-reaction monitoring
(MRM) library at the Donnelly Centre for Cellular and Biomolecular Research.
The partnership will give scientists access
to technologies that will allow them to accelerate the quantification of hundreds of metabolically important compounds for cell biology and disease research. “Routine metabolite
quantification plays an essential role in helping scientists understand how diseases modify
metabolic pathways,” Steve Fischer, market
director for Agilent’s Life Science Research
Division, tells DDNews. “The development of
a routine, targeted metabolite MRM method
and MRM library will make available a targeted metabolomics solution that will be used
by many researchers worldwide.”
Metabolomics is an field of research that
aims to compare the relative differences
between biological samples based on their
metabolite profiles. It can provide researchers
an instantaneous snapshot of the
entire physiology of an organism.
The system at the heart of the
partnership involves Agilent’s
Infinity 1290 UHPLC and 6460
triple quadrupole mass spectrometry technologies. “This highperformance, workhorse system will allow
scientists at the Donnelly Centre to analyze
thousands of biological samples a month to
support targeted, high-throughput metabolomics studies,” says Fischer. This mass spectrometry process will be conducted after a
researcher has already completed a biological hypothesis of which metabolic pathways
are implicated in a disease process. The
system will help confirm and quantify specific metabolites on a large, statistically valid
sample set.
Agilent will work with Drs. Amy Caudy and
Agilent (the headquarters of which are
pictured here) uses collaborations as a key
component of its strategy to maintain strong
ties with current and prospective customers,
notes Steve Fischer, market director for
Agilent’s Life Science Research Division.
CREDIT: AGILENT TECHNOLOGIES
CREDIT: AGILENT TECHNOLOGIES
TOOLS &
TECHNOLOGY
The system at the heart1of4/30/2014
the partnership
INDIGO_DDN_Ad_2014.04.29.pdf
1:16:10 PM
between Agilent and University of Toronto involves
Agilent’s Infinity 1290 UHPLC and 6460 triple quadrupole mass spectrometry technologies.
Adam Rosebrock at the Donnelly Centre to
create the MRM library and methodology. The
MRM library will be a database that contains
compound information and fragmentation
spectra of MRM transitions and their optimal
collision energy and other method information, such as retention time. This database
will allow users the flexibility to select which
metabolites they wish to analyze using Agilent’s mass spectrometry system.
The collaboration originated when Caudy
and Rosebrock purchased instruments from
Agilent in 2010 for metabolomics shortly after
arriving at the University of Toronto. Agilent
remained in touch with the researchers, and
after several years the researchers saw an
opportunity for a collaborative relationship.
“We are impressed with Agilent’s mass spectrometry instruments and software solutions,
and we look forward to working together to
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enable use of LC-MS metabolomics by a larger
scientific audience,” according to Rosebrock,
a principal investigator whose lab focuses on
understanding the biochemistry underlying
cell growth and division.
Agilent is a measurement company that
designs and manufactures a wide range of
instruments used in chemical analysis, life
sciences, diagnostics, electronics and communications. The company offers several
instruments for the study of metabolomics.
These tools enable users to conduct research
in a diverse range of areas, including toxicology, environmental analysis, agriculture,
biofuel development and nutrition. Metabolomics results can also be used to supplement
gene expression or proteomics studies.
Fischer tells DDNews he expects the new
metabolomics MRM library to be completed
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RNA
CONTINUED FROM PAGE 12
the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), partner
institutes throughout the world were able to
come together and build what they see as a
practical solution to a shared problem.
Since the 1950s, scientists have thought of
RNA as an intermediate molecule that provides a link between stable DNA and proteins.
However, in recent decades it has become clear
that RNA plays a much wider range of roles in
living organisms. Researchers have discovered
a lot about different types of RNA, but until
now these data have not been put in one place.
“During the last decade, there has been a
great increase in the number of noncoding
RNA genes identified, including new classes
such as microRNAs and piRNAs,” explains
Alex Bateman, head of Protein Sequence
Resources at EMBL-EBI (the European Bioinformatics Institute). “There is also a large
amount of experimental characterization of
these RNA components. Despite this growth
in information, it is still difficult for researchers to access RNA data, because key data
resources for noncoding RNAs have not yet
been created. The most pressing omission is
the lack of a comprehensive RNA sequence
database, much like UniProt, which provides
a comprehensive set of protein knowledge.”
Before RNAcentral, finding the RNAs
encoded by a specific genome required gathering information from several independent
resources, for example miRBase for microRNAs and HAVANA for lncRNAs. “There is
plenty of published data on noncoding RNAs,
but each subtype is maintained separately,”
according to Bateman. “This is the first time
we have a central place where you can find
it all: piRNAs, ribosomal RNAs, everything.
A lot of that information has typically been
locked up in supplementary materials, or
referred to only by a non-standard gene
name. RNAcentral is a big step towards
making RNA sequence as easy to access for
research as protein sequence.”
RNAcentral 1.0 gives researchers access to
data from 10 different expert databases and
provides stable accession numbers that can
be used consistently in the literature, other
molecular databases and search engines. The
RNAcentral website features a faceted search
that enables users to explore different RNA
sequences according to source, species and
molecular function. Further expert databases
will be included in future releases.
The RNAcentral consortium has its roots
in a workshop held on the Wellcome Genome
Campus in 2010. At that time members of the
RNA community came together to discuss
the lack of centralized access to RNA data.
“It is really satisfying to see this project
come to fruition,” said Sam Griffiths-Jones of
the University of Manchester. “The growth
in non-coding RNA sequence and functional
information is phenomenal and shows no signs
of slowing. There has never been a greater
demand for a universal resource for these data.
The collaboration of RNAcentral consortium
members to produce this resource represents
an enormous step forward for the RNA field.”
According to BBSRC Chief Executive Prof.
Jackie Hunter, “Fundamental research into
noncoding RNAs has many potential applications, including disease diagnostics, new therapies and biotechnology. With the abundance
of data now available due to next-generation
DNA sequencing, there is an urgent need for
informatics tools to decipher it. RNAcentral
is a vital resource that will aggregate and inte-
RESEARCH & DEVELOPMENT
grate information to unify the data landscape
and improve the discoverability and use of
data by researchers worldwide.”
The resource uses EMBL-EBI infrastructure, notably data-submission and cross-reference services provided by the European
Nucleotide Archive. It takes advantage of
the nightly, global synchronisation of data
from the International Nucleotide Sequence
Database Collaboration. Future versions of
RNAcentral will include additional data types
and information about RNA structure, modifications, molecular interactions and function. A paper describing RNAcentral tools
and features in detail has been accepted
for publication in the journal Nucleic Acids
Research.
RNAcentral partners are EMBL-EBI, the
University of Manchester, the Wellcome Trust
Sanger Institute, the University of California
Santa Cruz, the University of Texas, Auburn
University, Sandia National Laboratory, the
University of Oxford, the Garvan Institute of
Medical Research, the International Institute
of Molecular and Cell Biology Warsaw and
Adam Mickiewicz University, Rockefeller University, the Chinese Academy of Sciences, the
Peking Union Medical College and Taicang
NOVEMBER 2014 | | DDNEWS 15
Institute of Life Sciences Information, Michigan State University, National Chiao Tung
University, Stanford University, the University of Thessaly, the Institute of Bioinformatics and Systems Biology of the Department of
Biological Science and Technology at National
Chiao Tung University and the National Center for Biotechnology Information.
“This resource will facilitate the next
generation of RNA research and help drive
further discoveries, including those that
improve food production and human and
animal health,” Bateman concluded. ■
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16 DDNEWS | | NOVEMBER 2014
UCLA
CONTINUED FROM PAGE 12
in Germany, who was the senior
author of this data set. He was happy
to collaborate with me and generated additional validation data sets for
this project. I also felt that it would
be necessary to determine whether
a similar effect could be observed in
human adipose tissue, which is why
I collaborated with several researchers from the Twins UK study: Tim
Spector, Jordana Bell and Panos
Deloukas.”
RESEARCH & DEVELOPMENT
“About a year ago, I published
an article (at genomebiology.com)
that describes a novel biomarker of
aging that allows one to measure the
age of the vast majority of human
tissues, organs and cell types,” he
adds. “Recent data have convinced
me that the epigenetic clock measures at least some aspects of biological age. Many people have asked
me whether caloric restriction or
certain diets keep us young. We do
not yet know whether the epigenetic
age of liver tissue relates to all causes
of mortality or even to the onset of
various age-related diseases. It is, of
course, a plausible hypothesis that
the age of the liver should have prognostic and diagnostic utility, but we
will need prospective cohort studies
to rigorously test these hypotheses.”
Also, it is well known that obese
people are more susceptible to certain types of cancer, Horvath notes.
“But we don’t quite understand
why that is the case,” he adds. “Our
study points to an intriguing explanation. Since age is a major risk fac-
For more information, visit www.DDN-News.com
tor of many cancers, it would make
sense that livers that are older than
expected are also at an increased
risk of malignant transformation.”
Horvath’s team also studied
whether weight loss reverses the
epigenetic age of liver tissue.
“Unfortunately, we could not
observe a beneficial effect within
nine months of bariatric surgery,”
says Horvath. “But it is unclear
whether a rejuvenating effect due
to weight loss can be observed after
a longer follow-up. I don’t think our
study points to new drugs and therapies for controlling obesity, per se.
But it might lead to drugs that control the adverse effects of obesity.”
“What is new in our study is the
very strong effect observed in liver
tissue: There, we find a strong correlation of 0.42 between BMI and
epigenetic age acceleration,” he
says. “At this point, only the epigenetic clock can be used to measure the ages of most human tissues
and cell types, but there are several
alternative epigenetic biomarkers of
aging that can be applied to blood
tissue.”
According to the Proceedings of
the National Academy of Sciences article, Horvath’s theory includes an
aging clock which uses a previously
unknown time-keeping mechanism
in the body to accurately gauge the
age of diverse human organs, tissues
and cell types.
Horvath used this epigenetic
clock to measure the biological age
of several tissues in mouse model
subjects. The aging clock proved
accurate in matching biological to
chronological age in lean subjects.
But liver tissues from obese subjects
tended to have a higher biological
age than expected.
In this latest study, Horvath
looked at almost 1,200 human tissue samples, including 140 liver
samples, to study the relationship
between epigenetic age acceleration and body weight. While obesity doesn’t affect the epigenetic
age of fat, muscle or blood tissue,
he and his collaborators found that
on average, the epigenetic age of the
liver increased by 3.3 years for every
excess 10 body mass index units.
Horvath will continue pursuing the research with Hampe, “a
leading expert on the epigenomic
underpinnings of non-alcoholic
fatty liver disease and related complications,” he says. “At this point,
it is too early to consider a potential marketing partner. I am looking for collaborators who would be
interested in testing whether the
epigenetic age of liver tissue is prognostic of adverse health outcomes
for liver cancer. I am also looking
for collaborators who are interested
in developing drugs that prevent
accelerated aging effects.” ■
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Microscopy & Remarkable Data
DO
While obesity doesn’t affect the
epigenetic age of fat, muscle or
blood tissue, UCLA research
indicates that the epigenetic age of
the liver may increase by 3.3 years
for every excess 10 body mass
index units.
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STEM
CONTINUED FROM PAGE 12
epigenome status may influence consistency
of both undifferentiated phenotype and differentiation behavior. Low genomic H3K9me3
and genome-wide DNA hypomethylation
point to epigenome erasure in reset cells, as
in early embryos. It will be of great interest
to determine the precise functional impact of
such epigenetic cleansing.”
Human pluripotent stem cells, which have
the potential to become any of the cells and
tissues in the body, can be made in the lab
either from cells extracted from a very earlystage embryo or from adult cells that have
been induced into a pluripotent state.
However, scientists have struggled to generate human pluripotent stem cells that are
truly pristine (or naive). Instead, researchers
have only been able to derive cells which have
advanced slightly further down the developmental pathway. These bear some of the early
hallmarks of differentiation into distinct cell
types—they’re not a truly “blank slate.” This
may explain why existing human pluripotent
stem cell lines often exhibit a bias toward producing certain tissue types in the laboratory.
In this latest work, the team led by the
Wellcome Trust-Medical Research Council
(MRC) Cambridge Stem Cell Institute at
the University of Cambridge has managed to
induce a ground state by rewiring the genetic
circuitry in human embryonic and induced
pluripotent stem cells. Their “reset cells”
share many of the characteristics of authentic naive embryonic stem cells isolated from
mice, suggesting that they represent the earliest stage of development.
“Capturing embryonic stem cells is like
stopping the developmental clock at the precise moment before they begin to turn into
distinct cells and tissues,” explains MRC
Prof. Austin Smith, co-author of the paper.
“Scientists have perfected a reliable way of
doing this with mouse cells, but human cells
have proved more difficult to arrest and show
subtle differences between the individual
cells. It’s as if the developmental clock has
not stopped at the same time and some cells
are a few minutes ahead of others.”
The researchers overcame this problem by
introducing two genes—NANOG and KLF2—
causing the network of genes that control the
cell to reboot and induce the naive pluripotent state. Importantly, the introduced genes
only need to be present for a short time. Then,
like other stem cells, reset cells can self-renew
indefinitely to produce large numbers, are stable and can differentiate into other cell types,
including nerve and heart cells.
By studying the reset cells, scientists will be
able to learn more about how normal embryo
development progresses and also how it can
go wrong, leading to miscarriage and developmental disorders. The naive state of the reset
stem cells may also make it easier and more
reliable to grow and manipulate them in the
laboratory and may allow them to serve as
a blank canvas for creating specialized cells
and tissues for use in regenerative medicine.
“Our findings suggest that it is possible to
rewind the clock to achieve true ground state
pluripotency in human cells,” Smith adds.
“These cells may represent the real starting
point for formation of tissues in the human
embryo. We hope that in time they will allow
us to unlock the fundamental biology of early
development, which is impossible to study
directly in people.”
Dr. Rob Buckle, head of regenerative medicine at the MRC, added: “Achieving a true
RESEARCH & DEVELOPMENT
ground state in human pluripotent stem cells
is seen as a significant milestone in regenerative medicine. With further refinement, this
method for creating ‘blank’ pluripotent cells
could provide a more reliable and renewable
raw material for a range of cellular therapies,
diagnostics and drug safety screening tools.
This is likely to be a highly attractive prospect
to industry and regulators.”
The paper published in Cell is entitled
“Resetting transcription factor control circuitry towards ground state pluripotency in
human.” ■
NOVEMBER 2014 | | DDNEWS 17
AGILENT
CONTINUED FROM PAGE 14
in the fall of 2015. It will be added to Agilent’s existing collection of MRM libraries, which address a variety of applications,
including pesticides, veterinary drugs,
forensics and toxicology.
Agilent uses collaborations as a key
component of its strategy to maintain
strong ties with current and prospective
customers. “Through customer collaborations, Agilent learns about the customer
problem in great detail so that we can satisfy that customer’s challenge and offer the
solution to the many customers that have
similar problems,” says Fischer. “This relationship is one of many that Agilent has
with customers.
“Agilent is already a leader in untargeted,
discovery mass spectometry based metabolomics, and the development of a routine,
targeted metabolite MRM method and
MRM library will establish Agilent as a leader in targeted MS-based metabolomics.” ■
EDITCONNECT: E111411
EDITCONNECT: E111408
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18 DDNEWS | | NOVEMBER 2014
PRECLINICAL
BR IEFS
Exemplar Genetics reports
on TP53 porcine model
SIOUX CENTER, Iowa—Exemplar Genetics’ geneti-
cally modified pig model of cancer was featured
in a recent issue of The Journal of Clinical Investigation, in an article that detailed that this model
expresses a TP53 mutation orthologous to one
commonly found in humans. Computed tomography, MRI data and molecular genetic analysis
have shown that the TP53 porcine represents
a large-animal tumor model that replicates the
human condition. Data suggest that this model
is appropriate for the development of clinically
relevant, noninvasive imaging approaches.
“The new porcine model of cancer opens
the door to developing more effective imaging
approaches and therapies for tumor detection and
treatment,” said Dr. John Swart, president of Exemplar Genetics. “The translational value to humans is
significant in that earlier detection and treatment
can greatly improve cancer mortality rates.”
Fruits of their efforts
Preclinical trials show experimental drug from seeds of
Australian Blushwood tree fruit destroys cancer tumors
BY LORI LESKO
YOUNGABURRA, Australia— Scientists at
QIMR Berghofer Medical Research Institute have developed an experimental drug
produced from the seeds of the fruit of
the Blushwood tree—found in a far north
Queensland rainforest—that has cured solid
cancer tumors in preclinical trials. The drug,
called EBC-46, has been found to be effective in treating pets with cancer, according
to Dr. Glen Boyle, lead author of the study
published Oct. 1 in the journal PLOS One.
The Australian research team reported
that just one injection of EBC-46 led to rapid
breakdown of tumors in a range of human
tumor models, suggesting the drug could be
GAITHERSBURG, Md.—Novavax Inc. recently shared
IN THIS SECTION
IN THIS SECTION
Antibiotics
Cutting
Head off the avenues of ESKAPE........ 18
Shionogi
antibiotic joins
Text ...........................................................
0
fight
against MDR pathogens ................ 200
Text ...........................................................
Cardiovascular
Head
An
agreement ................................. 200
TextACS
...........................................................
Hepatitis
Text ........................................................... 0
OnCore marks milestones
in hep B mission ..................................... 18
Oncology
Exemplar Genetics reports
on TP53 porcine model ........................... 18
Fruits of their efforts .............................. 18
Vaccines
Novavax RSV vaccine found
effective in baboons ............................... 18
BY KELSEY KAUSTINEN
NEW HAVEN, Conn.—Melinta Therapeutics
has released an update on its ESKAPE Pathogen Program, presenting two posters at the
Interscience Conference on Antimicrobial
Agents and Chemotherapy on its RX-P873
molecule that demonstrated its activity
against a range of Gram-negative bacteria,
including multidrug resistant strains and
those designated on the U.S. Center for Disease Control and Prevention’s (CDC) list of
urgent threats.
The ESKAPE pathogens consist of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii,
Pseudomonas aeruginosa, Enterobacter species
and Escherichia coli. These resistant bacteria
are the most difficult to treat, and 66 per-
DOYLESTOWN, Pa.— OnCore Bio-
cent of all hospital infections are the result
of these pathogens. Drug-resistant bacteria
have, in recent years, been named one of
the leading health concerns in the United
States. According to the CDC, approximately
2 million people in the United States develop
infections caused by resistant bacteria, and
more than 23,000 people die each year from
RX-P873 CONTINUED ON PAGE 21
ONCORE CONTINUED ON PAGE 20
SEEDS CONTINUED ON PAGE 19
Cutting off the
avenues
of
ESKAPE
Novel antibiotics from
Melinta show in-vitro
potential against
resistant bacteria
BY ZACK ANCHORS
pharma has made a series of important
steps toward its goal of developing a
cure for chronic hepatitis B. During
the last couple months, the biopharma
firm has gained an exclusive worldwide license to a series of second-generation cyclophilin inhibitors for the
treatment of hepatitis B and acquired
a pharmaceutical company with two
novel drug discovery programs that
could prove crucial in the development of a treatment for the disease.
OnCore was founded in 2012 by a
team of former executives from Pharmasset (acquired by Gilead Sciences
in 2011) who were involved in developing the drug Sovaldi, a hepatitis C
therapy that was approved by the FDA
last December. The new company’s
mission is to discover and develop an
all-oral cure for hepatitis B.
Hepatitis B is a serious infection of
the liver that is transmitted by exposure
to infectious body fluids. It can lead to
chronic liver disease, which increases a
patient’s risk of death from liver cirrhosis and liver cancer. The World Health
Organization estimates that more than
780,000 people die every year due to
infection. The therapies that are currently available to treat the disease work
by suppressing the hepatitis B virus
(HBV), but do not lead to a cure in the
vast majority of patients. Identifying a
functional or complete cure remains a
significant area of unmet medical need.
OnCore’s strategy to develop a
treatment for hepatitis B involves
developing an all-oral treatment that
targets covalently closed circular DNA
(cccDNA) in HBV-infected hepatocytes. cccDNA is a unique DNA structure that develops in the cell nucleus
of some viruses as they propagate.
The company believes this strategy of
targeting cccDNA has the potential to
result in a functional cure that lowers
the risk of death from liver disease to
the same level experienced by a person
with a naturally resolved infection.
The company is working to
develop a treatment that combines
agents against cccDNA with other
novel direct-acting antiviral mechanisms that engage immune response.
“EcoLogic is based on our understanding of how the
rainforest functions from an ecological point of view,” says
Dr. Victoria Gordon of her company’s discovery technology.
“Our discovery success rate (at the early discovery stage) is
greater than 10 times more successful than any of our
competitors. For anticancer, we concentrated on how plants
and mammals interact and formulated collection strategies
primarily around herbivory responses in both groups,”
Novavax RSV vaccine found
effective in baboons
preclinical data regarding its respiratory syncytial
virus (RSV) vaccine in baboons. The study found that
immunizing pregnant baboons in the third trimester
with Novavax’ RSV F-protein nanoparticle vaccine
caused them to generate anti-F IgG antibodies that
were transferred to their newborn babies, and
infants born to these immunized mothers demonstrated protection from RSV challenge comparable
to that seen from palivizumab therapy.
Dr. Greg Glenn, senior vice president of
research and development at Novavax, noted
that “This study adds to substantial evidence and
validation supporting our RSV maternal immunization strategy as we move towards the initiation
of our first study in pregnant women in the next
few months.”
effective in treating human patients as well.
“We were able to achieve very strong
results injecting EBC-46 directly into melanoma models, as well as cancers of the head,
neck and colon,” Boyle said. “In most cases
the single injection treatment caused the loss
of viability of cancer cells within four hours,
and ultimately destroyed the tumors.”
EBC-46 works in part by triggering a cellular response which effectively cuts off the
blood supply to the tumor and kills it.
“In preclinical trials we injected it into our
models and within five minutes, you see a
purpling of the area that looks like a bruise,”
Boyle said.
OnCore marks
milestones in
hep B mission
From Melinta’s three
novel classes of
antibiotics, more than
2,500 molecules have
been produced, and
Melinta is completing
preclinical work to
advance the most
promising leads into
Phase 1 clinical studies.
PRECLINICAL
For more information, visit www.DDN-News.com
CONTINUED FROM PAGE 18
“About 24 hours later, the tumor
area goes black, a couple of days later
you see a scab and at around the 1.5
week mark, the scab falls off, leaving
clean skin with no tumor,” he said.
“The speed certainly surprised me.”
In more than 70 percent of preclinical cases, the response and
cure was long-term and enduring,
with very little relapse over a period
of 12 months, he said.
EBC-46 was actually discovered
by the Queensland biotechnology
company EcoBiotics. It is EcoBiotics’ subsidiary, QBiotics, that is
developing the drug as a human
and veterinary pharmaceutical.
The experimental drug has been
used by veterinarians to successfully destroy or shrink tumors in
companion animals, including
dogs, cats and horses. QBiotics is
currently undertaking formal veterinary clinical trials with EBC46 in Australia and the United
States, Boyle said. A final regulatory approval is still required for a
human Phase 1 clinical trial.
“At this point, EBC-46 will only be
trialed in the short-term for tumors
which can be accessed by direct
injection or topical application,”
Boyle said. “There is no evidence to
suggest EBC-46 would be effective
against metastatic cancers.”
Ethical approval was recently
granted for Phase 1 human clinical
trials, but even if those proved successful, it is unlikely the drug would
replace conventional chemotherapy
treatment for cancer, he said.
“Chemotherapy is still used
because it is very effective for a lot
of people,” Boyle said. “But EBC-46
could perhaps be used in people
who, for some reason, chemotherapy
doesn’t work, or for elderly patients
whose body can’t sustain another
round of chemotherapy treatment.”
The preclinical trials at QIMR
Berghofer have been largely funded
by QBiotics with additional support
from Australia’s National Health
and Medical Research Council.
Dr. Victoria Gordon, CEO and
managing director of EcoBiotics,
and her husband, fellow scientist Dr.
Paul Reddell, discovered the drug
and spent years developing EBC-46
and demonstrating its effectiveness
in animals, including treating hundreds of horses, dogs and cats.
“Paul and I discovered EBC46 via our biodiscovery technology we call EcoLogic,” Gordon tells
DDNews. “EcoLogic is based on our
understanding of how the rainforest
functions from an ecological point
of view. Using our knowledge of
plant ecological attributes and plantanimal-microbe-insect interactions,
we develop collection strategies for
plant material we believe will have
particular bioactivity such as anticancer, antibiotics, antifungal, antiinflammatory, etc. Our discovery
success rate (at the early discovery
stage) is greater than 10 times more
successful than any of our competi-
tors. For anticancer, we concentrated on how plants and mammals
interact and formulated collection
strategies primarily around herbivory responses in both groups.”
“Our company group (EcoBiotics
as the parent entity and QBiotics as
the subsidiary) has been contracting the QIMR for the past 14 years
to work on research directed by our
research managers,” she adds.
EBC-46 was discovered through
EcoBiotics’ discovery technology EcoLogic about eight years ago,
according to Gordon. Prof. Peter
Parsons and Boyle have been working on the early-stage preclinical
development of the drug as directed
and paid for by QBiotics, which has
spent about AU$30 million so far
and owns the patents on EBC-46
(which have now been granted in all
major regions), she said, adding that
Boyle’s particular focus in the development efforts thus far has been on
the mechanism of action of the drug.
The company team (including
directly employed as well as con-
tracted participants) has worked on
formal preclinical development of
the drug (including toxicology
studies, pharmacokinetic and pharmacodymanic studies), domestication and grow-out of the source
plant (Blushwood), R&D as well
as GMP manufacture of the active
pharmaceutical ingredient and
the drug product, veterinary clinical development and now human
clinical development, Gordon says.
EcoBiotics was founded by Gordon and Reddell in 2000, based on
Isotype
Control
PD-L1
Events
SEEDS
NOVEMBER 2014 | | DDNEWS 19
Green = PD-L1
PD-L1
Red = Keratin
the biodiscovery technology they
developed and call EcoLogic.
“We have built the company up
over the years and now have laboratories and offices in Far North
Queensland and offices in Brisbane,” Gordon says. “We placed
EBC-46 into a subsidiary company
for development (QBiotics) so that
we could focus the capital-raising
strategy on drug development rather than drug discovery, which are
two quite disparate areas.” ■
EDITCONNECT: E111412
20 DDNEWS | | NOVEMBER 2014
PRECLINICAL
For more information, visit www.DDN-News.com
AN ACS AGREEMENT
MedImmune will in-license
Shionogi’s biologic program
for acute coronary syndrome
CONTINUED FROM PAGE 18
MedImmune, the global biologics
research and development arm of
AstraZeneca, recently in-licensed a
biologic program from Shionogi for
the potential treatment of acute
coronary syndrome.
CREDIT: MEDIMMUNE
BY KELSEY KAUSTINEN
GAITHERSBURG, Md.— A global license
agreement was announced in early October
between MedImmune, AstraZeneca’s global
biologics research and development arm,
and Osaka, Japan-based Shionogi & Co. Ltd.,
under which MedImmune will in-license
Shionogi’s novel preclinical biologic program
for the treatment of acute coronary syndrome
(ACS). Though AstraZeneca has had an
ongoing relationship with Shionogi, having
licensed the cholesterol drug Crestor—which
AstraZeneca and Shionogi co-market—from
Shionogi in 1998, this is some of the first work
between MedImmune and Shionogi.
“Cardiovascular and metabolic disease
(CVMD) is a core therapeutic area for MedImmune, and Shionogi’s biologic program
will be a valuable and strategic complement
to our existing cardiovascular program,” Cristina Rondinone, vice president and head of
the MedImmune CVMD Innovative Medicines Unit, said in a news release. “We are
committed to sourcing the best scientific
research across the globe. We were pleased
to identify this early-stage program and will
work to advance its research and development as quickly as possible to hopefully bring
an important new medicine to ACS patients.”
The American Heart Association describes
ACS as “an umbrella term for situations
where the blood supplied to the heart muscle is suddenly blocked.” Heart attacks and
unstable angina are both examples of ACS.
Per the terms of the deal, MedImmune will
acquire exclusive rights to Shionogi’s cardiovascular biologic program and will assume
responsibility for all future research, development and manufacturing. AstraZeneca will
assume responsibility for any future commercialization, and Shionogi will have an option
to co-market in Japan. No financial details
were disclosed for this agreement.
“Shionogi and AstraZeneca have been
working together to bring Crestor to patients
ONCORE
for nearly two decades. Such a positive relationship created the foundation for this agreement with MedImmune,” Dr. Kohji Hanasaki,
senior vice president of Shionogi’s Pharmaceutical Research Division, commented
in a statement. “Shionogi is now pursuing
research and development in the therapeutic
areas to which we should devote resources
in the new medium-term business plan. We
think that this biologic program gets the best
chance of success by joining our promising
research with MedImmune’s proven capabilities for advancing biologic research as well
as AstraZeneca’s commercial capabilities in
marketing cardiovascular therapies.”
Contrary to the approach of most cholesterol medications, this biologic program seeks to
target high-density lipoprotein (HDL) levels,
or good cholesterol, rather than trying to lower
low-density lipoprotein (LDL) levels. The program acts on a biological mechanism that plays
a physiological role in the metabolism of HDL.
In the body, HDL works to move cholesterol
out of blood vessels and plaques, and higher
HDL levels have the potential to decrease individuals’ residual risk of cardiovascular disease.
“Maybe action against LDL is not enough
for some patients,” Rondinone explains. “You
will need to raise HDL for those patients who
have really low HDL and actually cannot take
cholesterol from the tissues and eliminate
that bad cholesterol. So this approach, and
some of the approaches that we are having
at MedImmune, is mainly to strive to modify
the metabolism of the good HDL and try to
make the HDL functional.”
“We have internal assets, but also we are
looking at innovation in every place: in companies, in academic institutions, in collaborations. So when we believe that there is some
interesting target program, we are willing to
collaborate,” Rondinone tells DDNews. “Collaborations such as the one we have entered
with Shionogi actually support the drive to
deliver new medicines to patients and are
shaping the way we treat this condition.”
In other recent partnering news, MedImmune, together with AstraZeneca,
announced four new collaborations with
the University of Cambridge in mid-October, building on the organizations’ existing
strategic partnership. The four agreements
include a three-year collaboration centered
on neurodegenerative diseases, a material
transfer agreement granting access to select
AstraZeneca compounds, a Ph.D. program
and an entrepreneur-in-residence program. ■
EDITCONNECT: E111415
OSAKA, Japan—Shionogi & Co. Ltd. thinks it may have a
new soldier in the war against multidrug-resistant (MDR)
pathogens, in the form of S-649266, a new parenteral
siderophore cephalosporin antibiotic discovered by the
company. According to recent preclinical studies, S-649266
exhibits marked potency against Gram-negative bacteria,
including MDR pathogens, and has demonstrated active
penetration into bacteria and stability to beta-lactamases
that hydrolyze carbapenem antibiotics.
S-649266 has unique structural features that exploit
the way Gram-negative bacteria acquire iron necessary
for growth. S-649266 binds to free iron and is actively
transported across the outer membrane with the iron. This
“Trojan horse” strategy allows S-649266 to enter the periplasmic space where it binds to penicillin-binding proteins
and disrupts cell wall synthesis.
“Multidrug-resistant bacteria continue to increase,
and with these difficult-to-treat infections come increased
morbidity, mortality and costs not just in dollars but in an
overall societal cost due to the impact of these problematic
infections,” said Richard P. Wenzel, professor of medicine
at Virginia Commonwealth University and former president
of the International Society for Infectious Diseases, in a
news release about the preclinical findings. “S-649266 has
many of the criteria needed to be of value in this ongoing
fight; we await clinical results with anticipation.”
Among some of the findings reported in the past few
months, data indicated that compared with other cephalosporins and carbapenems, S-649266 showed robust invitro activity against Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae, including MDR
strains. Against carbapenemase producers, S-649266 was
said to be more active than meropenem and cefepime. In
addition, S-649266 was reportedly shown to be 10 to 1,000
times more stable to carbapenemase than ceftazidime,
cefepime and meropenem.
“Opinion leaders we’ve been working with in the U.S.,
Europe and Japan believe the efficient use of the iron
uptake system may allow S-649266 to be an effective
approach to treat Gram-negative bacterial infections that
CREDIT: HIROMITSU MORIMOTO
Shionogi antibiotic joins
fight against MDR pathogens
Shionogi has high hopes that S-649266 will
be effective in treating Gram-negative
bacterial infections unable to be treated by
available antibiotics.
are not able to be treated by available antibiotics,” said
Dr. Tsutae Den Nagata, chief medical officer for Shionogi.
“S-649266 is the most advanced product in our anti-infective development portfolio. We are looking forward to the
next stage of its development.” ■
OnCore anticipates that combination
therapy will be required to completely
eradicate HBV from patients’ livers.
OnCore gained rights to cyclophilin
inhibitors that are central to this strategy through a licensing agreement
with NeuroVive Pharmaceutical AB, a
Swedish mitochondrial medicine company. The license agreement has a total
value of up to $150 million, excluding
royalty payments. OnCore will pay
NeuroVive an initial upfront payment,
development and sales milestones and
royalties based on future sales.
NeuroVive’s cyclophilin inhibitors,
known as sangamides, are based on a
new and unique polyketide chemistry
platform. The lead drug candidate in
the company’s cyclophilin program,
NVP018, has undergone extensive preclinical development. OnCore anticipates that NVP018 will be evaluated
in clinical trials in 2015.
“NVP018 is a promising antiviral
drug candidate and has tremendous
clinical potential for oral use as a novel
treatment for patients with chronic
hepatitis B infection,” said Michael
Sofia, OnCore’s chief scientific officer.
“We believe that a curative therapy for
HBV will likely contain an immunomodulatory agent, such as NPV018,
combined with multiple antiviral agents
with differing mechanisms of action.”
Jan Nilsson, NeruoVive CEO, said
the OnCore management team’s
experience developing a treatment
for hepatitis C made the company
an appealing partner. “OnCore stood
out in negotiations, which included
several leading pharmaceutical companies, because of its exclusive focus
on hepatitis B and its plan to bring the
drug candidate to market as quickly
and efficiently as possible,” he said.
OnCore’s acquisition of Enantigen
Therapeutics, a privately held pharmaceutical company, is also intended
to support its goal of developing a
hepatitis B cure. The acquisition will
allow OnCore to assume development
of Enantigen’s two novel discovery
programs, one targeting inhibition
of surface antigen secretion and one
targeting capsid assembly inhibition.
“We are very proud of the discovery work that we have done in hepatitis B,” said Entanigen President and
CEO Xiaodong Xu. “We believe that
OnCore is in the best position to rapidly advance our programs into human
clinical trials, and we look forward to
joining the OnCore research team to
help realize their vision.”
“Our plan is to combine Enantigen’s
drug candidates with our existing alloral portfolio of HBV compounds and
advance multiple combination regimens into human clinical trials,” said
OnCore CEO Patrick Higgins. “Enantigen programs, together with our
lead cyclophilin inhibitor, NPV018,
and our cccDNA formation and capsid assembly inhibition programs, give
OnCore the most comprehensive platform of assets consolidated to target a
cure for hepatitis B.” ■
EDITCONNECT: E111414
For more information, visit www.DDN-News.com
RX-P873
CONTINUED FROM PAGE 18
antibiotic-resistant infections.
Melinta’s ESKAPE Pathogen Program
combines the company’s crystallography
and computational chemistry experience to
generate new classes of antibiotics and new
molecules to treat extensively drug resistant
and multidrug resistant bacteria. As noted on
the company’s website, “Melinta researchers
generated three unique molecular scaffolds
with high binding affinity, low off-target
effect and broad-spectrum antibiotic properties. Compounds based on one of these
molecular scaffolds—the pyrrolocytosines—
have shown in-vitro activity and preclinical
efficacy against multidrug resistant Gramnegative and Gram-positive strains of bacteria known to cause complicated urinary tract
infections, skin and lung infections, as well as
sepsis.” From Melinta’s three novel classes of
antibiotics, more than 2,500 molecules have
been produced, and Melinta is completing
preclinical work to advance the most promising leads into Phase 1 clinical studies.
RX-P873 falls within the pyrrolocytosine
class of compounds. It was specifically tested
against Gram-negative species of bacteria,
“Melinta’s discovery
team employs a
highly disciplined
structure-based design
approach that we
believe can deliver both
next-generation
antibiotics and
completely new classes,
which can be fine-tuned
to address current and
emerging threats.”
Dr. Erin Duffy,
chief scientific officer
of Melinta
including 10 from the Enterobacteriaceae
family, as well as Pseudomonas aeruginosa
and Acinetobacter baumannii. The compound demonstrated potent activity against
the Enterobacteriaceae family, as it inhibited
more than 97 percent of isolates. RX-P873
was also shown to be highly active against
P. aeruginosa, including strains that are
resistant to ceftazidime or meropenem, and
was the most active agent tested against A.
baumannii; in that area, it displayed greater
activity than colistin.
“Melinta’s discovery team employs a
highly disciplined structure-based design
approach that we believe can deliver both
next-generation antibiotics and completely
new classes, which can be fine-tuned to
address current and emerging threats,” Dr.
Erin Duffy, chief scientific officer of Melinta,
said in a news release. “As seen in the above
studies, RX-P873 shows high and consistent
in-vitro potency across a variety of Gramnegative pathogens, including those commonly associated with complicated urinary
tract infections, complicated intra-abdominal infections and lung infections. We are
encouraged by these early-stage results and
PRECLINICAL
look forward to completing our preclinical
efforts and advancing molecules from the
ESKAPE Pathogen Program into the clinic.”
Melinta also recently shared news on one
of its late-stage antibiotics, delafloxacin, a
novel fluoroquinolone compound in Phase
3 development for the treatment of acute
bacterial skin and skin structure infections
(ABSSSI) and uncomplicated gonorrhea.
The U.S. Food and Drug Administration has
designated delafloxacin as a qualified infectious disease product for ABSSSI, uncomplicated gonorrhea and community-acquired
bacterial pneumonia.
NOVEMBER 2014 | | DDNEWS 21
On Sept. 6, Melinta announced, along
with Hartford Hospital, that in-vitro results
from a recent study highlighted delafloxacin’s
activity in low-pH environments, which are
indicative of infection sites. When tested
in samples from patients suspected to have
urinary tract infections (UTI), delafloxacin
demonstrated activity against E. coli and K.
pneumoniae, both of which are associated
with complicated UTIs. Two days later,
the company shared results from in-vitro
studies supporting delafloxacin’s potential in
targeting Neisseria gonorrhoeae, the organism
that causes gonorrhea. This pathogen
has developed resistance to all classes of
antimicrobials that have previously been
recommended to treat gonorrhea, Melinta
noted in a press release. In comparison,
delafloxacin demonstrated activity against all
50 of the ciprofloxacin-resistant isolates tested
in a study with University of Washington
collaborators. In a separate in-vitro study,
the compound proved to be more rapidly
bactericidal against ciprofloxacin-susceptible
and -resistant N. gonorrhoeae strains than
ceftriaxone, the recommended first-line
treatment for gonorrhea. ■
EDITCONNECT: E111413
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22 DDNEWS | | NOVEMBER 2014
SPECIAL REPORT
So life-like
D I S E AS E M O D E L I N G
After decades of questionable results,
are disease models turning a corner?
I
BY RANDALL C WILLIS
T’S YOUR SON’S BIG DAY, his birthday, and he is sur-
rounded by friends, cake, balloons and a ton of wrapping paper. But he’s been bouncing off the wall waiting
for his gift from you. With a big smile, you give him a
beautifully wrapped box.
Are you human or a mouse?
It is undoubtedly true that the biggest expense
in developing a new drug and getting it to market is accommodating the failure of a molecule
to translate preclinical success to the clinical
setting. For any number of reasons, something
is often lost between the efficacy and safety of
a compound in an animal or cell culture model
of a disease and in patients who actually have
the disease.
“We have found more ways to cure heart
disease in mice than you can imagine,” says
Brian Wamhoff, co-founder and vice president
of research and development for HemoShear,
a company working on more physiologically
relevant in-vitro models of human disease.
Wamhoff’s comment echoes the sentiment
expressed years ago by oncology specialist
Judah Folkman, who suggested that medical
research has become very good at curing cancer in mice.
“You can create models of fatty liver disease
in a mouse,” says Wamhoff. “It looks like it; it
“You can create models of fatty liver
disease in a mouse. It looks like it; it
smells like it. But how that mouse
develops fatty liver disease is completely
different than how a human does it.”
Brian Wamhoff, vice president of research
and development for HemoShear
CREDIT: NATIONAL INSTITUTES OF HEALTH
“I know how much you love airplanes,” you
wink as he rips into the package like a hyena
on carrion.
Desperately, he claws at the top of the box
and reaches inside to withdraw…a single
sheet of blank printer paper.
You beam with pride. He stares confused.
His friends stare at their shoes.
“I couldn’t get you an actual plane,” you
explain. “But if you fold this just thus and so,
it’s a pretty good approximation.”
A decade later, the same boy struggles at his
lab bench to develop a new drug compound,
when suddenly another scientist runs into the
lab, all excited and carrying a small case.
“You have it?” the boy smiles, his friend
nodding like a hypercaffeinated bobblehead.
The boy rips off the cover and reaches inside
to withdraw…a culture flask of pinkish cells.
“I couldn’t get you an actual prostate,” the
friend explains. “But if you shake this just thus
and so, it’s a pretty good approximation.”
Cells from a human organoid (here from a healthy prostate) can be xenografted into mice as
controls for cancer research.
smells like it. But how that mouse develops
fatty liver disease is completely different than
how a human does it.”
“So you develop a drug to treat fatty liver
disease in a mouse with a target that may or
may not exist in a human, and then you go into
a human and wonder why didn’t this work or
worse, why is it causing liver injury now?” he
adds, giving voice to the frustration felt across
the pharma industry.
As Wamhoff suggests, part of the problem
may be that in many animal models, a disease
is just that: a model. It gives all the outward
appearance of being, say, rheumatoid arthritis (RA). The joint inflammation may show
the same pathophysiology as human RA, but
the question becomes if it is really the same
condition at the molecular level, be that gene
expression or metabolic pathway perturbation.
And even if the disease is the same, does the
compound react with the rest of the model
animal’s physiology as it does in a human? Is
the animal more or less tolerant of the test
compound? Or are there unforeseen off-target
effects to which the animal is less prone or
completely immune?
Highlighting the ubiquity of the frustration of insufficient animal models, Wamhoff
points to comments made by Elias Zerhouni,
former director of the U.S. National Institutes of Health (NIH) and current president
of global research and development at Sanofi,
in June 2013.
“We have moved away from studying human
disease in humans,” Zerhouni lamented to the
NIH’s Scientific Review Management Board
meeting. “We all drank the Kool-Aid on that
one, me included.”
“The problem is that it hasn’t worked, and
it’s time we stopped dancing around the prob-
SPECIAL REPORT
lem,” he continued, suggesting researchers
have become too reliant on questionable animal data. “We need to refocus and adapt new
methodologies for use in humans to understand disease biology in humans.”
And that shift away from studying human
disease in humans has potentially been
expensive.
“It takes about seven years to get into the
clinic and anywhere between $50 million and
$150 million depending on what you’re developing,” Wamhoff suggests. “If the target and
the disease biology you’re starting with from
day one are wrong, you lose seven years.”
Thus the interest in moving back to more
human-based studies, and the opportunity for
companies like HemoShear.
“What our partners are telling us now is
that we want to start with more meaningful
targets and more meaningful human disease
biology,” Wamhoff continues. “It may still take
seven years, but after those seven years, we’re
going into the patient for the first time with
more understanding of the human disease
than we’ve ever had before.”
The recent research of Robert W. Davis
and colleagues in the Inflammation and Host
Response to Injury, Large-Scale Collaborative
Research Program may point to molecular reasons why the translation of results from mouse
to human may be so difficult.
Publishing their results in PNAS in early
2013, the researchers examined gene-expression profiles in both humans and mouse models of trauma, burn and endotoxin assault.
They found that the genomic responses across
the different inflammatory stresses were highly similar within the human populations but
that these patterns were not reproducible in
the mouse models of the same stresses, suggesting a disconnect that could easily translate
to different responses to potential treatments.
To some extent, they suggested, the differences could be explained in evolutionary
terms, with different immune systems maturing from different environmental stressors.
“Relative to the human response, mice
are highly resilient to inflammatory challenge,” the authors wrote. “For example, the
lethal dose of endotoxin is 5 to 25 mg/kg for
most strains of mice, whereas a dose that
is 1,000,000-fold less (30 ng/kg) has been
reported to cause shock in humans.”
By no means, however, are the researchers advocating for the elimination of mouse
models, but rather for the application of more
stringent model parameters.
“Because virtually every drug and drug
candidate functions at the molecular level,
one practical approach forward is to raise
the bar by requiring molecular detail in the
animal model studies indicating whether the
model mimics or fails to mimic the molecular behavior of key genes, key pathways or the
genome-wide level thought to be important
for the relevant human disease,” they suggested. “The quality of the animal model could
then be determined by how well it reproduces
the human disease on a molecular basis rather
than simply phenotype.”
One of the complaints about this study,
however, was that the researchers only examined one strain of mice, and several commentators suggested that the findings might be less
clear if a broader range of test animals had
been studied.
To some extent, this belief was borne out
in a similar study by Michigan State University’s Daniel Hollern and Eran Andrechek,
published earlier this year in Breast Cancer
Research.
NOVEMBER 2014 | | DDNEWS 23
CREDIT: HEMOSHEAR
For more information, visit www.DDN-News.com
HemoShear believes the best organ models involve not just the right cells, but also physiological forces found in vivo, such as hemodynamics.
(Left to right are Brian Wamhoff, vice president of research and development; Vincent Aurentz, chief business officer; James Powers, CEO; Brett
Blackman, chief scientific officer; and Nicole Hastings, vice president of operations.)
Using extensive databases of mouse mammary tumor samples used to model human
breast cancers, the researchers compared gene
expression and pathway activation patterns
both within and across mouse models (e.g.,
Myc, Neu, p53, BRCA). Even within models,
they found significant heterogeneity at both
the gene expression level and the pathway
activation level, with some genes or pathways elevated in sample subgroups within
each model.
They then compared their mouse analysis
with similar analyses in human breast cancer
tissues and found a large number of mouse
mammary tumor models had similar gene
expression profiles to human breast cancers.
Interestingly, however, they found that no
single group of human breast cancer was modeled by a single mouse model at the pathway
level.
Thus, the researchers concluded that mouse
mammary tumors could be effective models
of human breast cancer, but cautioned that
“great care should be taken to appropriately
choose the mouse model to use and that a
genomic and histological characterization
of tumors should be completed following
experimentation.”
So what about cell culture models using
human cells?
Closer with stem cells?
Cell culture models bring researchers closer
to the organism of interest—in this case,
humans—but even here problems can arise,
because primary human cell cultures can be
difficult to grow and maintain. Immortalized
cells, meanwhile, are easier to grow but may
be so significantly modified at the molecular
level from their normal progenitors that the
results of compound screening efforts may be
suspect.
The advent of stem cell technologies, however, has opened a door to not only studying
normal cells—healthy or diseased—but also
studying the cells of individuals with the disease of interest.
“What you can do today is get or make a
stem cell from that person, turn it into a liver
and now technically in that dish you have a
liver cell that has the same genetic mutations
as the liver cell in that child,” Wamhoff says.
Furthermore, as highlighted time and
again at the International Society for Stem
Cell Research (ISSCR) conference back in
June, gene editing tools such as CRISPR and
TALENS mean that researchers can go into
these disease-affected cell lines and “fix” the
errant genes to create healthy controls that
have essentially the same genetic makeup as
the donating patient. This affords scientists
the opportunity to then test for the impact on
the compound on these cultures and clearly
distinguish between disease-specific effects
and potential off-target effects.
Such efforts may be particularly useful
when examining conditions where cell biopsy
can be difficult and/or dangerous, such as in
neurological conditions.
The Salk Institute’s Fred Gage and colleagues presented some of their efforts to
model autism spectrum disorder (ASD)
by generating neural progenitor cells and
mature neurons from affected and age/gendermatched control cell lines. While the results
are quite preliminary, the researchers noted
altered cell cycle and levels of excitatory and
inhibitory markers of neural cells during early
stages of cell differentiation, providing a possible window into autism pathology.
Also working in ASD, researchers at CHOC
Children’s Research Institute described their
efforts to build a repository of more than 200
cells lines from ASD patients and unaffected
volunteers that can be differentiated into neurons and glia. The goal is to provide a resource
to evaluate and compare data from different
cells lines to better understand the causes and
pathophysiology of ASD, whether to develop
new therapeutics or better diagnostics.
But even here there may be a problem, for it
seems that newly minted stem cells may possess all of the tools of their newfound trade,
but that doesn’t make them identical to the
cells they’re mimicking.
“It turns out that they are very naïve,”
Wamhoff explains. “They’re immature at best,
almost fetal-like. So they’re lacking all of the
properties that the adult cell in the disease
state has.”
In a review published in Acta Pharmacologica Sinica, Harbin Medical University’s
Xiao-hong Xu and GSK China’s Zhong Zhong
concur, placing their focus on neurological
diseases.
“Many neurodegenerative diseases are
late-onset diseases, and their key phenotypes
may not manifest easily within a short period
of time in culture,” they wrote, further suggesting that many of these conditions also
involve interactions between cell types and/
or responses to environmental stressors.
“Therefore, it may be necessary to expose
cells to the relevant biological, chemical or
environmental stressors to reveal the underlying disease phenotypes when modeling lateonset, non-cell-autonomous and complex
multifactorial diseases using iPSCs,” they
concluded.
At ISSCR, Daniela Cornacchia and colleagues from Sloan-Kettering Institute for
Cancer Research and Weill Cornell Medical
College described their efforts to do just that,
by looking for factors that could induce aging
in iPSCs. Earlier efforts by the same group had
shown that they could reinduce age markers
erased during cellular reprogramming through
ectopic expression of progerin, the mutant
protein involved in the premature aging disease progeria. In the current studies, they set
about to identify age-related transcriptional
and epigenetic markers by comparing primary
cells from young and old donors, as well as the
iPSCs arising from those cells.
“Differential factors identified by our
studies are employed to yield an improved
‘aging cocktail,’ aimed at testing our primary
hypothesis that induced in-vitro aging allows
the development of more faithful models of
late-onset degenerative disorders including
[Parkinson’s disease],” they wrote.
A potential challenge to this approach,
however, is that you are introducing artificial
factors to the cellular mix, albeit factors based
on biological reasoning.
Wamhoff, in contrast, takes a more reductionist view, advocating the idea of going back
to the original physiology.
“You need to take those cells and put them
back in their physiological context,” he continues. “You need to find their neighbors and
bring them back in. You need to restore blood
LIFE-LIKE CONTINUED ON PAGE 24
LIFE-LIKE
CONTINUED FROM PAGE 23
flow, restore contraction.
“And when you do that, the really naïve rare disease liver cell you
created from a stem cell can now
become like an adult rare disease
liver cell, and now you can go after
a therapy.”
Spheroids and organoids
As noted in the feature Life moves
on (July 2014 issue of DDNews),
there has been significant movement toward the development of
3D cell cultures as a mechanism to
gain some of the biologically critical information lost when cells are
plated 2D.
In a review published in Stem Cells
in 2013, Robert Hynds and Adam
Giangreco of University College
London noted that complex intracellular communication and organization networks normally found in
tissues can be difficult to identify or
may be absent in 2D cultures.
“This is because in vivo, cells exist
within a complex network that provides important signalling and
biomechanical components,” they
wrote, echoing Wamhoff’s thoughts.
“Overall, 3D cultures recapitulate invivo cell-cell and cell-matrix interactions more successfully than 2D
plastic substrate cultures. Thus, 3D
culture models allow for the emergence of more physiologically relevant cell phenotypes.”
Increasing awareness of this phenomenon has led to rapid growth
in the market for cells, tools and
reagents for 3D cell culture. Companies like InSphero and Scivax
USA produce spheroid cell lines for
a variety of tissue types, while other
companies such as 3D Biomatrix,
AMS Biotechnology, Essen BioScience and Thermo Fisher provide
reagents, instruments and assays for
labs to develop and test their own
cell lines.
At the same time, suggested
Anna Herland and colleagues from
the Karolinska Institutet, despite
spheroids providing some improvement in disease models over 2D cultures, there is still room for further
improvement.
“Due to the self-assembling
nature of spheroid cultures, they
are difficult to control, and the cell
microenvironment differs significantly depending on the distance to
the spheroid surfaces,” they wrote
in a paper published this year in
Biomaterials.
They and other researchers took
the idea of 3D culturing one step
further by generating cultures that
more closely resembled the organs
they were trying to mimic, moving from a relatively homogeneous
clump of cells to create a more clinically relevant microenvironment.
With a nod to their morphology,
these bodies were called organoids.
Earlier this year, Yan Li and colleagues at Emory University and
Florida State University described
various efforts to use iPSCs to
develop organoids, publishing their
thoughts in Organogenesis.
How’d they do that?
flow on hepatocyte
morphology, function and metabolic
activity, researchers at HemoShear cultured rat hepatocytes
for two weeks in either a nonflow collagen sandwich or in
a perfused Transwell device
that simulated controlled
hemodynamics.
They then monitored the
hepatocytes using a combination of methods, including
confocal microscopy and transmission electron microscopy, a
cytochrome P450 activity assay
and an MTT assay for toxicity in
the presence of dexamethasone.
The also examined the impact
of hemodynamic flow by looking at the expression of various
metabolic genes at both the
RNA expression level using RTPCR and protein level using
western blotting.
In all cases, the morphology,
function and metabolism of
the hepatocytes more closely
resembled that found in vivo in
the cells cultured under hemodynamic flow conditions.
CREDIT: HEMOSHEAR
T
O TEST THE IMPACT
OF hemodynamic
HemoShear researchers can
perform upward of 120
simultaneous experiments in their
vascular and hepatic platforms.
“Taken together, these results
highlight the importance of
interfacing in-vitro biology with
in-vivo physiological parameters,” the authors concluded.
“Specifically, the retention of
in-vivo-like hepatocyte phenotype and metabolic function
coupled with drug responses at
more physiological concentrations requires the restoration of
in-vivo physiological transport
parameters in vitro.” ■
For more information, visit www.DDN-News.com
Scientists at Harvard’s Wyss Institute have
created a microfluidic chip that not only mimics
the morphology of the human lung, but also its
ability to “breathe.”
“Most organoids are formed
through the process involving
intrinsic tissue mechanics and the
programmed internal interactions,
known as self-organization,” they
explained, breaking that process
into steps involving relative cell
positioning, control of cell status
and morphogenesis.
Through these processes, the
cells adapt within the context of
one another to more closely resemble the morphology and various cell
types of the target organ, whether
liver, intestine, heart, lung or pancreas, among others.
The goal, according to Hynds and
Giangreco, is to then use these more
complex systems much as we currently use 2D cell culture models of
human disease.
“Multiwell plate-based organoid assays would then be channeled into compound toxicity and
efficacy screening systems such as
gene expression microarray, protein
mass-spectrometry and multiplex
ELISA platforms,” they suggested.
“High-throughput and high-content
analysis would be achieved using
automated cell manipulation and
readout systems.”
But even organoids have their
limitations. Beyond a certain size,
diffusion becomes a limiting factor for any test because of a lack of
circulation, whether of nutrients or
test compounds.
To some extent, this issue can be
moderated through improvements
in bioreactor technology, but as
Wamhoff indicated earlier, there is
more to life than simply having the
right cell combinations and being
able to feed them.
Organ recitals
“It was not just a matter of bringing
two cells together in a laboratory,
because people had done that before
and that wasn’t working,” he says.
“There is something else missing.”
That something else was physiology and the physical forces that act
on those cells within the human
body.
“In a blood vessel, the cell that
lines the blood vessel wall senses
blood flow as soon as the heart starts
to beat in development,” he continues. “The cell responds to blood
flow and that blood flow dictates
the function of that cell. And that
cell talks to its neighbor and dictates
the function of it.”
Thus, to create a more accurate
model of human health or human
disease, it is critical to reintroduce
the dynamics of physiology back
into the cell culture system, and
while technically challenging, this
has been done in a number of ways.
At the Wyss Institute at Harvard,
for example, Founding Director Don
Ingber and colleagues have taken a
microfluidics approach to essentially create organs-on-chips. Organappropriate cells line the channels
where they can be exposed to each
other and to fluids or gases. But just
as importantly, the chips—about the
size of a memory stick—have been
designed to allow physical processes
such as flexing to be incorporated.
In a video, Ingber introduces
the lung-on-a-chip model: “It has
human airway cells from the air sac
on a membrane that’s porous. On
the other side of the membrane are
human capillary blood vessel cells.
There’s air on one side. There’s flowing medium with human blood cells
in it like blood on the capillary side.
And the whole thing stretches and
relaxes, just like our lung does when
we breathe.”
The breathing action is the result
of changes in air pressure in two
channels that line the main physiological channel. As the vacuum
increases in these passages, it
stretches the tissue, which then
relaxes as the vacuum is diminished.
“We mimic various types of physiological responses to drugs, toxins
or various types of materials that
we encounter on a daily basis,” adds
Technology Development Fellow
Dan Huh.
In proof-of-concept experiments, the researchers were able
to introduce bacteria to the airway
and watch as white cells in the
blood stream responded by moving
through the membrane and attacking the bacteria. They monitored
cell migration using high-content
imaging.
The group was also able to mimic
IL-2-induced edema that can occur
in cancer patients receiving the
cytokine. At IL-2 levels commonly
given to cancer patients, small
amounts of fluid translated from
the blood stream side to the airway
when the system was static. When
the system mimicked lung expansion and contraction, however, the
fluid completely filled the airway
chamber and blood clots were noted
in the airway.
Since their first publication in
2010, the organization has developed more than 10 organ models,
including chips for liver, gut, kidney
and bone marrow, and in late July,
they announced the launch of the
company Organs-on-Chips to commercialize the technology.
Aside from the chips themselves,
however, the group has also developed an instrument to automate the
various chips and fluidically link the
organs-on-chips together to better
mimic whole-body physiology,
human-body-on-chips.
HemoShear took a somewhat different approach (see the sidebar in
this section titled “How’d they do
that?”).
“We set out to create, first, a
healthy human blood vessel in a
laboratory,” Wamhoff explains. “And
we did that by superimposing on the
vascular system human physiological parameters that were deduced
from a human high-resolution MRI.”
To do this, they co-cultured endothelial cells and smooth muscle cells
in a 75-mm Transwell plate and
then added a cone and plate drive
to simulation hemodynamics, as
well as in-flow and out-flow tubing
to move culture fluids across both
cellular surfaces.
As he goes on to explain, this
work couldn’t have been done 15
to 20 years ago, as the technology
CREDIT: WYSS INSTITUTE HARVARD
SPECIAL REPORT
24 DDNEWS | | NOVEMBER 2014
For more information, visit www.DDN-News.com
to understand how the mechanical
forces were somehow sensed and
then recreate them on the bench
really didn’t exist until the early
2000s, when molecular physiologist
Wamhoff and company co-founder
and biomechanical engineer Brett
Blackman first met at the University
of Virginia.
The combination of technologies was a total game-changer to
Wamhoff.
“When you take a cell and you
put it in a dish, you can squirt a
drug on it and get the response that
you think you’re looking for,” he
explains. “It turns out that the concentration of that drug is usually so
high that you can never achieve that
concentration in a human. So how
do you make a decision off of that?”
“Once we let the cells talk to each
other and gave them the physiological forces back, they now started
responding to drugs at in-vivo
concentrations.”
But as with drug discovery, success on the bench does not always
translate into broader commercial
success. Thus, it was critical for
HemoShear to validate both their
vascular and liver models.
As Wamhoff explains, potential
pharma partners weren’t about to
sign on to collaborate with HemoShear if they couldn’t validate their
system, because any IND filings arising from the research would slam up
against FDA questions.
“It took us well over five years and
a lot of drugs and burning a lot of
cash to validate it,” he says.
The company has screened more
than 200 drug compounds, most of
them FDA-approved therapeutics,
to validate that they can reproduce
the known in-vivo effect at clinical
concentrations.
“We can show efficacy, safety or
harm, and we’ve had a pretty good
track record,” he adds.
As a more recent show of success,
the company announced in October
the successful completion of the first
phase of a project with the National
Cancer Insitute to recreate the cancer tumor microenvironment.
“We had tumor vasculature, the
tumor cells and the stromal support
cells, and the hypothesis would be
that if you bring all of that together
in the right physiological context,
you’d see drug responses at clinical therapeutic concentrations,”
explains Wamhoff.
As proof-of-concept, the company created a non-small cell lung
cancer tumor platform and then
probed their construct with cisplatin, a drug commonly used to
treat various cancers. Unlike what
had been seen in mouse or other
in-vitro models, HemoShear was
able to demonstrate that they could
effectively reduce tumor growth at
clinically relevant IC50 levels.
The next step in the agreement is
to generate models for other tumor
types and then validate those models
against other FDA-approved drugs
and combination therapies.
Aside from filling in for traditional preclinical mouse models and
tissue culture, Wamhoff also sees
opportunities for the HemoShear
system in areas such as drug repositioning (scanning other disease
models), identification of off-target
effects and potentially testing drugs
in broader patient populations.
The last opportunity may
become significant, as many drugs
are approved based on data from
focused patient populations, e.g.,
Caucasian adults aged 25 to 55.
SPECIAL REPORT
But what about the impact of those
drugs in the aged, children or people
of different ethnic backgrounds or
environmental exposures?
The company has already performed experiments where they
examined differences in the gastrointestinal bleeding profiles of
Caucasian women 70 years or older
vs. Caucasian women less than 70
years old to understand the underlying cause of the bleeding.
But for all of their technical
achievements, these new disease
WHY R
NOVEMBER 2014 | | DDNEWS 25
models run second to animal and
traditional cell culture models in
one significant way: throughput.
Wamhoff is the first to admit that
the HemoShear platform is low- to
medium-throughput, although he
balances that against the type of
information arising from his system and the company’s arsenal of
upward of 120 simultaneous experiments being more than enough for a
company HemoShear’s size.
That being said, he acknowledges
that the pharma industry has built
ISK IT
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owned by the American Type Culture Collection unless indicated otherwise.
?
billion-dollar infrastructures around
high-throughput screening, infrastructures that these companies
are not going to mothball simply
because new technologies have
arrived.
Thus, he suggests, HemoShear
and the nanofluidic device companies are going to have to evolve their
systems to figure out how to plug
into the high-throughput world.
Wamhoff calls that the biggest
challenge in the near future. ■
EDITCONNECT: E111429
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NOVEMBER 2014 | | DDNEWS 27
CLINICAL TRIALS
BRIEFS
Acceleron advances
ACE-083 into the clinic
CAMBRIDGE, Mass.—Acceleron Pharma Inc. has
begun a Phase 1 trial of ACE-083, a novel muscle
drug engineered to selectively increase muscle
mass and strength in the muscles it is administered to by blocking proteins in the transforming
growth factor-beta protein superfamily that modulate muscle growth. Acceleron is developing this
investigational protein therapeutic for diseases
in which improved muscle strength stands to provide a clinical benefit, such as certain forms of
muscular dystrophy and inclusion body myositis.
“[We] believe that ACE-083 has the potential to
treat a wide array of diseases in which patients
have lost muscle mass and strength in specific
muscles or muscle groups,” Dr. John Knopf, CEO
of Acceleron, said in a news release.
Partners on lung
cancer immunotherapy
INGELHEIM, Germany & RIDGEFIELD, Conn.—Boehring-
er Ingelheim and CureVac have jointly announced
an exclusive global license and development collaboration centered on CureVac’s CV9202, a novel
investigational therapeutic mRNA vaccine being
developed for lung cancer. The therapeutic is a
combination of mRNA molecules that code for six
antigens that are overexpressed in lung cancer.
CureVac will receive approximately $45 million,
with the potential for up to about $556 million in
milestone payments, as well as sales royalties.
Boehringer Ingelheim will receive exclusive global
rights to develop and commercialize CV9202, and
will begin clinical investigation of the compound in
at least two different lung cancer settings, in combination with afatinib in patients with advanced
or metastatic epidermal growth factor receptormutated non-small cell lung cancer (NSCLC) and
in combination with chemo-radiation therapy in
patients with unresectable stage III NSCLC.
Strong statement Easing
Monoclonal antibody HIV
drug succeeds in
monotherapy clinical trial
BY ILENE SCHNEIDER
VANCOUVER, Wash.—According to the U.S.
Centers for Disease Control and Prevention
(CDC), some 1.14 million people aged 13
years and older are living with human immunodeficiency virus (HIV) infection. There are
about 50,000 new HIV infections per year.
Because HIV is such a big problem, the U.S.
Food and Drug Administration (FDA) has
given fast-track status to PRO 140, a drug
candidate from CytoDyn Inc.
PRO 140 belongs to a new class of HIV/
AIDS therapeutics—viral-entry inhibitors—
that are intended to protect healthy cells
from viral infection. PRO 140 is a humanized monoclonal antibody directed against
CCR5, a molecular portal that HIV uses to
enter cells. PRO 140 blocks the HIV coreceptor CCR5, and clinical trial results thus
far indicate that it does not affect the normal
function of the cell.
CytoDyn, a biotechnology company
focused on developing subcutaneously delivered
humanized cellspecific monoclonal antibodies as
entry inhibitors
for the treatment
and prevention
“We believe this
of HIV, recently
drug could change
announced the
the paradigm of
continuation of
HIV treatment,”
strong positive
says CytoDyn CEO
results for four
and President Dr.
weeks of monoNader Pourhassan
of PRO 140. “The
therapy with PRO
patient gets a
140. Patients with
holiday from taking
HIV-1 are currentpills, and the drug
ly participating in
answers an unmet
the company’s
need by
Phase 2b treatsuppressing the
patient’s viral load.”
ment substitution
trial. The company has requested an “end of Phase 2b meeting” with the FDA to discuss Phase 3 plans.
The Phase 2b clinical study was designed
PRO 140 CONTINUED ON PAGE 29
Progress on dementia
Intra-Cellular Therapies
announces topline safety
results from Phase 1/2
trial of lead dementia
drug candidate
BY LLOYD DUNLAP
NEW YORK—Intra-Cellular Therapies Inc.,
IN THIS SECTION
IN THIS SECTION
Antivirals/M&A
activity
Recognizing potential in RSV
Head
(ALIOS from cover).................................. 31
Text ........................................................... 0
HIV/AIDS
Text
...........................................................
Strong
statement.................................... 270
Head
Muscle mass/strength
Text
...........................................................
0
Acceleron
advances ACE-083
Text the
...........................................................
into
clinic .......................................... 270
Neurology/CNS
Easing the pain ....................................... 27
Hope for spinal injury? ........................... 28
Progress on dementia............................. 27
Oncology
Matching drug and
trial options to patients .......................... 30
Partners on lung
cancer immunotherapy ........................... 27
a biopharmaceutical company focused on
the development of therapeutics for central
nervous system disorders, has announced
topline results from ITI-007-200, a Phase
1/2 clinical trial designed to evaluate the
safety, tolerability and pharmacokinetics of
low doses of its lead drug candidate, ITI-007,
in healthy geriatric subjects (trial part one)
and in patients with dementia, including
Alzheimer’s disease (trial part two). The data
presented at the 2014 annual meeting of the
American Neurological Association relate to
part one of the trial. Additional data, including part two of the trial, will be presented at
a future scientific conference.
The initial results demonstrated that ITI007 is safe and well tolerated in healthy geriatric subjects and met the primary objectives
of the study. Further, the results indicate a
ITI-007 CONTINUED ON PAGE 28
Intra-Cellular Therapies recently released data
for dementia drug ITI-007 that relate to part
one of the trial, focused on healthy geriatric
subjects, that indicates a wide safety window
for use in the elderly. Data from part two of
the trial, which focuses on patients with
dementia, will be presented at a future
scientific conference.
the pain
Improved treatment
for spasticity
on the horizon
BY ZACK ANCHORS
LEXINGTON, Mass.—The first clinical study of a new drug under development by Concert Pharmaceuticals
holds promise for people who suffer
from spasticity, a chronic condition
that involves painful tensing and
spasms of muscles. The biopharmaceutical company’s results from its Phase 1
study of CTP-354 suggest that the drug
could present significant advantages
over currently available treatments
for spasticity. Concert is one of several
companies working to find a new and
more effective treatment for spasticity. GW Pharmaceuticals is planning to
launch a Phase 3 trial for its cannabisbased treatment this fall.
“All of the current treatments for
spasticity have substantial limitations,
both in terms of dosing regimen and
efficacy,” Roger Tung, CEO of Concert,
tells DDNews. “We think there’s great
potential for a medicine that’s easier to
comply with and that doesn’t have the
sedative effects of the most commonly
used treatments.”
Roughly 12 million patients suffer
from spasticity worldwide, according
to a 2006 estimate by the American
Association of Neurologic Surgeons.
The condition can result from a wide
range of disorders, including multiple sclerosis, spinal cord injury,
cerebral palsy, amyotrophic lateral
sclerosis, stroke and hereditary spastic paraplegia. Symptoms range from
mild muscle tightness to more severe
symptoms, including crippling and
painful inability to move limbs that
can result in disability and diminished
quality of life.
Concert’s recent study focused specifically on the treatment of patients
suffering from spasticity as a result of
spinal cord injury and multiple sclerosis. “We think there are about 250,000
patients in the U.S. that fit those two
categories, and we think about half or
so are not satisfied with their treatment or are not receiving adequate
CTP-354 CONTINUED ON PAGE 30
CLINICAL TRIALS
28 DDNEWS | | NOVEMBER 2014
For more information, visit www.DDN-News.com
Hope for spinal injury?
ITI-007
CONTINUED FROM PAGE 27
StemCells Inc. takes
step toward treating
cervical spinal cord
injury and possibly
achieving a cure
NEWARK, Calif.—StemCells Inc.
has launched its Pathway Study, a
Phase 2 proof of concept clinical
trial using its proprietary HuCNSSC platform of human neural stem
cells, for the treatment of cervical
spinal cord injury (SCI). This is the
company’s first study accessing the
efficacy of neural stem cells for the
treatment of paraplegics dependent on wheelchairs and breathing tubes.
StemCells’ Pathway Study is
reportedly the first clinical study
designed to evaluate both the safety
and efficacy of transplanting stem
cells into patients with traumatic
injury to the cervical spinal cord.
“The expansion of this trial into
patients with cervical injury is exciting because even a gain of one to two
segments in cervical spinal cord
injury patients can allow for additional function in the upper extremities,” Greg Schiffman, chief financial
officer of StemCells, tells DDNews.
The decision to pursue a therapy for SCI “was based on the large
unmet medical need combined
with the strength of the preclinical
science supporting the use of our
HuCNS-SC cells to treat victims of
spinal cord injury,” Schiffman said.
“We showed the cells could repair
and replace damaged or lost cells
such as the myelinating oligodendrocytes or new neurons.”
Approximately 1.3 million people
in the U.S. report being paralyzed
due to an SCI, and there currently
are no effective treatments available. Approximately 56 percent
CREDIT: STEMCELLS INC.
BY LORI LESKO
StemCells’ Pathway Study is reportedly the first clinical study designed to
evaluate both the safety and efficacy of transplanting stem cells into
patients with traumatic injury to the cervical spinal cord. Illustrated here is
an image of StemCells’ proprietary HuCNS-SC human neural stem cells.
trial will follow the patients for one
year from the time of enrollment.
“StemCells Inc. has been evaluating our proprietary human neural stem cells (HuCNS-SC) for the
treatment of spinal cord injury for
over 10 years,” Schiffman says. “Our
first preclinical work was published
in the Proceedings of the National
Academy of Sciences in 2005, demonstrating that our cells could promote locomotor recovery in spinal
cord-injured mice.”
“Our first clinical trial in spinal
cord injury was initiated in 2011
for victims with thoracic injuries
to their spinal cord,” Schiffman
adds. “The thoracic cord is responsible for sensory function. Earlier
“The expansion of this trial into patients
with cervical injury is exciting because even
a gain of one to two segments in cervical
spinal cord injury patients can allow for
additional function in the upper extremities.”
Greg Schiffman, chief financial officer
of StemCells Inc.
of the spinal cord injuries occur
in the cervical region. Overall,
approximately 13 percent of SCI
patients have no mobility, and 35
percent have limited mobility after
the traumatic injury.
The upcoming trial will be conducted as a randomized, controlled,
single-blind study and efficacy will
be primarily measured by assessing
motor function according to the
International Standards for Neurological Classification of Spinal Cord
Injury. The primary efficacy outcome will focus on change in upper
extremity strength as measured in
the hands, arms and shoulders. The
this year, the company completed
enrollment and reported interim
results from this trial on eight
patients with at least six months
of follow-up post transplantation.
Half of the patients transplanted
had significant post-transplant
gains in sensory function. The
interim results also continue to
confirm the favorable safety profile of the cells and the surgical
procedure.”
“The key to its success so far
has been the HuCNS-SC product
candidate,” he continues. “We have
conducted four clinical trials so far
in disorders involving the brain, eye
and spine. We have seen results
consistent with our preclinical
models in all of these studies. We
believe that we have a platform in
our HuCNS-SC human neural stem
cells that has the ability to address a
broad number of indications in the
CNS, including spinal cord injuries.
We see our HuCNS-SC platform as
a next generation of cellular therapy and find that the vast majority
of people seem to support the idea
of using cells to treat serious disorders that have no other treatment
options available.”
Schiffman believes that the cell
therapy field is at a point “where
clinical data is being generated and
I think we will see several breakthrough therapeutic approaches
validated over the next three to
five years. This is a time of excitement and promise for the field of
regenerative medicine, and I look
forward to a time where we have
several breakthrough stem cellbased therapies approved to treat
serious disorders where there are
no treatments available today.”
“The initiation of the Pathway
Study represents a major milestone for StemCells Inc. as we
pursue the development of a truly
breakthrough therapy for spinal
cord injury,” said Martin McGlynn,
president and CEO of StemCells.
“While we are thrilled by the prospect that patients with thoracic
level injuries might be able to
regain lost sensory function below
the site of the injury, the possibility that patients with injuries to the
cervical region of the cord might
regain or improve lost motor function could be truly life-changing.” ■
EDITCONNECT: E111419
dose-related pharmacokinetic
profile in geriatric subjects consistent with previous studies
in younger subjects. This study
marks an important milestone
in defining the low dose range of
ITI-007 to be developed for the
treatment of behavioral disturbances associated with dementia
and related disorders.
In these healthy geriatric subjects, ITI-007 was safe and well
tolerated at doses up to and including 30 mg. Subjects did not exhibit
extrapyramidal adverse events or
clinically relevant changes in cardiovascular parameters. The tolerability and pharmacokinetic profile of ITI-007 in geriatric subjects
indicate a wide safety window for
ITI-007 in the elderly.
Previous positron emission
tomography studies demonstrated that a 10 mg dose of
ITI-007 represented an approximate 10 percent occupancy of
D2 receptors in the striatum.
Doses of ITI-007 ranging from
1 to 10 mg resulted in improved
sleep in patients with primary
insomnia (clinical trial ITI-007004). Taken together, these
data indicate that low doses of
ITI-007 demonstrate proof of
mechanism by engaging key
brain targets and pharmacodynamic effects consistent with
the mechanisms of action, and
are safe and well tolerated in relevant patient populations. Based
on previously reported data and
the data from the geriatric study
announced today, the company
plans to further evaluate low
doses of ITI-007 for the treatment of behavioral disturbances associated with dementia,
including Alzheimer’s disease.
To date, the FDA has not
approved any drug to treat the
behavioral symptoms of dementia, including Alzheimer’s disease. As symptoms progress and
become more severe, physicians
often resort to off-label use of
antipsychotic medications in
these patients. Current antipsychotic drugs are associated with
a number of side effects, which
can be problematic for elderly
patients with dementia. In addition, antipsychotic drugs may
exacerbate the cognitive disturbances associated with dementia.
“Dementia is associated with
behavioral symptoms including
agitation, aggression and irritability. These symptoms often gradually increase in frequency and
severity during the course of the
disease, becoming distressing to
patients and caregivers and contributing to early institutionalization,” said Dr. Sharon Mates, CEO
and chairman of Intra-Cellular
Therapies. “We believe the ITI007-200 results are consistent
with the existing favorable safety
and tolerability profile of the drug
and its pharmacokinetic profile.
The results allow the future testing of a range of low doses of ITI007 that offer the potential clinical benefits of optimal 5-HT2A
antagonism and additional potential benefits offered by the gradual
engagement of other receptors
as the dose is increased. The outcome of ITI-007-200 represents
an important step forward in the
clinical development of ITI-007
for the treatment of behavioral
disturbances associated with
dementia and related disorders.”
ITI-007 is Intra-Cellular Therapies’ lead product candidate,
whose mechanism of action is
believed to have the potential to
yield a first-in-class antipsychotic
therapy and, at lower doses, a firstin-class therapy for the behavioral
disturbances associated with
dementia. In preclinical and clinical trials to date, ITI-007 combines potent serotonin 5-HT2A
receptor antagonism, dopamine
receptor phosphoprotein modulation, glutamatergic modulation
and serotonin reuptake inhibition
into a single drug candidate. At
dopamine D2 receptors, ITI-007
has been demonstrated to have
dual properties and to act as both
a postsynaptic antagonist and a
presynaptic partial agonist. ITI007 has also been demonstrated
to stimulate phosphorylation of
glutamatergic NMDA NR2B, or
GluN2B receptors in a mesolimbic specific manner.
At the lowest dose studied to
date (1 mg), ITI-007 has been
demonstrated to act primarily
as a potent 5-HT2A serotonin
receptor antagonist. As the dose
is increased, additional benefits
are derived from the engagement
of additional drug targets, including modest dopamine receptor
modulation and modest inhibition of serotonin transporters.
The company believes that
combined interactions at these
receptors may provide additional benefits above and beyond
selective 5-HT2A antagonism
for treating agitation, aggression and sleep disturbances in
diseases that include dementia,
Alzheimer’s disease and autism
spectrum disorders, while avoiding many of the side effects
associated with more robust
dopamine receptor antagonism.
As the dose of ITI-007 is further
increased, leading to moderate
dopamine receptor modulation,
inhibition of serotonin transporters and indirect glutamate
modulation, these actions complement the complete blockade
of 5-HT2A serotonin receptors.
In this dose range, ITI-007 may
be useful in treating the symptoms associated with schizophrenia, bipolar disorder, major
depressive disorder and other
neuropsychiatric diseases. ■
EDITCONNECT: E111417
CLINICAL TRIALS
For more information, visit www.DDN-News.com
PRO 140
CONTINUED FROM PAGE 27
to investigate the potential of
allowing patients to enjoy treatment interruption from their current highly active antiretroviral
therapy (HAART) regimen concurrent with a monotherapy consisting of weekly injections of PRO
140. The results from the treatment
substitution trial to date have demonstrated 100-percent success in
suppressing the viral load among
patients who had weekly injections of PRO 140 for four weeks
of monotherapy. There were zero
virologic failures among 21 patients
who have reached four weeks of
monotherapy, and 36 patients out
of 40 have received at least the first
injection of PRO 140. Now CytoDyn is requesting FDA clearance
to conduct a larger, similar Phase
3 licensing trial to demonstrate further the efficacy of PRO 140.
As Dr. Nader Pourhassan,
president and CEO of CytoDyn,
explained, “Currently, there is no
approved antibody therapy. We
have the antibody … HIV patients
will be able to stop taking pills and
have a better quality of life while
letting the body come back to itself.
We believe we can suppress the
infection for three months with the
injections alone with low toxicity,
low side effects and high patient
acceptance.”
Comparing these results with
previous studies used as histori-
“Currently, there
is no approved
antibody therapy.
We have the
antibody … HIV
patients will be
able to stop
taking pills and
have a better
quality of life
while letting the
body come back
to itself. We
believe we can
suppress the
infection for three
months with the
injections alone
with low toxicity,
low side effects
and high patient
acceptance.”
Dr. Nader
Pourhassan,
president and
CEO of CytoDyn
cal controls supports the current
study’s successful outcome. In a
37-patient trial of treatment interruption from HAART, the use of
multiple antiretroviral drugs in
an attempt to control HIV infection, approximately 50 percent
of patients experienced viral load
breakout before four weeks, and
approximately 100 percent showed
viral load breakout at eight weeks.
In another similar study, results
indicated that 10 of 12 patients
experienced viral load breakout
after just two weeks of treatment
interruption from HAART.
According to Pourhassan, “We
believe this is a very strong indication that PRO 140 is effective to
allow four weeks of drug holiday
with weekly injections. PRO 140’s
safety has been well documented
in previous studies, as well as our
current study.”
PRO 140 has been the subject of
four Phase 1/1b and two Phase 2a
clinical trials, each of which demonstrated its ability to significantly
NOVEMBER 2014 | | DDNEWS 29
reduce HIV viral load in human test
subjects. The PRO 140 antibody
appears to be a powerful antiviral
agent, leading to potentially fewer
side effects and less frequent dosing
requirements as compared to daily
drug therapies currently in use.
Pourhassan described the commercial potential of PRO 140 as
“huge.” CytoDyn acquired it from
Progenix in 2012. Progenix, which
worked on PRO 140 for more than a
decade, chose to focus its efforts on
cancer drugs. CytoDyn has received
about $20 million for clinical trials with the drug in the past and
recently received $8.4 million
from the U.S. National Institutes
of Health for a testing program at
Drexel University.
“We believe this drug could
change the paradigm of HIV treatment,” Pourhassan said. “The
patient gets a holiday from taking pills, and the drug answers an
unmet need by suppressing the
patient’s viral load.” ■
EDITCONNECT: E111416
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30 DDNEWS | | NOVEMBER 2014
Matching drug and
trial options to patients
LEWISVILLE, Texas & CLEVELAND—
Together, med fusion, an integrated
molecular center of excellence
and clinical trials service organization, and GenomOncology, an Ohio-based genomics
technology and services provider, recently announced a
partnership to optimize treatment strategies based on the patient’s
disease state and tumor profile.
The companies believe that
GenomOnoclogy’s proprietary technology platform, the GO Clinical Workbench, and support services will complement med fusion’s expanded solid tumor
disease-specific panels and deliver a comprehensive laboratory report detailing
relevant drug and clinical trial options.
An expansion of med fusion’s solid
tumor menu is underway, including
options for non-small cell lung cancer and
colorectal cancer. The expanded oncology
menu is powered in part by next-generation sequencing (NGS) technology that
med fusion validated this summer in its
CLIA- and CAP-accredited laboratory.
GenomOncology’s GO Clinical Workbench reportedly streamlines the use of
NGS data in conjunction with other ana-
lytic modalities, simplifies the creation
of a summary report and provides a fully
traceable workflow and rulesbased decision support for
the clinical interpretation of
genomic data.
“Cancer is a complex disease of the genome where
each tumor has its own set of
genetic alterations,” said Dr. Tom Lohmann, chief medical officer of med fusion.
“Increased understanding of the underlying genetic changes that may be driving
tumor growth or metastasis can enable
precise treatment strategies tailored to the
genetic profile of each patient’s cancer.”
“Genomics-based precision medicine
requires the clinical interpretation of
genomic data—streamlined use of nextgeneration sequencing information in
conjunction with other analytic modalities—as well as rules-based decision support,” added Manuel Glynias, president
and CEO of GenomOncology. “The availability of an expert knowledge base like
My Cancer Genome, exclusively integrated with the GO Clinical Workbench, provides a clinical report that educates physicians and gives them confidence as they
make treatment decisions for patients.” ■
TOOLS &
TECHNOLOGY
CTP-354
CONTINUED FROM PAGE 27
treatment,” says Tung.
Several oral treatments are currently available to treat spasticity and are used widely,
but each has significant drawbacks. Patients
typically need to take doses of most of these
drugs three to four times a day, which is
considered by many to be an overly burdensome dosing regimen. “We understand from
talking to physicians and patients that this
dosing regimen is very inconvenient for both
caregivers and patients,” says Tung. Another
shortcoming of current treatments involve
their sedative effects, which can impair cognition and cause patients to have difficulty
staying awake, preventing individuals from
participating in many everyday activities.
Concert conducted a clinical trial that
tested multiple dosing levels through a randomized, double-blind, placebo-controlled
study of 30 healthy volunteers. The trial was
designed to evaluate the safety, tolerability
and pharmacokinetics of 10-day repeat dosing of three different amounts of CTP-354.
Results showed that the molecule was generally well tolerated, with mild dizziness and
drowsiness being the most common adverse
effects. No sedation was observed.
“We found that the compound was very
well absorbed, with the amount present in
blood stream proportional to the amount
taken orally,” Tung tells DDNews. “The compound had a very long half-life—about 20
hours—which is in great contrast to the available drugs, which have half-lives of three to
four hours.” The study also examined the
effect of food on the drug’s effect in patients
and found that CTP-354 provided similar
exposure under both fed and fasted conditions, suggesting that it can be dosed without
regard to meals.
Concert presented the findings of its Phase
1 trial in July at the at the American Neurological Association’s annual meeting.
CTP-354 is a novel, potentially first-inclass drug, but its development is built on
a version of a drug initially developed by
Merck. The compound L-838417, a subtypeselective GABAA receptor modulator, was
discovered by Merck, which profiled the
compound extensively in preclinical efficacy models and found potential efficacy
against both inflammatory and neuropathic
pain. But Merck ultimately abandoned the
development of L-838417 because it also
demonstrated substantial pharmacokinetic
limitations.
Concert was able to apply its expertise in
precision deuterium chemistry to use the
failed Merck compound to create CTP-354,
which it then patented. Concert was able
to achieve more favorable pharmacokinetics with the new molecule, even though it
retained many of the same chemical qualities
of L-838417.
The company plans to move forward soon
with multiple Phase 2 clinical trials of CTP354. “We remain on track to advance the
program into Phase 2 testing later this year,
initially targeting spasticity in patients with
spinal cord injury followed by the start of a
Phase 2 trial in multiple sclerosis patients in
early 2015,” said Tung.
Tung tells DDNews that he anticipates
potential for CTP-354 beyond its use to treat
spasticity if the upcoming trials continue to
build an attractive profile for the drug. “We
view spasticity as offering a very targeted
population with a specific medical need, but
there may be potential for CTP-354 to treat a
range of other conditions,” he said. ■
EDITCONNECT: E111418
CLINICAL TRIALS
For more information, visit www.DDN-News.com
CONTINUED FROM PAGE 1
and demonstrates a high barrier to
the development of viral resistance.
RSV is the most common cause of
serious lower respiratory tract infections in infants, and though most
healthy adults can recover from RSV
infection fairly quickly, infection
can also be severe for the elderly,
immunocompromised or those with
preexisting pulmonary issues. The
U.S. Centers for Disease Control
and Prevention note that “Almost
all children will have had an RSV
infection by their second birthday.”
There is also a link between RSV
infections and the later development of asthma in children. No
effective treatments exist for RSV.
On Oct. 13, Alios announced
results from a Phase 2 challenge
study of AL-8176, a randomized,
double-blind, placebo-controlled
study conducted in healthy adult
volunteers who had been infected
with RSV intranasally. Sixty-two
healthy volunteers received either
placebo or one of three dosing regimens of AL-8176: 375 mg administered orally twice daily, or 750 mg
given as a single loading dose followed by twice-daily maintenance
doses of 150 mg or 500 mg. In the
study, AL-8176 reached its primary
and secondary endpoints of reduction in viral load and improvement
in symptom scores compared to placebo. The drug candidate was found
to be well tolerated, with no discontinuations and no clinically significant laboratory abnormalities.
All three dosage groups of
AL-8176 demonstrated a rapid,
significant reduction in RSV viral
load following treatment, with
a mean time to nondetectability
of RSV load of 1.3 to 2.3 days for
the AL-8176 treatment groups. At
day 12, all subjects that received
AL-8176 were RSV RNA undetectable, and remained so upon followup on days 16 and 28.
“Alios BioPharma’s pipeline is
closely aligned with our vision
to continue to address important
unmet medical needs through scientific innovation,” Dr. Johan Van
Hoof, global head of infectious
diseases and vaccines at Janssen,
noted in a statement. “This acquisition will allow us to combine their
innovative compounds with our vast
experience in viral diseases to deliver novel medicines and treatment
options for patients worldwide.”
Correction
The article “Cognitive computing in the
clinic” in the October 2014 issue erroneously attributed several quotes and
comments to Dr. Nicholas LaRusso of
the Mayo Clinic that should have been
attributed to Dr. Michael Weiner, director
of healthcare strategic services at IBM. To
see the corrected copy in the online version of the story, you can enter E101402 in
the Edit-Connect Code window at
http://ddn-news.com/15
“We are so pleased to be joining the Janssen Pharmaceutical
companies of Johnson & Johnson, who have an impressive track
record of bringing breakthrough drugs for viral diseases to market.”
Dr. Lawrence M. Blatt, president and CEO of Alios BioPharma
This could be a boost in Johnson & Johnson’s ability to compete with rival Gilead Sciences
in another arena, as Gilead is also
advancing an RSV drug candidate:
GS-5806, an investigational oral
Copyright Cisbio Bioassays. All rights reserved. All trademarks are property of Cisbio Bioassays.
ALIOS
NOVEMBER 2014 | | DDNEWS 31
RSV fusion inhibitor that saw
positive results in a Phase 2a study
earlier in the year. Michael Yee,
an RBC Capital Markets analyst,
noted that an RSV drug could
potentially see annual sales of at
DISCOVER AN
EPIGENETICS ASSAY
PORTFOLIO YOU’LL
NEVER OUTGROW
least $1 billion.
The companies raced each other
to be the first to get a hepatitis C
compound approved last year, and
while both got a horse to the track,
so to speak—Gilead’s Sovaldi and
Johnson & Johnson’s Olysio—
Sovaldi has outperformed its
competition, seeing better Phase
3 clinical trial results and becoming “the drug to most rapidly ever
reach billion-dollar blockbuster status, with sales totaling more than
$5 billion in the first six months
of this year,” according to a Motley
Fool article. Alios also has three
hepatitis C compounds in its pipeline, in preclinical, IND and Phase
2 development. ■
EDITCONNECT: E111401
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For more information, visit www.DDN-News.com
32 DDNEWS | | NOVEMBER 2014
American Society for Cell Biology
54TH ANNUAL MEETING
Pennsylvania Convention Center Philadelphia December 6-10, 2014
■
in Philadelphia together with the International Federation for Cell
Biology, an event that will have a very strong international focus
under the leadership of one of ASCB’s greatest champions of international outreach, President Jennifer Lippincott-Schwartz. Of special
interest this year, points out Executive Director Stefano Bertuzzi, is a
special session co-organized by the International Affairs Committee
and the Women in Cell Biology Committee that will explore the role
and the challenges of women in science in different countries. “This
is an event not to be missed by men or women,” Bertuzzi enthuses.
In the recent past, ASCB has strengthened its relationship
with several European organizations, such as EMBO, as well as
the French Society of Cell Biology, at whose 2013 conference on
imaging ASCB sponsored speaker Derek Toomre of Yale University,
and the German Society for Cell Biology, at whose annual meeting
ASCB sponsorship enabled 2013 Kaluza Prize Winner Tina Han
to present the award-winning research she did at the University
of Texas Southwestern Medical Center. These are small steps
geared, Bertuzzi notes, toward promoting exchanges and engagement among organizations in the same field. ASCB was also a
sponsor of the Seventh Congress of the Asia-Pacific Organization
for Cell Biology (APOCB), which was held in Singapore in February 2014. The next APOCB meeting will be in India in 2018, and
ASCB is planning a higher level of engagement with that event.
“Finally, during the summer Yixian Zheng and I traveled to
China,” says Bertuzzi, “where we met with top leaders in cell
biology, biophysics and other basic sciences. The economies of
East, Southeast and South Asia—including China, India, Japan,
Malaysia, Singapore, South Korea and Taiwan—have been greatly
expanding their investments in science, and in 2011 accounted
for 34 percent of global research and development investments.
These international activities and many others are the concrete
implementation of ASCB’s interest in international collaboration.”
Graduate School Fair
PHILADELPHIA—ASCB is holding its annual Graduate School Fair
from 12:30 p.m. to 2:30 p.m. on Saturday, Dec. 6, 2014, in the
Grand Hall of the Pennsylvania Convention Center. ASCB invites
you to represent your institution (whether U.S. or international)
at the Graduate School Fair. The hall will be open at 9 a.m. on
Saturday, Dec. 6, for setup. The tables will be arranged alphabetically by school. Participants will also have two chairs and free
WiFi, though no electric or poster boards are available. Also, fair
exhibitors may bring laptop presentations, giveaways, brochures,
table coverings, etc. It is “quite an informal event,” the organizers
emphasize. Cost is $100 per institution.
Brand new for 2014—
the ASCB Learning Center
PHILADELPHIA—The exhibit floor as you know it is gone, ASCB
states, announcing that “It’s time to interact in a whole new way.
Be a part of the newest and most innovative interactive exhibitor
community—The ASCB Learning Center,” which will be open from
9:30 a.m. to 4:30 p.m. Sunday, Dec. 7, through Tuesday, Dec. 9.,
and will be populated by approximately 1,200 exhibitors. Morning
and afternoon refreshment breaks will be provided Sunday through
Tuesday from 9:30 a.m. to 11:30 a.m. and noon to 4 p.m., with a
cash bar available.
A new universality
in cell biology
Engineering, physics,
computational
modeling and
quantitative methods
are all part of this year’s
ASCB special sessions
BY LLOYD DUNLAP
PHILADELPHIA—It is not by chance that
the American Society for Cell Biology’s
54th ASCB Annual Meeting is co-hosted
this year by the International Federation
of Cell Biology (IFCB). Indeed not.
“You are a cell biologist, whether you
think of yourself that way or not,” notes
Wallace Marshall, chair of the Program
Committee for the 2014 ASCB Annual
Meeting. “Regardless of what field is
stamped on your union card, if you care
about cell biology, you need to go to the
ASCB Annual Meeting, which this year
is being held jointly with the International Federation for Cell Biology.”
Cell biology and disease
The field of cell biology is constantly
evolving, Marshall notes, “and an
important goal of the annual meeting
is to track new developments. In recent
years, there has been a growing appreciation of the role of cellular dysfunction in diseases. Studies at the interface
of medicine and cell biology have shed
important light on both fields, and so for
the past several years the ASCB Annual
Meeting has devoted special attention
to highlighting the cell biological basis
of disease and medicine.”
“At this year’s ASCB/IFCB meeting,
we will continue this trend in two ways,”
Marshall observes. “First, we will have
a special bench-to-bedside panel discussion on translation of cell biological
discoveries to the understanding and
treatment of disease. Second, we have
included disease experts as organizers of
many of the sessions, and these experts
B. KRIST FOR VISIT PHILADELPHIA
A new level of international engagement
BETHESDA, Md.—This year ASCB will be hosting its annual meeting
■
Opened in June 1993, the Pennsylvania Convention Center in Philadelphia will play
host to the 2014 annual meeting of the American Society for Cell Biology in December.
will help stimulate thinking about disease connections across the full spectrum of cell biological topics.”
“Another emerging trend in cell
biology is the constantly increasing
importance of quantitative concepts
and approaches,” he adds. “The living
cell is an emergent phenomenon, produced by the mutual interaction of huge
numbers of molecules. The only way to
begin to understand how such a complex system assembles and functions is
to harness the same tools and conceptual approaches that have proven useful
in engineering and physics.”
In recent years, Marshall notes, the
importance of computational modeling and quantitative methods has been
emphasized in special sessions, such as
ones on mathematical modeling.
“But having one or two special sessions
on quantitative thinking also creates a sense
that this is a different way of approaching
cell biology, perhaps as a supplement to ‘real’
cell biology,” he says. “Indeed, I attended one
session on the role of modeling in which it
was implied that models are something to be
added onto the end of a cell biology paper to
increase publishability, much as a piece of
parsley may be added as a garnish to a steak
dinner. In my humble opinion, this approach
is completely backwards and misses the most
important value of a model, that it can be
used to help design the experiments from the
outset of a project.
“So this year, rather than isolating modeling and quantification in their own separate compartment, like toxic enzymes to be
sequestered in the lysosome, we decided to
let quantitative and physical sciences pervade
the entire meeting by appointing quantitative cell biologists to co-chair many of the
minisymposium sessions.”
Marshall explains that to balance the tasks
of increasing coverage of disease and quantitative biology, while retaining the traditional
core topics of cell biology, they assembled a
tripartite Program Committee, consisting of
a “core” subcommittee (Mohan Balasubramanian, Magdalena Bezanilla, Orna Cohen-Fix,
Ana Maria Cuervo, Beatriz Fontoura, Cynthia
Jensen, Franck Perez, William Prinz, Lois
Weisman, Mark Winey, Richard Youle and
Xiaodong Wang); a “cell biology and disease”
subcommittee (Helen Blau, Catherine Dulac,
Tom Misteli, Gregory Pazour, Jody Rosenblatt and Marino Zerial); and a “physical
and quantitative cell biology” subcommittee (Marileen Dogterom, Aki Kusumi, David
Odde and Jitu Mayor).
“Keeping all the conference calls between
these groups organized was only possible
through the tireless efforts of ASCB’s Meeting and Abstracts Manager Alison Harris,”
he adds. “Three other participants deserve
special mention. ASCB President Jennifer
Lippincott-Schwartz and Executive Director
“We are truly blessed in
our field to have a single
unifying event each year
that brings us all together
in one place. The tradition
of a single, recurring
meeting in cell biology that
has now been running for
54 years helps to create a
group identity. This is
particularly important for
cell biology, an inherently
interdisciplinary field that
has historically drawn on
methods and concepts
from a wide range of
disciplines, including
molecular biology,
cytology, genetics,
microscopy and physics.”
Wallace Marshall, program
chair for the 2014 ASCB
Annual Meeting
ASCB ANNUAL MEETING 2014
NOVEMBER 2014 | | DDNEWS 33
R. KENNEDY FOR VISIT PHILADELPHIA
For more information, visit www.DDN-News.com
In the warmer months, people love to hang out in Rittenhouse Square, where they can grab a seat on a coveted bench or a shady spot on the
grass. Popular park activities include picnicking, reading, socializing, dog walking, Frisbee throwing and, of course, people-watching.
Stefano Bertuzzi never failed to offer their
own insights and perspectives, which we
found invaluable as we grappled with difficult decisions about topics and organization.
In addition, Cynthia Jensen of the IFCB has
been one of the most active participants in
all of our conference calls and has played an
invaluable role in helping to organize this
joint meeting.”
Four reasons
to attend ASCB 2014
“First of all,” the ASCB’s program chair
emphasizes, “you need to go to the meeting
because it is simply the most efficient way to
learn about the latest thinking, methods and
results in the field. Whether you are an established investigator or someone just starting
out, you need to have access to this cuttingedge information.”
“The ASCB Annual Meeting was the first
scientific conference I ever attended,” Marshall continues. “I had been in graduate
school only a couple of years, and as an electrical engineer who had become interested
in living cells, I had the sense that many of
my classmates had some outside source of
information about cell biology that I didn’t
have access to. Gradually it emerged that this
magic source of information was the ASCB
Annual Meeting. So that year I signed up for
the meeting and showed up with my poster. It
was like a window onto a whole wider world
had been opened. Now I could see the people
whose papers I had been reading, hear them
discussing their latest results in their own
words and even have the chance to talk about
my own science with these same individuals when they came to my poster. I haven’t
missed a single ASCB Annual Meeting since.
I make sure to go every year because I can’t
afford to miss it, and neither can you.”
Second, he says, “We are truly blessed in
our field to have a single unifying event each
year that brings us all together in one place.
The tradition of a single, recurring meeting
in cell biology that has now been running
for 54 years helps to create a group identity.
This is particularly important for cell biology,
an inherently interdisciplinary field that has
historically drawn on methods and concepts
from a wide range of disciplines, including
molecular biology, cytology, genetics, microscopy and physics.”
Third, he notes, ASCB has a strong tradition of providing mentoring and career support for its members, especially students and
postdocs. Again this year, the meeting will
include a Professional Development thread
comprising a host of activities that can help
attendees get jobs or enhance their careers.
These activities include a grant writing workshop, scientific career panels, one-on-one CV
review, sessions on international training and
funding opportunities, career discussion and
mentoring roundtables, and much more.
“Finally, the ASCB as a society fights for
science funding and helps all of us through its
advocacy, outreach and career development
activities,” Marshall points out. “The Annual
Meeting provides a focal point for regrouping
and discussing where these efforts are going.
By attending the meeting you have access to
workshops and special sessions in a range of
important issues and topics. This is the best
time and place to make your voice heard in
guiding the future of the field and shaping
its role in society.”
“On the whole,
I’d rather be in Philadelphia”
The subhead above comes to us by way of
late, great performer W.C. Fields when he
was contemplating his eventual death; also,
movies like “Rocky” depict Philadelphia as
a gritty, tough city, but this image belies the
architectural beauty, cultural diversity and
rich history of one of America’s oldest cities.
Within cell biology, Philadelphia has long
been a research hub, and that continues to be
the case today. In that respect, there are few
more appropriate cities for the ASCB/IFCB
meeting. But if you are attending, you might
want to ensure getting there early, because
Saturday starts the meeting with memberorganized special interest sessions. These
intense sessions feature topics and speakers
selected by the people who know cell biology
best—the members of ASCB.
That night at 6 p.m., keynote talks from
Steven W. Squyres and Robert M. Hazen will
offer a panoramic view of reality that spans
the history of the cosmos to the origin of life.
Special award talks from Keith Porter Lec-
turer Michael Sheetz and E.B. Wilson Medalists Bill Brinkley, John Heuser and Peter
Satir will cap the program on Sunday and
Tuesday evenings. But while these special
talks will be exciting and thought-provoking,
another important reason to go to a meeting is to learn detailed information that can
help you in your own research. And for this
purpose you just can’t beat posters. Posters provide the best way to learn the most
cutting-edge information from the people
actually doing the work and to engage in
a back-and-forth discussion that is usually
not possible just before, during or after lectures, no matter how interactive the format
of some of them. Posters are the heart of any
serious meeting, and this has always been
particularly true at ASCB.
In recognition of the importance of posters, this year ASCB has carefully structured
the meeting schedule to ensure that everyone
has plenty of opportunity to view them and
meet the presenters. The former concept of
the exhibit hall has been transformed into the
ASCB Learning Center, and from noon to 3
p.m., Sunday through Tuesday, all meeting
activities will take place there. Poster presentations and ePoster talks are scheduled
for that time slot. This will also provide an
opportunity to interact with the exhibitors,
who have been encouraged to provide attendees with a variety of learning experiences,
not just “sales pitches.” Visit the exhibits and
attend their tech tutorials and tech showcases to learn about the latest advances that help
move cell biology forward. Between the posters and exhibits, Marshall insists, you really
can learn a lot in the ASCB Learning Center.
Each day the posters are augmented with
symposia and minisymposia on a range of
topics that span all of cell biology.
Between the special talks, workshops,
posters, symposia and minisymposia, think
of the ASCB/IFCB meeting as an all-you-caneat buffet of cell biology for your mind to
feast on—after all, Philly is famous for some
signature eating options, like cheesesteaks
and soft pretzels, among its many other
features. But they probably won’t help your
career along as well as the ASCB/IFCB fare
will. ■
EDITCONNECT: E111428
34 DDNEWS | | NOVEMBER 2014
ASCB ANNUAL MEETING 2014
For more information, visit www.DDN-News.com
Keynote speakers
will span the origin
of life to the cosmos
Carnegie Institution of Science
and Deep Carbon Observatory
Dr. Hazen is a research scientist at the Carnegie Institution of Washington’s Geophysical
Laboratory and Clarence Robinson Professor of
Earth Science at George Mason University. He
received degrees in geology at the Massachusetts Institute of Technology in 1971 and a Ph.D.
at Harvard University in earth science in 1975.
After studies as NATO Postdoctoral Fellow at
Cambridge University in England, he joined the
Carnegie Institution’s research effort.
Hazen is the author of more than 350
articles and 20 books on science, history and
music. A Fellow of the American Association for the Advancement of Science, he has
received the Mineralogical Society of America
Award (1982), the American Chemical Society Ipatieff Prize (1986), the ASCAP Deems
Taylor Award (1989), the Educational Press
Association Award (1992), the Elizabeth
Wood Science Writing Award (1998) and the
Distinguished Public Service Medal of the
Mineralogical Society of America (2009).
Hazen’s recent research focuses on the role of
minerals in the origin of life, including such
processes as mineral-catalyzed organic synthesis and the selective adsorption of organic
molecules on mineral surfaces. He has also
developed a new approach to mineralogy,
called “mineral evolution,” which explores the
co-evolution of the geosphere and biosphere.
In addition to his mineralogical research,
he is principal investigator of the Deep Carbon Observatory, which is a 10-year international effort to achieve fundamental advances
in understanding the chemical and biological
roles of carbon in Earth’s interior.
Some of Hazen’s books, such as The Music
Men, Wealth Inexhaustible and Keepers of the
Flame—all three co-authored with his wife,
Margaret Hindle Hazen—explore ties between
technology and culture. The Breakthrough, The
New Alchemists, Why Aren’t Black Holes Black,
The Diamond Makers and Genesis describe the
forefront of scientific research. He has also
written widely for popular audiences, including articles in Newsweek, Scientific American,
Smithsonian Magazine, New Scientist and The
New York Times Magazine. He appears frequently on radio and television programs on
science, and he developed two popular video
Visitors and locals use the Phlash to get to the city’s historic and cultural attractions easily and
quickly. From May until Labor Day, the big purple bus transports people every day, every 15
minutes from 10 a.m. to 6 p.m., and then it runs on weekends until December 28. The Phlash is
$2 per ride or $5 for an all-day pass, and its more than 20 stops are conveniently located near
popular places—Independence Visitor Center, Independence National Historical Park,
Philadelphia Museum of Art, Penn’s Landing, Reading Terminal Market, Pennsylvania
Convention Center, Philadelphia Zoo and Please Touch Museum.
courses: The Joy of Science and The Origins of
Life, both produced by The Teaching Company.
In addition to his scientific activities,
Hazen is a professional trumpeter. He is
presently a member of the National Philharmonic, the Washington Bach Consort and the
National Gallery Orchestra.
Steven W. Squyres
James A. Weeks Professor
of Physical Sciences
Dr. Squyres’ research focuses on the robotic
exploration of planetary surfaces, the history
of water on Mars, geophysics and tectonics
of icy satellites, tectonics of Venus, planetary
gamma-ray and X-ray spectroscopy. Research
for which he is best known includes study of
the history and distribution of water on Mars
and of the possible existence and habitability
of a liquid water ocean on Europa.
From 1978 to 1981 he was an associate of the
Voyager imaging science team, participating in
analysis of imaging data from the encounters
with Jupiter and Saturn. He was a radar investigator on the Magellan mission to Venus, a member of the Mars Observer gamma-ray spectrometer flight investigation team and a co-investigator on the Russian Mars 96 mission. Squyres
is currently the scientific principal investigator
for the Mars Exploration Rover Project. He is
also a co-investigator on the Mars Express mission and on the Mars Reconnaissance Orbiter’s
High-Resolution Imaging Science Experiment.
He is a member of the Gamma-Ray Spectrometer Flight Investigation Team for the Mars
Odyssey mission and a member of the imaging
team for the Cassini mission to Saturn.
His scientific publications include “The Athena Mars rover science investigation,” “The Spirit
rover’s Athena science investigation at Gusev
Crater, Mars,” “In-situ evidence for an ancient
aqueous environment at Meridiani Planum,
Mars,” “The Opportunity rover’s Athena science
investigation at Meridiani Planum, Mars,” “Sedimentary rocks at Meridiani Planum: Origin,
diagenesis and implications for life on Mars,”
“Rocks of the Columbia Hills,” “Two years at
Meridiani Planum: Results from the Opportunity rover,” “Overview of the Opportunity Mars
Exploration Rover mission to Meridiani Planum:
Eagle Crater to Purgatory Ripple,” “Detection of
silica-rich deposits on Mars” and “Exploration
of Victoria Crater by the rover Opportunity.” ■
M. FISCHETTI FOR VISIT PHILADELPHIA
Robert M. Hazen
J. FUSCO FOR VISIT PHILADELPHIA
this year’s ASCB meeting, keynote speakers Robert M.
Hazen and Steven W. Squyres bring career-long research
specialties in the origins of life and exploration of space.
“Mineral evolution, mineral ecology and the co-evolution of life and rocks” will be the subject of Hazen’s address, while “The
habitability of Mars as revealed by the Mars Exploration Rovers Spirit
and Opportunity” will be discussed by Cornell University’s Squyres. The
keynote talks occur on the evening of the meeting’s opening day, Saturday, Dec. 6, at 6 p.m. The event will be followed by an opening night
reception and the International Research and Training Exchange Fair.
Philadelphia’s Love Park turns into a fun, alfresco and medieval shopping extravaganza when the
German-style Christmas Village takes over each holiday season. More than 50 decorated booths
showcase international seasonal gifts, traditional German Christmas ornaments, jewelry and highquality arts and crafts. Hot mulled wine, gingerbread and bratwursts add to the festive atmosphere.
J. VARNEY FOR VISIT PHILADELPHIA
U
NDERSCORING THE MULTIDISCIPLINARY FOCUS OF
Introduced to the region by German (“Pennsylvania Dutch”) settlers in the 18th century,
pretzels—dough twisted into three loops, then baked, salted and served hard—quickly became a
favorite local snack. Now, of course, there’s the famous Philly soft pretzel, purchased from street
vendors or from bakery storefronts such as the Philly Soft Pretzel Factory. No matter what form
the pretzel takes—braided, sticks, nuggets and bagels—it’s often accompanied by mustard.
For more information, visit www.DDN-News.com
NOVEMBER 2014 | | DDNEWS 35
DIAGNOSTICS
SAN DIEGO—Illumina Inc. and four leading cancer
centers have established the Actionable Genome
Consortium (AGC), an initiative that will recommend
openly published standards for widespread use of
next-generation sequencing to aid in treatment decision for cancer patients. Specifically, the AGC will
aim to define the principles and content of the “cancer actionable genome,” a comprehensive description of genomic alterations that define individuals’
tumors. The founding members include, other than
Illumina, the Dana-Farber Cancer Institute, Fred
Hutchinson Cancer Research Center, MD Anderson
Cancer Center and Memorial Sloan Kettering Cancer
Center. The AGC will publish a list of actionable
events—including best practices regarding biopsy
samples, performance standards for sequencing,
guidelines for clinical reports and standards for
genetic variants—and include a research arm for
collaborative, cross-institutional projects regarding
leading challenges in molecular oncology.
Rockland receives SBIR grant
LIMERICK, Pa.—The National Institutes of Health’s
National Heart, Lung and Blood Institute has
awarded Rockland Immunochemicals Inc. a
Small Business Innovation Research grant worth
$224,473 for the development of an antibodybased point-of-care device for diagnosing sickle
cell disease (SCD). Early detection can mitigate
the risk of life-threatening infections and increase
survival, but there are currently no simple tests
capable of differentiating patients with the sickle
cell trait from sickle cell disease conditions.
“Rockland’s antibody technology platform will
help to overcome these barriers tremendously.
We will create novel hemoglobin isoform-specific
antibodies and configure a lateral flow point-ofcare assay,” said Dr. Carl Ascoli, Rockland’s chief
science officer. “As a result of this project, the antibody-based lateral flow point-of-care device will
allow rapid and inexpensive diagnosis of sickle cell
disease in infants and young children in industrialized and low-income and low-resource settings.”
IN THIS SECTION
Diabetes
Metabolon taps Metdia for European
marketing of prediabetes tests .............. 35
Oncology
Advanced Cell Diagnostics
receives major NCI grant........................ 36
Proton therapy, oncology care ................ 35
Removing the ‘sword of Damocles’ ....... 35
Sequencing/Oncology
Industry leaders launch Actionable
Genome Consortium ............................... 35
Sickle cell disease
Rockland receives SBIR grant ................ 35
Metabolon taps Metdia for European
marketing of prediabetes tests
The collaboration includes
Metabolon’s Quantose IR
and Quantose IGT tests
BY KELSEY KAUSTINEN
RESEARCH TRIANGLE PARK, N.C.—Metabo-
lomics company Metabolon Inc. recently
inked a partnership with Spanish biomedical
company Metdia Biotech S.L. for the commercialization of Metabolon’s Quantose IR and
Quantose IGT prediabetes tests in Europe.
Under the collaboration, Metdia will market
the tests to hospital and clinical laboratories
in Spain, Portugal, France, Italy, the United
Kingdom, Germany, Switzerland, Sweden,
Norway, Denmark, Finland, the Netherlands,
Belgium and Austria. Financial details for the
partnership were not disclosed.
“Licensing our Quantose IR and Quantose
IGT technology to Metdia in Europe is an
important next step in expanding the availability of these obesity-related diagnostic
tests outside the U.S.,” Dr. John Ryals, president and CEO of Metabolon, commented in
CREDIT: METABOLON INC.
Industry leaders launch
Actionable Genome Consortium
Metabolon recently partnered with Spanish biomedical company Metdia Biotech for the
marketing of its prediabetes tests in Europe.
a statement. “We are confident in Metdia’s
broad knowledge of the molecular diagnostics market in Europe. Earlier this year,
Quantose IR became commercially available
in Mexico through Patia Biopharma, a leading Latin American diabetes public health
company. We are delighted to see our technology available to contribute to the health
of millions of people in these two major
markets.”
Prediabetes, according to the American
METABOLON CONTINUED ON PAGE 36
Removing
the ‘sword
of Damocles’
MetaSite Breast diagnostic test aims to
remove threat hanging over heads of
most breast cancer patients
BY LORI LESKO
MONTCLAIR, N.J.—Known for
its innovative technologies in
predicting systemic mestastasis
in cancer cases, life-sciences
company MetaStat Inc. has
announced positive results
from its MetaSite Breast test,
published online in the Journal
of the National Cancer Institute.
The study successfully indicated
the test could accurately predict
the probability of which breast
cancer patients need chemotherapy—and which patients do not.
Systemic metastasis—cancer
that spreads from a primary
METASTAT CONTINUED ON PAGE 37
CREDIT: IBA
BRIEFS
IBA focuses, in part, on the development and supply of
dosimetry solutions (pictured here) for quality assurance of
medical equipment and increased patient safety. The company
recently signed a global collaboration with Dutch company
Royal Philips to provide advanced diagnostic and therapeutic
solutions for the treatment of cancer.
Proton therapy,
oncology care
Although only 35 to 40 percent
of all breast cancers will ever
metastasize, almost 85 percent
of women with newly diagnosed
breast cancer are treated
with chemotherapy. MetaStat
hopes to spare women from
needless chemo with its
MetaSite Breast diagnostic.
IBA and Philips collaborate to personalize
cancer diagnosis and treatment
BY ILENE SCHNEIDER
ANDOVER, Mass.—IBA (Ion Beam Applications S.A.), a provid-
er of proton therapy and radiopharmacy solutions, and Dutch
company Royal Philips, a diversified health and well-being
company, signed a global collaboration to provide advanced
diagnostic and therapeutic solutions for the treatment of
IBA CONTINUED ON PAGE 37
36 DDNEWS | | NOVEMBER 2014
DIAGNOSTICS
For more information, visit www.DDN-News.com
Advanced Cell Diagnostics receives major NCI grant
Award will fund development
of proprietary in-situ RNA
detection technology
BY JIM CIRIGLIANO
HAYWARD, Calif.—The U.S. National Can-
cer Institute (NCI) has awarded a two-year,
$1.4-million grant under its Small Business
Innovation Research Phase II Program to
Advanced Cell Diagnostics Inc. (ACD), a
company with a focus on in-situ nucleic acid
detection for life-sciences research and clinical diagnosis.
The grant will allow ACD, along with its
academic partner Cleveland Clinic, to work
toward the development and validation of
a diagnostic test based on the company’s
proprietary RNAscope technology for discriminating various B-cell non-Hodgkin
lymphomas (NHLs) from benign lympho-
proliferative diseases. The test would be
an important advance in diagnosing B-cell
lymphomas due to the shortcomings of conventional methods of establishing clonality
in the majority of NHLs.
“Reliable in-situ detection of any RNA
in routine clinical specimens has been
an unmet need for over 40 years despite
many efforts and improvements,” says
Dr. Xiao-Jun Ma, chief scientific officer
of ACD. “Traditional RNA in-situ hybridization (ISH) techniques are limited to
the small fraction of highly expressed
genes, leaving 95 percent of the expressed
genes undetectable. ACD’s RNAscope
technology addresses the need of detecting that 95 percent of the transcriptome.”
RNAscope is said to be the first automated
multiplex chromogenic and fluorescent insitu hybridization platform capable of detect-
CREDIT: ACD
“Developing and
validating an RNAscopebased diagnostic test is
similar to that of the
more familiar PCR or
IHC-based assays. In
some ways, it is actually
simpler due to the
rapid assay development
time (new probes can be
had within two weeks)
and the assurance
of probe sensitivity
and specificity.”
Dr. Xiao-Jun Ma, chief
scientific officer of ACD
METABOLON
CONTINUED FROM PAGE 35
Diabetes Association (ADA), is characterized
by “blood glucose levels that are higher than
normal but not yet high enough to be diagnosed as diabetes.” It is sometimes referred
to as impaired glucose tolerance or impaired
fasting glucose.
Metabolon’s Quantose IR is a laboratorydeveloped test that reflects insulin resistance
based on insulin and three non-glycemic biomarkers. It can determine an individual’s risk
of progression to prediabetes earlier than traditional glycemic measures such as hemoglobin A1c. According to the ADA, the A1C test
measures a patient’s average blood glucose
over the past two to three months, with prediabetes diagnosed in the range of 5.7 to 6.4
percent and diabetes at 6.5 percent or higher.
Quantose IGT reflects the degree of
impaired glucose tolerance in a patient, which
is a core metabolic defect in dysglycemia and
a known risk factor for prediabetes. Quantose
IGT can be used as an alternative to an oral
glucose tolerance test or to determine patients
who may be candidates for such a test.
Eric Button, senior vice president of diagnostics at Metabolon, says this is the first
time the companies have worked together. It
is a sensible partnership, though, as Metdia
is focused on providing disruptive technolo-
ing and quantifying RNA biomarkers in situ
at single-molecule sensitivity.
A prime example of the potential of the
RNAscope technology is in the detection
of Ig kappa/lambda light chain mRNAs,
which are expressed at extremely low levels
in most B-cell lymphomas, falling into the
undetectable 95 percent category for conventional techniques. Clinical laboratory
detection of Ig light chain restriction (LCR)
is a helpful tool in the differential diagnosis
that includes lymphoid hyperplasia, atypical
lymphoid hyperplasia, chronic inflammation
and B-cell neoplasia.
When fresh tissue is available for examination, LCR can be readily detected as an
abnormal kappa/lambda surface immunoglobulin ratio using flow cytometry. However
these samples are often unavailable in many
clinical settings. Existing solutions, including chromogenic in-situ hybridization and
immunohistochemistry (IHC), only address
a small fraction of B-cell lymphomas, such
as multiple myelomas and those lymphomas
with plasmacytic differentiation. ACD’s assay
reportedly will be applicable to essentially all
B-cell lymphoma variants.
“This breakthrough is achieved through a
proprietary probe design and signal amplification strategy that allows robust signal
generation for true target detection but not
for nonspecific background,” says Ma. “This
is in contrast to previous efforts focusing
mainly on signal enhancement and little on
the background problem.”
“Developing and validating an RNAscopebased diagnostic test is similar to that of the
more familiar PCR or IHC-based assays,” he
notes. “In some ways, it is actually simpler
due to the rapid assay development time
(new probes can be had within two weeks)
and the assurance of probe sensitivity and
specificity.”
“The biggest challenge may be that we
need to be more vigilant about how samples
are fixed and processed since we are detecting RNA, which is more labile than DNA and
protein,” Ma says. “We have developed our
technology to be compatible with established
standards such as CAP/ASCO guidelines for
clinical sample preparation. We also strongly
recommend the inclusion of positive and
negative control probes in the assay to assess
RNA adequacy and sample quality. In our
experience, most routinely processed clinical specimens, including archival materials
that are more than 10 years old, are adequate
for RNAscope staining.”
Cleveland Clinic will provide their expertise in pathology and clinical medicine to
guide the development and validation of the
assay to help to ensure the final product is
well-validated and suited for everyday clinical use by pathologists. Cleveland Clinic will
also provide access to patient samples and
corresponding reference data generated by
standard of care testing.
The Small Business Innovation Research
grant is a highly competitive program that
encourages domestic small businesses to
engage in research and development that
holds promise for commercialization. ACD
had previously received a one-year Phase I
grant and completed the project in 2013,
which made it eligible to apply for Phase II
funding. The Phase II award will be applied
to expenses to cover personnel, materials and
supplies and facilities related to the proposed
research.
“This award is a further validation of the
clinical utility of RNAscope technology,” Dr.
Yuling Luo, president and CEO of ACD, said
in a news release announcing the receipt
of the grant. “We are very pleased that NCI
has recognized the diagnostic potential of
RNAscope technology and are grateful for
its continued support.” ■
EDITCONNECT: E111423
“To stem the tide of the prediabetes/diabetes epidemic, we must get
ahead of the development of these conditions and focus on prevention.
That’s where Quantose IR comes in. The test is a tool that provides
information to physicians, so they can identify at-risk patients and
take steps to prevent the development of prediabetes and diabetes.”
Eric Button, senior vice president of diagnostics at Metabolon
gies and devices for the prevention, diagnosis
and treatment monitoring of prediabetes and
diabetes.
“Diabetes is a significant global health concern, and the costs to society are high and
growing rapidly,” Oscar Rodríguez, director
of Metdia Biotech, said in a news release.
“According to the International Diabetes
Federation, more than 55 million adults in
the European Region are coping with diabetes
every day. Another 66 million have impaired
glucose tolerance, a known risk factor for prediabetes. Tests using Metabolon’s Quantose
technology provide cost-effective assessment
tools that help physicians identify patients
with prediabetes and monitor the impact of
therapeutic interventions. If prediabetes is
caught early, physicians can prescribe treat-
ment that might prevent progression to type
2 diabetes.”
Diabetes numbers in the United States
aren’t any better. The U.S. Department of
Health and Human Services estimated that
approximately 86 million adults in the United States ages 20 and up had prediabetes in
2012, while the ADA reports that 29.1 million
Americans (9.3 percent of the population)
had diabetes.
Button adds that “90 percent of people
with prediabetes do not know they have it,”
which is a serious concern, seeing as how the
condition increases someone’s risk of not just
type 2 diabetes, but also heart disease and
stroke. Fortunately, if the condition is caught
early, steps can be taken to avoid the development of diabetes; the ADA reports that an
individual with prediabetes can lower their
diabetes risk by 58 percent by losing 7 percent
of their body weight and exercising moderately for 30 minutes a day, five days a week.
The fact that early intervention can increase
a person’s chances of avoiding a decline into
diabetes provides significant support for tests
like Metabolon’s.
“To stem the tide of the prediabetes/diabetes epidemic, we must get ahead of the
development of these conditions and focus
on prevention,” Button tells DDNews. “That’s
where Quantose IR comes in. The test is a
tool that provides information to physicians,
so they can identify at-risk patients and take
steps to prevent the development of prediabetes and diabetes.” ■
EDITCONNECT: E111420
DIAGNOSTICS
For more information, visit www.DDN-News.com
METASTAT
CONTINUED FROM PAGE 35
tumor through the bloodstream to other
areas of the body—is responsible for about
90 percent of all solid tumor cancer-related
deaths, according to Dr. Oscar Bronsther,
MetaStat CEO.
Being able to predict the probability of systemic metastasis allows doctors to better customize cancer treatment decisions by identifying patients with a high-risk of systemic
metastasis who need aggressive therapy, and
sparing patients with a low-risk of systemic
metastasis from the harmful side effects and
expense of chemotherapy, Bronsther said.
“Some 240,000 women are newly diagnosed with breast cancer every year in America,” Bronsther tells DDNews. “Virtually all
will have their tumors surgically removed.
That is the first step in their journey. What
comes after that is answering the question of
whether there is a need for chemotherapy,
traditionally used to prevent cancer from
spreading through the rest of the body.”
“Because we lack a good (approved) cancer
diagnostic, we lack the ability to effectively treat
women with no progression or mestastasis at
all,” he adds. “If we had a test right up front …
that would tell a woman with breast cancer
whether the risk of mestastasis was nearly zero.
Then the sword of Damocles wouldn’t have to
hang over her head for a decade.”
If oncologists had access to MetaSite
Breast, its diagnostic ability could dramatically improve lives and give the future back
to most breast cancer survivors, Bronsther
says, because only 35 to 40 percent of all
breast cancers will ever metastasize. Unfortunately, at present “almost 85 percent of
women with newly diagnosed breast cancer
are treated with chemotherapy. Yet, only a
fraction of these patients can actually benefit
from chemotherapy, because only a fraction
of these tumors have the biological potential
to spread through the bloodstream,” he notes.
A complete course of chemotherapy is
extremely expensive and, more importantly,
takes at least six months and is associated
with significant morbidity and a small mortality, he says. Thus, “Having the ability to
identify those patients whose tumors are
unlikely to metastasize, we can therefore
spare those patients the complications.”
The journal paper, titled “Tumor Microenvironment of Metastasis and Risk of Distant
Metastasis of Breast Cancer,” states how the
MetaSite Breast test, a diagnostic assay that
quantifies the number of “tumor microenvironments of metastasis” (TMEM) in tumor
specimens, showed a strong and statistically
significant association with the risk of distant
spread—or metastasis—for the most common type of breast cancer.
The test performed well at assessing metastasis risk for the study’s most populous cancer
subgroup: women with estrogen receptorpositive (ER+)/ HER2/Neu-negative (HER2-)
disease (i.e., their cancer cells possess estrogen receptors but lack HER2 protein).
Women with ER+/HER2- disease account
for approximately 60 percent of all cases of
breast cancer, according to the study. When
women with this common type of breast cancer were divided into three groups based on
their TMEM scores, the risk of distant metastasis turned out to be 2.7 times higher for women
with tumors in the highest-scoring TMEM or
MetaSite group compared with women with
tumors in the lowest-scoring group.
The findings confirmed results from a
smaller study of the test involving 30 pairs of
biopsy specimens that was published in 2009.
For comparison, TMEM predictions were
compared on the same tumor samples to
predictions from the IHC4 test, a diagnostic
that assesses risk of recurrence by measuring
levels of several proteins (ER,PR, HER2 and
Ki-67) involved in tumor cell proliferation
and response to hormone therapy in breast
tumor tissue, the journal study reported.
As for assessing metastatic risk in the
study’s most common type of breast cancer
(ER+/HER2-), “TMEM results were highly
statistically significant, while IHC4 scores
were borderline significant at best,” the study
stated. “MetaStat believes this is due to its
unique understanding of the mechanics and
the function-based processes of tumor cell
migration and entry into the bloodstream.”
MetaStat is currently developing a commercially viable version of the MetaSite Breast
test with automated systems to facilitate rapid
repeatable implementation in a high-throughput clinical lab setting, Bronsther says.
“We are thrilled to see additional positive
validation of the MetaSite Breast test,” Bronsther stated in a news release. “We believe it
confirms the path-breaking approach that our
function-based diagnostics, based on the biology of the mena protein and its isoforms, provide an understanding in cancer metastasis.”
“We believe our suite of breast cancer diagnostic tests, comprised of MetaSite Breast
and MenaCalc, will offer women and their
oncologists highly prognostic and actionable
information,” Bronsther continued. “These
diagnostic tests aim to empower patients
with the information they seek to create the
most personal and appropriate approach to
their unique tumors.”
MetaStat plans on commercializing its
suite of breast cancer diagnostics in December 2015 or January 2016, based on CLIA and
GLP certification. The company’s commercialization efforts will be headed by Heiner
Dreissman, former president and CEO of
Roche Molecular Systems. ■
EDITCONNECT: E111421
NOVEMBER 2014 | | DDNEWS 37
IBA
CONTINUED FROM PAGE 35
cancer. No finite timing has been set,
and both IBA and Philips see this as an
enduring collaboration.
IBA’s proton therapy solutions are
scalable and adaptable, offering universal full-scale proton therapy centers as
well as next-generation compact, singleroom solutions. IBA also focuses on the
development and supply of dosimetry
solutions for quality assurance of medical equipment and increased patient
safety as well as particle accelerators for
medical and industrial applications. Royal
Philips offers products in the areas of cardiac care, acute care and home healthcare, energy-efficient lighting solutions
and new lighting applications, as well as
grooming and oral healthcare products.
According to Olivier Legrain, CEO of
IBA, the two companies have been partners for some time, working together to
improve the patient experience of proton
therapy. As he explained, “This new collaboration was a natural next step for both IBA
and Philips, allowing the two companies
to exploit their leading positions in proton therapy and image guidance systems
to provide advanced diagnostic and therapeutic solutions for the treatment of cancer. The collaboration aims to transform
cancer care and will provide clinicians with
more efficient, effective and personalized
treatment for their patients, while also
dramatically reducing the time to start of
treatment and the cost of that treatment.”
The collaboration covers sales, marketing and research and development
of imaging and therapy solutions in
oncology. By merging their respective
expertise, IBA and Philips plan to innovate with an integrated vision for more
efficient, personalized cancer care. The
companies believe that leveraging highquality imaging and proton therapy offers
Cambridge Healthtech Institute’s 14th Annual
the potential to increase confidence in the
diagnosis and treatment of cancer, reduce
short- and long-term side-effects and
potentially enhance the quality of life of
the patient before, during and after treatment, while reducing costs.
Additionally, the collaboration will
enable both organizations to mutually
leverage technologies and solutions: IBA
will benefit from Philips’ diagnostic imaging products offered to oncology care centers, while Philips will leverage IBA proton therapy solutions within its offering
for customers in select markets around
the world. The commercial collaboration
also includes an integrated offering for
Molecular Imaging Centers, combining
IBA’s expertise in PET radioisotope production centers with Philips’ imaging and
diagnostics expertise.
Gene Saragnese, executive vice president
and CEO of imaging systems at Royal Philips, added, “Proton therapy is one of the
most exciting technological advancements
in the oncology field. We look forward to
collaborating with IBA to enhance access
to best-in-class technology for both Proton
Centers and Molecular Imaging Centers,
as well as to accelerate the development
of our informed therapy guidance vision
in ways that can change the future of care,
and improve the quality of life for patients.”
Legrain concludes, “This is an exciting
and important step for IBA. A closer collaboration with a company of Philips’ caliber and global reach, where we are able to
combine both companies’ expertise and
excellence in oncology care, will accelerate
innovation and provide more efficient and
effective solutions in molecular imaging and
treatment solutions. This collaboration is an
important step toward adaptive treatment
of cancer and a personalized treatment
approach to enable the best possible result
for cancer patients across the globe.” ■
EDITCONNECT: E111422
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NOVEMBER 2014 | | DDNEWS 39
BUSINESS &
GOVERNMENT POLICY
BRIEFS
Genisphere reaches
collaboration goal
HATFIELD, Pa.—Genisphere LLC recently achieved
its goal for 2014 of 25 collaborations in targeted
drug delivery, a number that includes collaborative
research projects with 17 investigators in 11 institutions. The company is shifting its focus to the use
of its 3DNA nanoparticles as a drug delivery platform, and it says it is currently the only commercial
source of DNA-based nanocarriers. Its first research
collaboration with MultiCell Technologies Inc. was
announced last year to investigate the use of the
3DNA platform for targeted delivery of MultiCell’s
MCT485 for primary hepatocellular carcinoma.
“To date, proof-of-concept preclinical data
have demonstrated specific targeting of tumors,
selective killing of targeted cells, tumor shrinkage
and no observed toxicity,” said Bob Getts, chief
science officer at Genisphere.
NeoStem licenses
Rockefeller University patents
NEW YORK—NeoStem Inc. and The Rockefeller University have begun an exclusive license agreement
for patented technologies that expand NeoStem’s
IP portfolio for its Targeted Cancer Immunotherapy
Program. The patents that NeoStem has licensed
are titled “Methods for use of Apoptotic Cells to
Deliver Antigen to Dendritic Cells for Induction or
Tolerization of T Cells.”
“By licensing these patents that relate to
NeoStem’s DC/TC (dendritic cell/tumor cell)
technology ... NeoStem continues to look proactively for opportunities to expand and defend its
technology platform as we simultaneously plan to
initiate our Phase 3 Intus clinical study that will
investigate our DC/TC technology in metastatic
melanoma this year,” said Dr. Andrew L. Pecora,
chief visionary officer at NeoStem.
IN THIS SECTION
Collaborations
Genisphere reaches
collaboration goal................................... 39
Licensing/Intellectual property
NeoStem licenses
Rockefeller University patents ............... 39
M&A activity
A ‘win-win’ in women’s health............... 39
AbbVie aborts plan to acquire Shire ...... 39
Horizon Discovery
acquires Sage Labs ................................ 42
Male health/M&A activity
Expanding the pipeline
(ENDO from cover) .................................. 42
Patent/Antitrust
District courts implement Supreme Court’s
Actavis decision...................................... 39
Tools and technology
On the cutting edge ................................ 40
A ‘win-win’ in women’s health
AMAG Pharmaceuticals to
acquire Lumara Health,
propelling company into
women’s health
of wooing, AbbVie and Shire came to a
roughly $55-billion agreement. But then,
in late September, the U.S. Department of
Treasury proposed unilateral changes to the
tax regulations designed to prevent or deter
U.S. companies from re-domiciling in other
countries—technically headquartering in
SHIRE CONTINUED ON PAGE 41
PATENT CONTINUED ON PAGE 40
Makena, one of the women’s health products
AMAG gains by acquiring Lumara, was
granted seven-year Orphan Drug exclusivity
in 2011 as the only FDA-approved product
indicated to reduce the risk of preterm birth in
women who are pregnant with one baby and
who have delivered one preterm baby
spontaneously in the past.
spontaneously in the past. Preterm birth is
defined as the delivery of a baby at less than
AMAG CONTINUED ON PAGE 41
AbbVie aborts plan
to acquire Shire
After U.S. tax officials begin to put up roadblocks
to inversion deals, deal falls apart
NORTH CHICAGO, Ill.—The IRS has claimed
its first victory with anti-inversion rules—or
perhaps its first victim, depending on your
perspective—in AbbVie with the scuttling
of an intended acquisition by the company
of Dublin, Ireland-based Shire plc.
It was just in August that, after months
L
AST TERM, the Supreme Court
in FTC v. Actavis overruled several Circuit Courts of Appeal
by holding that so-called
“reverse payment settlement
agreements” (RPSAs) in Abbreviated
New Drug Application (ANDA) litigation were not presumptively legal under
antitrust law so long as the licensed
rights were within
the “scope of the patent” exclusivity. The
Court opined that
some agreements
might be antitrust
violations without
regard to the extent
Kevin Noonan,
of patent protection partner,
(or even without McDonnell
regard to issues of Boehnen
patent validity and Hulbert &
enforceability)—for Berghoff LLP
example, when “disproportionately
large” reverse payments were involved.
Ever since the Federal Trade Commission won this partial victory (having in
the past contended that RPSAs were per
se illegal), the FTC and private litigants
have been trying to extend antitrust
scrutiny beyond the bounds of the limits set by the court. The most common
such attack has been on RPSAs having
non-monetary components, such as
so-called “authorized generics,” where
the branded drug maker agrees not to
introduce its own generic version into
the marketplace, or where the branded
drug maker agrees to permit a particular generic manufacturer to provide or
purchase active pharmaceutical ingredients to be used in generic versions of the
branded drug. These efforts have met
with varying degrees of success, with
some district courts permitting these
arrangements to be subjected to antitrust scrutiny and others rejecting the
extension of the court’s precedent. The
most recent instance has been in a New
Under the terms of the original acquisition agreement, Shire is entitled to a break fee of
approximately $1.64 billion, payable by AbbVie, if AbbVie stockholders do not approve the
adoption of the merger agreement at an AbbVie stockholder meeting or such a meeting does
not occur by Dec. 14, 2014.
BY JEFFREY BOULEY
by Kevin Noonan
District courts
implement
Supreme
Court’s Actavis
decision
BY LLOYD DUNLAP
WALTHAM, Mass.—AMAG Pharmaceuticals
Inc. has entered into a definitive agreement
to acquire Lumara Health Inc., a privately
held pharmaceutical company specializing
in women’s health, for $675 million ($600
million in cash and $75 million in stock)
and additional contingent consideration of
up to $350 million based on achievement of
certain sales milestones. Lumara Health also
announced recently that the company signed
a separate agreement to divest certain other
assets to a third party.
Lumara Health markets the fast-growing
product Makena (hydroxyprogesterone caproate injection), which was granted sevenyear Orphan Drug exclusivity in February
2011 and is the only U.S. Food and Drug
Administration (FDA)-approved product
indicated to reduce the risk of preterm birth
in women who are pregnant with one baby
and who have delivered one preterm baby
Patent Docs
BUSINESS & GOVERNMENT POLICY
40 DDNEWS | | NOVEMBER 2014
On the cutting edge
A roundup of instrumentation, software
and other tools and technology news
T
BY JEFFREY BOULEY
HIS TIME in our month-
ly Tools & Technology
roundup, we have on
tap massively parallel stem cells, rapid
and reproducible antibody/ antigen expression, a stem
cell growth matrix
and mass spec imaging of 3D microtissues.
However, as this is the
November issue and
not the December issue,
we have no lords a’leaping, golden
rings or partridges in pear trees.
productivity, significantly cutting
costs whilst accelerating the development of innovative therapies for
serious medical conditions.”
Dr. Yen Choo, Plasticell’s executive chairman and senior author
of the scientific paper, added:
“Optimizing laboratory methods to obtain
affordable, industrialized cell manufacturing
protocols is absolutely
key to the development
of cell therapies. The
paper describes a study in which
we used combinatorial screening
to obtain a 250-fold reduction in
cell bioprocessing costs, through
a 50-fold increase in cell yield
accompanied by a fivefold reduction in reagent costs via the use
of cell culture media comprising
small-molecule drugs.”
TOOLS &
TECHNOLOGY
Can Plasticell’s
massively parallel
approach help transform
regenerative medicine?
STEVENAGE, U.K.—Stem cell bio-
tech Plasticell Ltd. announced
recently the publication of scientific research which it says demonstrates how the company’s innovative high-throughput Combinatorial Cell Culture (CombiCult) technology allows a single scientist to
carry out 10,000 stem cell biology
experiments in parallel. The scientific paper points to the potential
of high-throughput technologies
“Discovery of robust
methods to differentiate
stem cells remains a
serious bottleneck for
the industry. This is a
major reason why only
two pluripotent stem
cell therapies have
progressed to clinical
trials despite the
spending of many
hundreds of millions of
dollars on pluripotent
stem cell translation.”
Chris Mason of University
College London
such as CombiCult to accelerate
painfully slow biomedical research,
which has hampered the development of new therapies ever since
human embryonic stem cells were
developed in 1998.
“Discovery of robust methods to
differentiate stem cells remains a
serious bottleneck for the industry.
This is a major reason why only
two pluripotent stem cell therapies
have progressed to clinical trials
despite the spending of many hundreds of millions of dollars on pluripotent stem cell translation,” said
Chris Mason, professor of regenerative medicine bioprocessing at
University College London, whose
research group carried out external
validation of the technology. “The
unique CombiCult technology can
dramatically increase research
Sutro Biopharma to
collaborate with UCSF
SAN FRANCISCO—Sutro Biopharma, a biopharmaceutical company
developing a new generation of
protein therapeutics, including
next-generation antibody drug
conjugates and bispecific antibodies, announced Sept. 9 its collaboration with the laboratory of Dr.
James Wells, professor and chair
of the Department of Pharmaceutical Chemistry at the University of
California, San Francisco (UCSF),
as part of the Recombinant Antibody Network.
Under the terms of the agreement, Sutro will provide its Xpress
CF technology for the rapid and
reproducible expression of antibodies and antigens by the Wells Lab
for the comprehensive profiling of
different target proteins and protein families in a high-throughput
manner.
“High-quality antibodies that
perform well and exhibit high
affinity and specificity are not
only very important therapeutics
for many diseases, they are also
essential for basic research,” said
Wells. “Technology that allows for
parallel screening of many variants to generate quickly validated
and renewable antibodies is an
indispensable tool for researching
the functions of specific proteins
under normal or pathophysiological conditions.”
Corning announces new
agreement with
BioLamina
CORNING, N.Y.—On Sept. 11, Corning Inc. announced it had entered
into an agreement with Swedish
company BioLamina to manufacture and package the Recombinant
Laminin-521 (rLaminin-521) pluripotent stem cell (PSC) and neu-
ral stem cell (NSC) growth matrix.
The collaboration will augment
Corning Life Sciences’ portfolio
of defined coating substrates and
extend the availability of this product to research labs worldwide.
Corning and BioLamina recognize a strong demand in the stemcell research market for chemically
defined, xeno-free systems, and
rLaminin-521 provides a defined,
animal-free substrate that allows
robust and scalable cell culture of
PSCs and NSCs with greater cell
purity—critical attributes for the
emerging stem-cell processing
market and a vital enabling component for future cell therapies
using these types of cells, they say.
“As cell-culture and cell-therapy technologies progress, it is
increasingly important to offer
today’s researchers more powerful and reliable culture systems,”
said Dr. Kristian Tryggvason, CEO
of BioLamina. Meanwhile, Dr.
Lynsey Willetts, Ph.D., director of
advanced cell culture at Corning
Life Sciences, added, “By working with BioLamina, Corning now
offers researchers who work with
pluripotent and neural stem cells
a more comprehensive and scalable cell culture solution—from
research to production.”
Protea and InSphero
succeed with MS
imaging of 3D
microtissues
MORGANTOWN, W.V.—The early
days of October saw Protea Biosciences Group Inc. and Schileren,
Switzerland-based InSphero AG
jointly announce an update from
their collaboration focused on mass
spectrometry (MS) imaging of InSphero’s 3D InSight microtissues.
In August 2014, Protea received
microtissues from InSphero and
hosted members of InSphero’s scientific team for onsite training on
the handling and preparation of
the microtissues.
Protea has since developed
workflows for processing the 3D
microtissues for MS imaging and
direct analysis. In addition, Protea
has generated data from 3D microtissues grown from HCT-116 colon
cancer cell line that showed the
ability for MS imaging to detect
and image numerous native proteins in 3D microtissues in a single
experiment as well as putatively
identify several proteins known
to be present at elevated levels in
colon cancer cells.
“[Now] we look forward to developing new applications through
the combination of our respective
technologies and moving forward
towards commercial offerings for
our pharmaceutical and biotechnology customers,” stated Protea
CEO Stephen Turner. ■
EDITCONNECT: E111427
For more information, visit www.DDN-News.com
PATENT
CONTINUED FROM PAGE 39
Jersey action by a number of direct
and indirect purchaser plaintiffs
over Pfizer’s Lipitor drug (atorvastatin calcium); in this case, the
district court granted the branded
(Pfizer Inc., Pfizer Manufacturing Ireland and Warner-Lambert
Co.) and generic (Ranbaxy Inc.,
Ranbaxy Pharmaceuticals Inc.
and Ranbaxy Laboratories Ltd.)
defendants’ motion to dismiss for
failure to state a cause of action.
The RPSA at issue was particularly complex, involving three
separate ANDA litigations as well
as more than two dozen other
actions in foreign jurisdictions,
and involving Pfizer drugs Accupril and Caduet as well as Lipitor.
The settlement agreement was a
“non-monetary” reverse payment,
containing terms that absolved
Ranbaxy from damages ordered
in one of the terminated Accupril
litigations. The agreement also
delayed generic entry into the
Lipitor market until Nov. 30, 2011;
the parties agreed to the same
market entry date for Caduet and
Accupril. In addition, Ranbaxy
paid Pfizer $1 million in damages
for its earlier “at-risk” launch of
generic Accupril. Finally, Pfizer
agreed to be Ranbaxy’s active pharmaceutical ingredient supplier for
Lipitor, and Ranbaxy changed its
formulation from putatively noninfringing amorphous atorvastatin
to putatively infringing crystalline
atorvastatin calcium.
The plaintiffs contended that
the RPSA was a purposeful antitrust violation because it delayed
entry of Ranbaxy’s generic atorvastatin calcium in part because
Ranbaxy switched from the noninfringing amorphous form to the
infringing crystalline form of atorvastatin calcium. In addition, the
plaintiffs argued that Pfizer provided financial incentives for the
RPSA by forgoing the lion’s share
of its damages from Ranbaxy’s
generic launch of Accupril. The
district court identified “the heart
of the issue” as being whether the
agreement between the branded
and generic drug companies was a
RPSA and, if so, whether the agreement warranted antitrust scrutiny
under the Actavis standards.
The district court decided that
plaintiffs had failed to put forth
sufficient evidence that the agreement was an RPSA warranting
antitrust scrutiny. The court agreed
that a “payment” could be anything
sufficient to discharge a debt or
obligation and was not limited to
cash payments, and the court further found no consistent or persuasive authority that the Actavis decision required a payment of money
between the parties.
However, the court found that
there must be a way to “convert”
whatever was exchanged between
the parties into a monetary
equivalent in order to apply
the Supreme Court’s Actavis
precedent. While the district court
recognized that the Supreme
Court’s “general concern” in
Actavis was whether there were
“genuine adverse effects on
competition” (not limited to
merely monetary arrangements),
the court also recognized that
the factual requirements needed
to state a proper claim are more
extensive for non-monetary
consideration between the
parties. Specifically, the court
asserted that plaintiffs would
need to establish a value for the
non-monetary payments alleged
in support of the complaint.
Here, the complaint alleged
no facts relating to the amount of
the damages Ranbaxy was at risk
for incurring in the Accupril II
case, and merely assumed these
damages to be on the order of the
$200-million bond Pfizer posted
in support of its injunction for
Ranbaxy’s “at-risk” sales or the
difference in gross sales ($525
million vs. $70 million).
The court found neither of these
assumptions to be plausible, citing
as unmet considerations evidence
of each party’s assessment of its
own risk, including the probability
of prevailing in the ANDA
litigation, the profits expected
when only the branded, or a
combination of only the branded
and the first ANDA filer were on
the market, the amount of patent
lifetime remaining in view of the
agreed-to generic entry date and
litigation costs for each party, as
well as industry-specific damages
measurements.
This case illustrates the
consequence of the Supreme
Court’s jurisprudential decision to
permit the contours of its Actavis
decision to be “worked out” in
district and appellate courts
below. While a perfectly proper
exercise of the court’s supervisory
powers over the circuit courts,
this way of changing the law has
produced and will continue to
produce uncertainties that can
be expected to seriously harm
competition and innovation,
two of the supposed reasons why
the court decided to reenter the
patent law arena with such vigor.
Rarely have the court’s decisions
had the potential for such harm to
the American economy and global
competitiveness, particularly in a
field where the U.S. has been a
leader for a generation. ■
EDITCONNECT: E111426
Kevin Noonan is a partner with
the law firm McDonnell Boehnen
Hulbert & Berghoff LLP and
represents biotechnology and
pharmaceutical companies on
a myriad of issues. A former
molecular biologist, he is also
the founding author of the Patent
Docs weblog, http://patentdocs.
typepad.com/.
For more information, visit www.DDN-News.com
SHIRE
CONTINUED FROM PAGE 39
those nations while often not actually moving any operations out of the
U.S.—to reduce their tax burdens, a
process known as inversion.
That got AbbVie to rethinking the
deal and its potential profitability, and
on Oct. 14, the company announced
that its board of directors would meet
“to reconsider the recommendation
made on July 18, 2014, that AbbVie
stockholders adopt the merger agreement needed to complete the proposed combination of AbbVie and
Shire” and “consider whether to withdraw or modify its recommendation.”
Some market-watchers had speculated that the deal would simply be
modified, as both companies, particularly AbbVie, had been emphasizing
their excitement about the potential
synergies rather than the tax benefits to
AbbVie. The theory was that AbbVie had
too much of its reputation invested in
the deal and would take a hit to its credibility if it backed off the acquisition.
Those analyses proved to be wrong
when, just a day after the announcement that the board would reconsider
the deal, AbbVie noted that Shire had
waived a three-day notice period and
the AbbVie board had made a “detailed
consideration of the impact of the U.S.
Department of Treasury’s unilateral
changes to the tax rules” and recommended that shareholders reject the
merger and acquisition (M&A) deal, as
“The breadth and scope of the changes,
including the unexpected nature of the
exercise of administrative authority to
impact longstanding tax principles, and
to target specifically a subset of companies that would be treated differently
than either other inverted companies or
foreign domiciled entities, introduced
an unacceptable level of uncertainty
to the transaction. Additionally, the
changes eliminated certain of the financial benefits of the transaction, most
notably the ability to access current and
future global cash flows in a tax-efficient
manner as originally contemplated in
the transaction. This fundamentally
changed the implied value of Shire to
AbbVie in a significant manner.”
“Although the strategic rationale of
combining our two companies remains
strong, the agreed-upon valuation is
no longer supported as a result of the
changes to the tax rules, and we did
not believe it was in the best interests
of our stockholders to proceed,” said
AbbVie Chairman and CEO Richard
A. Gonzalez. Under the terms of the
original acquisition deal, AbbVie will
have to pay a break fee of approximately $1.64 billion.
While that is the third-largest fee on
record to break an M&A deal, the sting
might not be too painful for AbbVie
in the end, as analysts have noted the
fee—like many other related costs
of the M&A negotiations and now
breakup—is tax-deductible. A contributed article by Robert W. Wood on the
Forbes website estimates that AbbVie
could realize at least $650 million in
tax savings. ■
EDITCONNECT: E111425
BUSINESS & GOVERNMENT POLICY
AMAG
CONTINUED FROM PAGE 39
37 weeks of pregnancy. Approximately one in
every nine babies is born preterm, or 11.7 percent of births in the United States. Premature
birth in the nation costs $26.2 billion annually, and average first-year medical costs are
approximately 10 times greater for preterm
infants than for full-term infants.
“This is a truly transformative transaction
that will propel AMAG into a profitable, highgrowth multiproduct specialty pharmaceutical
company positioned for what we expect to be
continued revenue and bottom-line growth,
further business diversification and shareholder value creation,” says William Heiden,
president and CEO of AMAG. Invoking what
is often cliché, he refers to the deal as a “winwin,” but in this case there may be good reason
for the characterization. Heiden and Lumara’s
CEO Greg Divis have a 10-year-old relationship dating back to their days at SheringPlough. Divis notes that AMAG “shares our
commitment,” and that Makena and AMAG’S
Feraheme (ferumoxytol) are a good fit.
“We believe the Lumara Health transaction will facilitate future product acquisitions
in an attractive new therapeutic area and is
an excellent strategic fit with our Feraheme
market expansion plans,” Heiden adds.
The acquisition of Lumara Health provides
AMAG with a strategic commercial entry
into the women’s health segment. Women’s
health includes one of the largest pools of
patients with iron deficiency anemia (IDA).
Accordingly, if AMAG is successful at gaining
FDA approval to expand the label of Feraheme beyond the current chronic kidney disease indication, the 75-person strong Lumara
commercial sales force could become a
meaningful contributor to the growth of
Feraheme in the future.
Of the 1.5 million patients with IDA, AMAG
estimates that fewer than 10 percent are now
treated with IV iron such as Feraheme. Thus,
an expanded label for the product could produce a significant uptick in sales.
NOVEMBER 2014 | | DDNEWS 41
Net sales of Makena over the 12 months
ending August 31, 2014, were greater than
$130 million, a 72-percent increase compared
to the prior-year period. In addition, based
on the three months ended August 31, 2014,
Makena and Lumara Health’s maternal health
business would be on pace to exceed annualized net sales of $180 million and EBITDA
of $110 million. AMAG believes that positive
market dynamics, including a favorable regulatory environment, and implementation of
a new patient-centric business strategy contributed to the significant recent growth of
Makena.
Heiden continued, “Makena is a unique
product with clear clinical benefits that
serves an important medical need for at-risk
pregnant mothers and their unborn children.
The consequences of preterm birth are a significant public health issue, and we believe
that Makena will be a tremendous addition
to our portfolio and will be complementary
to AMAG’s in-office injectables commercial
expertise. We’re also looking forward to welcoming to AMAG the talented Makena commercial team, which has put Makena on a
remarkably strong sales growth trajectory. We
believe that our combined larger-scale, combined portfolio diversification, new resources
and broader commercial expertise will allow
AMAG to create new long-term growth opportunities and allow us to better serve patients.”
Another arrow in the new company’s
quiver is the Drug Quality and Security Act
that placed new restrictions on compounding pharmacies. Heiden notes that 46 percent of the competition for Makena comes
from compounders, and he expects AMAG
to whittle away at this business. In addition,
he points out that the physicians who specialize in women’s care frequently prescribe
off-label drugs out of a perceived lack of a
better alternative.
“I strongly believe AMAG is the right
partner to support the continued growth of
Makena and our maternal health business,”
said Lumara’s Divis. “This transaction is a
great reflection of the outstanding work our
team has done to build the maternal health
franchise to what it is today, and I am pleased
that this same team will continue to grow the
brand within AMAG. It has been clear from
the start of our discussions that AMAG shares
our commitment to at-risk pregnant mothers,
their babies and their healthcare providers.”
The transaction is expected to result in
projected combined 2015 product sales of
$350 million and is expected to be immediately accretive to adjusted earnings per share,
with cost synergies of at least $20 million
per year. Following the closing of the transaction, AMAG expects to have approximately
$100 million in cash and 25.2 million basic
shares outstanding. AMAG intends to provide additional financial guidance for 2015
as promptly as practicable following completion of the transaction.
Upon closing, Lumara Health’s commercial
operations will function as a separate business unit within AMAG, reporting directly
to Heiden. AMAG intends to name current
Lumara Health executives who will be joining
AMAG’s leadership team at or prior to closing.
The transaction has been unanimously
approved by both companies’ boards of directors. The transaction has also been approved
by the stockholders of Lumara Health. It is
expected to be completed in the fourth quarter of 2014, following termination or expiration of the waiting period under the HartScott-Rodino Antitrust Improvements Act of
1976 and completion of financing.
In addition to the $675 million at closing,
the terms of the agreement provide for contingent consideration of up to $350 million
based on the achievement of various sales
milestones for Makena, including sales
achievement of $300 million, $400 million
and $500 million in consecutive 12-month
periods. AMAG believes that its tax attributes
following the closing of the transaction represent an important corporate asset that can
provide long-term shareholder benefits. ■
EDITCONNECT: E111424
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42 DDNEWS | | NOVEMBER 2014
For more information, visit www.DDN-News.com
Horizon Discovery acquires Sage Labs
CAMBRIDGE, U.K. & ST. LOUIS—
There are a number of reasons for
Horizon Discovery Group plc to
want to acquire Sage Labs Inc. For
one thing, it would enhance Horizon’s U.S. footprint and strengthens
both its U.S. and European Union
(EU) sales force, and it would
strengthen Horizon’s intellectual
property (IP) with regard to CRIS-
PR technology as it gains exclusive
rights for in-vivo zinc finger nuclease
(ZFN) applications.
And all this for the price of $48
million, according to Horizon’s lateSeptember announcement of a deal
to acquire Sage. This deal “builds
upon the acquisition of CombinatoRx in July and makes Horizon
the world’s leading gene-editing
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company and the go-to company
for the provision of integrated
product, service and research solutions at all stages of translational
genomics and personalized medicine research from sequence to
treatment,” according to Horizon.
Horizon will gain exclusive
access to ZFN for in-vivo model
generation and certain exclusive
and non-exclusive CRISPR in-vivorelated IP to add to its extensive
in-vitro IP in CRISPR, ZFN and
rAAV, the latter of which is a
ENDO
CONTINUED FROM PAGE 1
transaction will include an election mechanism for Auxilium
stockholders to elect cash and
stock, all-stock or all-cash consideration, subject to proration in
accordance with the terms of the
definitive agreement. The pershare consideration represents
a premium of 55 percent to Auxilium’s closing price on Sept. 16,
2014, the day Endo made public
its proposal for Auxilium.
Immediately prior to the
entering into the merger agreement with Endo, Auxilium terminated its proposed merger
agreement with QLT Inc., in
accordance with the terms of the
QLT merger agreement.
According to Endo, the addition of Auxilium’s leading men’s
health products and development
portfolio should “significantly
enhance Endo’s branded pharmaceutical business.”
“We are pleased to have
reached this agreement with
Auxilium, which we believe will
create value for both Endo and
Auxilium shareholders, as well
as for patients, customers and
employees,” said Rajiv De Silva,
president and CEO of Endo.
“By adding Auxilium’s complementary commercial portfolio,
we believe this transaction is
aligned with our strategy of pursuing accretive, value-creating
growth opportunities. We intend
to leverage Auxilium’s leading presence in men’s health,
as well as our R&D capabilities
and financial resources, to accelerate the growth of Xiaflex and
Auxilium’s other products. We
look forward to working with
the Auxilium team to achieve
the growth and synergy potential of this compelling strategic
combination.”
Xiaflex seems to be a big selling point in the acquisition.
It is a collagenase clostridium
histolyticum (CCH) biologic
compound currently approved
in the United States, European
Union, Canada and Australia for the treatment of adult
Dupuytren’s contracture patients
worldwide exclusive to Horizon.
According to Horizon, it will
focus on expanding Sage’s predominantly U.S. customer base by
increasing its presence in Europe,
Japan and beyond via access to
Horizon’s business development
and commercial infrastructure. The
acquired business will continue to
be known as Sage Labs Inc., and will
operate as a wholly owned subsidiary of Horizon Discovery Group.
The acquisition was expected to
be complete by Oct. 2, though there
with a palpable cord and in the
United States for the treatment
of adult men with Peyronie’s
disease with a palpable plaque
and penile curvature deformity.
Xiafl ex is currently in a Phase
2a study for the treatment of
edematous fibrosclerotic panniculopathy, commonly known
as cellulite.
Leerink Partners, an investment bank specializing in healthcare, forecasts pre- and post-deal
five-year revenue compound
annual growth rates of 3 percent and 8 percent, respectively. “Key to the improved growth
outlook is Auxilium’s ability
to launch Xiaflex in Peyronie’s
disease, where diagnosis rates
remain low but Xiaflex offers a
first-line alternative to surgery,”
writes Jason Gerberry of Leerink.
“Based on a recent MEDACorp
survey of urologic surgeons,
specialists see Xiaflex as a firstline treatment and plan to prescribe the drug to one-third of
their patients within 12 months
post-launch.”
Global research and consulting firm GlobalData values Auxilium’s pharmaceutical assets at
approximately $2.5 billion, which
it says is in line with Endo’s outlay. Largely driving the company’s
valuation is Xiaflex with a net
present value of $920 million,
followed by Testopel at $570
million and Stendra at $558 million, says Adam Dion, GlobalData’s analyst covering healthcare
industry dynamics.
Dion also notes that Endo
intends to leverage its resources
to optimize and drive increased
adoption of three key Auxilium
drugs, which are Xiaflex, Testopel and Testim, the latter two
both being hormone replacement agents.
“Testopel and Testim generated
combined sales of $271 million in
2013, and will supplement Endo’s
hypogonadism therapy Fortesta,”
he explains.
However, GlobalData believes
Endo’s purchase price might be
slightly on the high side, “given
that Auxilium was negotiating
from a position of weakness.”
was, as of press time, no confirmation on either company’s website
that the deal had been finalized officially—however, Sage Labs was posting news dated Oct. 23 from Horizon
on its website, which said that Horizon had “announced the launch of
its patient-derived xenograft (PDX)
models of breast cancer under its
Sage Labs brand. The new panel is
the largest available collection of
highly characterized PDX models,
and is licensed from Washington
University.” ■
“Auxilium’s top-line revenue
was flat in 2013, and the company
has been faced with slowing sales
of Testim and witnessed a 50-percent year-on-year drop in sales
from Xiaflex,” Dion notes. “The
company responded by announcing that it would cut about 190
jobs, or 30 percent of its workforce, as part of a plan to save $75
million per year. Auxilium was
also considering purchasing the
Canadian eye drugmaker QLT in
an effort to shave costs to a lower
tax domicile, but recent changes
to tax laws most likely thwarted
those efforts.”
Dion says that Endo’s motivation behind the deal centers on
cash generation and cost-cutting,
with the company expected to
achieve annual cost synergies of
about $175 million. “This synergy run-rate is expected to be
immediately accretive in the first
year after closing, and includes
Auxilium’s reduction in annual
operating expenses previously
announced in September,” he
explains. “After the transaction,
Endo will have a stronger balance
sheet, increased cash flow with
improved financial flexibility to
continue with its diversification
strategy, transforming itself into a
larger specialty pharma and medical device maker.”
Zacks Investment Research
remarked in an analyst note, “We
believe it is a wise decision for
Endo to acquire Auxilium Pharma. Endo has been struggling
financially due to generic competition affecting its key painkillers Lidoderm and Opana ER.
The Auxilium Pharma acquisition
will not only help Endo to offset
the impact of genericization with
new products but will also help to
diversify its portfolio.”
For his part, Adrian Adams,
CEO and president of Auxilium, noted in the news release
about the acquisition deal that
“We are proud of the work Auxilium has done to develop a
portfolio of important products
that are improving the lives of
patients to create significant
stockholder value.” ■
EDITCONNECT: E111402
PEOPLE & PROMOTIONS
For more information, visit www.DDN-News.com
NOVEMBER 2014 | | DDNEWS 43
People & Promotions
Perrigo Co. plc
Clivetty Martinez, Ph.D.
V.P. of Corporate Global Compliance &
Chief Privacy Officer
ALLEGAN,
Mich.—
Pharmaceutical supplier
Perrigo Co. announced
Sept. 18 that it had hired
Dr. Clivetty Martinez for
the roles of vice president
of corporate global compliance and chief privacy
officer. Martinez will be
responsible for overseeing
the daily compliance program’s activities, driving
awareness of Perrigo’s code of conduct and core
values, identifying areas of compliance risk and
guiding the efforts of the compliance teams at
each Perrigo location worldwide. Martinez brings
to Perrigo 14 years of global compliance experience
in the healthcare and pharmaceutical industries.
Myriad Genetics Inc.
R. Bryan Riggsbee
Executive V.P., Chief Financial Officer & Treasurer
SALT LAKE CITY—Early October saw Myriad Genetics
announce the appointment of R. Bryan Riggsbee
as executive vice president, chief financial officer
and treasurer. Riggsbee most recently served as
the senior vice president of corporate finance at
Laboratory Corp. of America Holdings, a $5.8-billion
clinical laboratory company, where he oversaw
the financial planning and analysis and treasury
functions. Previously, he served in various finance
positions at General Electric Co.
Nurix Inc.
Arthur T. Sands, M.D., Ph.D.
Chief Executive Officer
SAN FRANCISCO—Nurix, a company known for dis-
covering and developing
therapies that modulate
the ubiquitin proteasome
system, announced Sept.
18 the appointment of Dr.
Arthur T. Sands as CEO,
succeeding interim CEO
Dr. Mark A. Goldsmith,
a partner at Third Rock
Ventures who will continue service to the company as chairman of its
board of directors. Prior to joining Nurix, Sands
co-founded Lexicon Pharmaceuticals and served
as president, CEO and director there since 1995.
At Lexicon, Sands pioneered the development of
large-scale gene knockout technology for use in
drug discovery and guided the evolution of Lexicon
from a research-stage company to a drug development company, catalyzed by numerous alliances
with Bristol-Myers Squibb, Takeda and Genentech,
and generating more than $450 million in revenue.
Dimension Therapeutics
Annalisa Jenkins, MBBS, MRCP
Chief Executive Officer
CAMBRIDGE, Mass.—Dr.
Annalisa Jenkins was
recently named as the
new CEO of Dimension
Therapeutics, a gene
therapy company focused
on developing novel treatments for rare diseases,
succeeding interim CEO
Dr. Thomas Beck. Jenkins
brings to Dimension nearly 20 years of experience in
building and leading teams that advanced programs
from scientific research through clinical development, regulatory approval and into healthcare
systems globally. Prior to joining Dimension, she
served as executive vice president and head of
global research and development for Merck Serono,
where she also led global medical affairs and quality. Prior to Merck Serono, Jenkins held several
roles of increasing responsibility at Bristol-Myers
Squibb, where she made significant contributions
to the progression and approval of a number of
key pipeline programs, including Eliquis, Orencia,
Sprycel, Yervoy, Erbitux, Abilify and Plavix.
Aptose Biosciences Inc.
Stephen B. Howell, M.D.
Chief Medical Officer
SAN DIEGO and TORONTO—
Aptose Biosciences, a
clinical-stage company
developing new therapeutics and molecular
diagnostics that target
the underlying mechanisms of cancer, recently announced that Dr.
Stephen B. Howell will act
in the capacity of chief medical officer. Howell is
a renowned medical oncologist and leader in the
development of novel drugs and drug delivery
systems for the treatment of cancer and in the
discovery of the molecular and genetic mechanisms underlying drug resistance. He holds the
position of distinguished professor of medicine
in the Division of Hematology-Oncology at the
University of California San Diego Moores Cancer
Center, where he also serves as the co-leader of
the Solid Tumor Therapeutics Program and directs
the Cancer Therapeutics Training Program.
ICON plc
Ira Spector, Ph.D.
Executive V.P. of Analytics and Consulting
a
global provider of outsourced development services to the pharmaceutical, biotechnology and
medical device industries,
in September announced
the appointment of Dr. Ira
Spector as executive vice
president of analytics and
consulting. In this role, he will lead ICON’s global
consulting and drug development services and will
also be responsible for ICON’s business process
improvement and analytics capabilities. Spector is
an expert in clinical development and brings to ICON
over 25 years of experience in managing global
drug and medical device development programs.
He joins ICON from Allergan Pharmaceuticals,
where he was senior vice president of global
development operations.
ONLINE
Here’s a tiny sampling of recent news stories on
our main website and Cancer Research News site.
Use the Editconnect number in the search windows
on our homepages to reach the stories.
Genentech, NewLink deal could
be worth more than $1B
Hemispherx Biopharma prevails
in multimillion dollar federal lawsuit
The companies will work to further develop
NewLink’s IDO inhibitor NLG919 and discover
next-generation IDO/TDO compounds
All claims by Cato Capital were dismissed
by a federal judge; company seeks $1-million
award for fees and costs against losing party
EDITCONNECT: E10211401
EDITCONNECT: E102213401
Yale announces three-year
extension of Gilead collaboration
AstraZeneca and University of
Cambridge announce new collaborations
Gilead will provide $30M in additional
funding and gain a licensing option for
resultant discoveries as the partners continue
pursuing novel cancer therapies
The agreements include a research
collaboration, a Material Transfer Agreement,
a doctoral training program and an
entrepreneur-in-residence program
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Theraclion
David Caumartin
Chief Executive Officer
MALAKOFF, France—Theraclion, a company special-
izing in cutting-edge medical equipment for echotherapy, announced today that it has strengthened
its management team by appointing David Caumartin
to succeed Stefano Vagliani as Theraclion’s CEO.
Caumartin is a healthcare specialist with 14 years
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Average No
copies each
issue during
preceding 12
months
No copies of
single issue
published
nearest to
the filing date
34,988
35,835
20,713
21,373
20,713
21,373
13,596
13,520
306
425
13,902
34,615
373
34,988
59.2%
13,945
35,318
517
35,835
60.5%
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issue of this publication.
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PEOPLE
AWARDS
& PROMOTIONS
& HONORS
44 DDNEWS | | NOVEMBER 2014
For more information, visit www.DDN-News.com
Awards & Honors
Inaugural Passion in Science Awards
honor 15 ‘unsung heroes’ of the lab
IPSWICH, Mass.—In
commemoration
of its 40th anniversary, New England
Biolabs Inc. (NEB) recently announced
its Passion in Science Awards, which
recognize members of the scientific
community who are committed to making a difference through their science,
humanitarian service, environmental
stewardship or artistic and creative
spirit—a set of awards that were given
out in late October as part of a two-day
international summit NEB held in Ipswich.
“We’ve always believed that science
is more than a vocation—it embodies an
ethos that inspires acts of compassion,
brilliance and originality. We want to
celebrate the many unsung heroes of
the lab, not just for their discoveries,
but for their passions that contribute to
making the world a better place,” said
James Ellard, CEO of NEB.
The awards are given in four categories: the Inspiration in Science Award,
which recognizes scientists whose passion for their field motivates them to push
the frontiers of knowledge on a daily basis;
the Environmental Stewardship Award,
which recognizes scientists who are
working to preserve our natural resources
or reduce waste either in the lab or outside
of it; the Humanitarian Duty Award, which
recognizes scientists who are improving
the welfare and happiness of others; and
the Arts and Creativity Award, which
recognizes scientists who demonstrate
a love of the arts and may also explore
their creative side in the laboratory.
For DDNews readers, the five winners in the 2014 Inspiration in Science
category of the Passion in Science
Award are probably the most pertinent.
One of them is Ite Laird-Offringa of the
Norris Cancer Center at the University of
Southern California, who was honored for
fighting lung cancer. Said Laird-Offringa:
“We are tackling lung cancer in many
ways. We are studying the epigenetic
changes underlying lung cancer development and progression, focusing on DNA
methylation.” A recent finding promises
to improve the sensitivity of detection of
methylated DNA in patients’ blood, and
Laird-Offringa and colleagues are partnering with NEB to further develop this
technology. The Norris team is also studying the epigenomes of alveolar epithelial
cells and the cancer-associated immune
response in the most aggressive type
of lung cancer, small cell lung cancer.
There is also Jason Furrer of the
University of Missouri, honored for inspiring by teaching, in large part because
of his efforts to give opportunities for
undergraduate students to participate in
the research lab in which he works, and
Laurie Doering of McMaster University
in Ontario for research work on the role
of astrocytes in autism.
Kalai Mathee of Florida International
University was honored for work on
understanding why certain pathogens
(primarily Pseudomonas aeruginosa) are
so refractory to antibiotic treatment and
why the P. aeruginosa organism leads to
the demise of patients with cystic fibrosis. Whitney Hagins of Massachusetts
Biotechnology Education was recognized
for work supporting science and biotechnology education in Massachusetts
through educational programs, work-
force development and lifelong learning.
In the Environmental Stewardship
category, the winners of the Passion in
Science Awards were Andrew Markley
of the University of Wisconsin–Madison
and Tonni Kurniawan of Xiamen University
in China. In the Humanitarian Duty category, NEB honored Karl Booksh of the
University of Delaware, Paul McDonald
of the Virginia Tech Carilion Research
Institute, Lori Baker of Baylor University
and Peter Hotez of the Sabin Vaccine
Institute. In the Arts and Creativity category, the winners were Shelly Xie of
the University of Texas Southwestern
Medical Center in Dallas, Tal Danino of the
Massachusetts Institute of Technology,
Alia Qatarneh of Harvard University
and Louise Hughes of Oxford Brookes
University in the United Kingdom. ■
Agilent Thought Leader
Fibrocell Science
Award supports cancer stem receives 2014
cell research at Mount Sinai Marcum Innovator
of the Year Award
SANTA CLARA, Calif.—Agilent Technologies
EXTON, Pa.— Recognized for pioneer-
CREDIT: AGILENT TECHNOLOGIES
Inc. announced Sept. 24 that Dr. Carlos
Cordon-Cardo of the Mount Sinai
Health System had received an Agilent
Thought Leader Award in recognition of
his groundbreaking work in molecular
and translational pathology. CordonCardo is the Irene Heinz Given and John
LaPorte Given Professor and chair of
pathology at Mount Sinai.
The Agilent award will support
ongoing cancer research conducted
by Cordon-Cardo and his team, who
are using a combination of genomic
and proteomic technologies from
Agilent to characterize tumor-initiating
cells with stem cell-like properties
derived from solid tumors taken from
subjects with various types of cancer.
The goal of studying this subpopulation
of cancer cells is to better understand
their ability to resist drug treatments
and metastasize.
“Our goal is to bring in the outstanding measurement tools from
Agilent to develop new diagnostic and
predictive biomarkers,” said CordonCardo. “This, in turn, will provide each
patient a better chance of cure by
defining their disease and optimizing
treatment while offering a superior
quality of life. This collaboration offers
Dr. Carlos Cordon-Cardo of the Mount Sinai Health System recently
received an Agilent Thought Leader Award for his work in molecular
and translational pathology.
a unique opportunity to translate data
into knowledge that maximizes personalized patient management, treatment
efficacy and clinical outcomes.”
“We are very pleased to support
Dr. Cordon-Cardo’s pioneering work in
cancer stem cell research at one of the
largest departments of pathology in the
United States,” said Jacob Thaysen,
vice president and general manager
of Agilent’s Diagnostics and Genomics
group. “Molecular characterization of
these cells, using Agilent technologies
and solutions, could result in the development of new cancer diagnostics.”
The Agilent Thought Leader Award
promotes fundamental scientific
advances by contributing financial
support, products and expertise to the
research of influential thought leaders
in the life sciences, diagnostics and
chemical analysis. ■
ing cell-based therapies for orphan
skin diseases, Fibrocell Science Inc.
recently received a 2014 Marcum
Innovator of the Year Award. These
awards recognize entrepreneurship
and innovation by companies in the
greater Philadelphia region that are
pioneering new advancements in
the biotech/healthcare, technology, manufacturing and business
services sectors. David Pernock,
chairman and CEO of Fibrocell
Science, accepted the award at a
ceremony in Philadelphia on Oct. 22.
“We are proud to be recognized
for developing innovative cell-based
therapies based on our proprietary
fibroblast technology,” Pernock
said. “These treatments have the
potential to relieve the suffering of
those with painful and debilitating
skin and connective tissue diseases,
such as recessive dystrophic epidermolysis bullosa, a rare genetic
blistering disorder. We appreciate
the recognition of our commitment
to developing treatments for these
patients, as well as our support of
the Philadelphia business community.”
Fibrocell Science is an autologous cell therapy company focused
on developing first-in-class treatments for rare and serious skin
and connective tissue diseases
with high unmet medical needs.
Fibrocell’s lead orphan drug program is in late-stage preclinical
development for the treatment of
recessive dystrophic epidermolysis bullosa. Working in collaboration with Intrexon Corp., a leader
in synthetic biology, Fibrocell is
genetically modifying autologous
fibroblast cells to express target
proteins that are inactive or missing
from patients with rare genetic skin
and connective tissue disorders.
Fibrocell is also pursuing medical applications for azficel-T, the
company’s proprietary autologous
fibroblast technology, for restrictive
burn scarring and vocal cord scarring. Both indications are currently
in Phase 2 clinical trials. ■
For more information, visit www.DDN-News.com
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NOVEMBER 2014 | | DDNEWS 45
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46 DDNEWS | | NOVEMBER 2014
Q&A: Gur Roshwald,Q&A
M.D., OF CELSUS THERAPEUTICS
For more information, visit www.DDN-News.com
Celsus seeks to develop the antiinflammatory drugs of the future
C
BY LLOYD DUNLAP
ELSUS THERAPEUTICS is a drug development company
focusing on novel anti-inflammatory, first-in-class synthetic drugs called multifunctional anti-inflammatory
drugs (MFAIDs). Celsus’ proprietary drug technology platform potentially offers an answer to an urgent
unmet need: the lack of satisfactory alternatives to corticosteroids
in the treatment of a multitude of inflammatory diseases. The company has assembled an experienced team that shares its vision and
is committed to making it a success. Dr. Gur Roshwald joined Celsus
as CEO early last year, and DDNews interviewed him about his new
company’s progress toward its goals.
DDNews: Dr. Roshwald, where did Celsus
Therapeutics originate and how did it come to be
U.S.-based?
Celsus was spun out from
technology developed at Hebrew University
in Jerusalem and was incorporated in 2005
in the U.K. Celsus listed in the U.S. in 2013
with new management at the helm and is
currently only traded on NASDAQ under the
ticker symbol CLTX.
As we advanced, the company required
management with drug-development and
public-market experience and access to greater institutional capital from well-established
healthcare funds. We decided on listing in
the U.S. where the biotech/specialty pharma
market is active and well-funded. When the
board of directors made the decision to go
public, new, experienced management with
deep healthcare and U.S. public company
experience was brought on board.
Gur Roshwald:
produce large families of eicosanoids; many
of them are involved in the development of
numerous pathological conditions, especially in
inflammation-related processes. These include
prostaglandins, thromboxanes and leukotrienes.
LysoPLs induce white cell activation and
extravasation, induce cell activation (by lyso
phosphatidylserine in particular), induce tissue damage, such as gastric ulceration, and
act as growth factors (especially lyso phosphatidic acid) to induce proliferation of cancer cells and tumor metastasis. Furthermore,
LysoPLs are also the precursors of platelet
activating factor (PAF), possibly the most
potent mediator of inflammatory processes.
MFAIDs inhibit sPLA2 with a different
chemistry than corticosteroids and are generally specific to inhibiting cell surface sPLA2
activity, thus providing the benefit of inhibition, but, due to the different chemistry,
none of the steroid side effects.
“The market potential for MRX-6 in skin inflammation
is more than $350 million per year in peak U.S. sales,
with sales in Europe and Asia bringing in a likely
equal amount. Cystic fibrosis and osteoarthritis are
both potential multibillion-dollar markets.”
DDNews: Please describe your “First-in-class
multifunctional anti-inflammatory program” and
how and why it provides a potential alternative
to corticosteroids.
Celsus’ lead products are firstin-class, novel, nonsteroidal, synthetic antiinflammatory drugs termed multifunctional
anti-inflammatory drugs (MFAIDs) that
focus on one of the most sought-after pharmaceutical targets in inflammation research:
the sPLA2 family.
This extracellular family of enzymes is a
universal early trigger in all of the inflammatory diseases studied that hydrolyze phospholipids on the cell membrane into two key
inflammatory precursors: arachidonic acid
(AA) and lysophospholipids (LysoPLs).
AA is metabolized via the cyclooxygenase
(COX) and lipoxygenase (LOX) pathways to
Roshwald:
DDNews: You have characterized MFAIDS as a
potential disruptive technology. How would you
define disruptive technology?
Roshwald: As Clayton Christensen describes,
it is a process by which a product or service
takes root initially in simple applications
at the bottom of a market and then relentlessly moves up market, eventually displacing
established products or services.
A good example would be cell phones
replacing landlines. For Celsus, it would be
our products replacing corticosteroids for
inflammation.
DDNews: What is currently happening with each
of your four pipeline therapeutics?
Roshwald: Our most advanced product is
MRX-6, a cream formulation currently in
Phase 2 development for the treatment of
atopic dermatitis (eczema). Our other pipeline
products are in preclinical animal testing for
inflammation in the eye, lung, joints and bowel.
DDNews: What class of molecule is MRX-6? How
are your four current drugs related (or different)?
Roshwald: MRX-6 is made of a series of
sPLA2 inhibitory lipids conjugated to a
glycosaminoglycan (hyaluronic acid). The
glycosaminoglycan (GAG) is anchored on
the cell surface through proteins known as
adherins (CD44, as an example), and provide
antioxidant benefit, while the lipids conjugated to the GAG act as competitive inhibitors of sPLA2 at the cell surface.
Our pipeline products are similar in that
we use various lipids, conjugated in different
ways to a set of potential sugars (GAGs).
DDNews: Please describe your expectations for
market potential and your patent position for each
product.
Roshwald: The market potential for MRX-6
in skin inflammation is more than $350 million per year in peak U.S. sales, with sales in
Europe and Asia bringing in a likely equal
amount. Cystic fibrosis and osteoarthritis are
both potential multibillion-dollar markets.
We have patent protection on our lead
compounds and methods-of-use patents in
the United States and major markets around
the world, in addition to our pending applications. The other compounds in our pipeline
are all new and have long-term composition
of matter, formulation and method-of-use
potential protection.
DDNews: Finally, what are the reasons you are
confident of success when Lilly, Wyeth and
Anthera have failed?
The key to successfully controlling this “universal inflammatory trigger,” or
sPLA2, has been demonstrated by the past
clinical failures of several pharmaceutical
companies. It can be summarized as follows:
1. Inhibit the entire sPLA2 family, not just
one or two of its isomers.
2. Do not interfere with the cPLA2 family,
a related group of enzymes that are located
inside the cell (unlike the sPLA2) and which
have a vital homeostatic role (unlike sPLA2)
that must not be interfered with.
There are about 12 different isomers of
sPLA2, and Lilly’s/Anthera’s compound
inhibited the most ubiquitous—subtype IIA.
Although they achieved good biomarker
results, it is unclear if the compound failed due
to an actual lack of benefit or simply because
the indications pursued were too difficult
(sepsis and post-MI inflammation). The lesson
learned is to only pursue indications where we
know steroids have demonstrated a benefit.
In Wyeth’s case, the compound inhibited
both sPLA2 and cPLA2, which was toxic.
Celsus’ MFAIDs were designed and synthesized to overcome these two critical, and
previously insurmountable, problems and
represent not just a single molecule but an
entire new genus of compounds, each different but with a similar mechanism of action.
Roshwald:
“Celsus’ lead products
are first-in-class, novel,
nonsteroidal, synthetic
anti-inflammatory drugs
termed multifunctional
anti-inflammatory drugs
(MFAIDs) that focus on
one of the most soughtafter pharmaceutical
targets in inflammation
research: the
sPLA2 family.”
Gur Roshwald, M.D., of
Celsus Therapeutics
The glycosaminoglycan backbone is too big
to enter the cell, thus not interfering with
cPLA2, but very good at anchoring the compound on the target cell surface. The lipids
are pan inhibitors of sPLA2. ■
Gur Roshwald joined Celsus Therapeutics as
CEO in March 2013. From April 2008 to February
2013, he was a vice president at Venrock, where
he was an investment professional on the
healthcare team investing in both private and
public companies. From May 2004 to March
2008, he was a vice president and equity
analyst at Piper Jaffray, publishing research on
specialty pharmaceutical companies. Prior to
Piper, Roshwald was in private practice in New
York and board-certified in internal medicine.
He received his M.D. from Albert Einstein
College of Medicine and his MBA from the New
York University Stern School of Business.
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FOR RESEARCH USE ONLY. Not for use in diagnostic procedures.
* Single Cell assay requires reverse transcription and amplification prior to analysis on the nCounter System.
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