BioPharma Dealmakers_September 2015

September 2015
From the publishers of Nature
Dedicated to nurturing collaboration and partnerships in the biopharma industry
Neuroscience set for deal spree
Evolving approaches in age-related disorders
Partnering to manipulate the microbiome
As originally published in the September 2015 edition of Nature Biotechnology
and the September 2015 edition of Nature Reviews Drug Discovery as an advertising feature.

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BIOPHARMA DEALMAKERS SEPTEMBER 2015
www.nature.com/biopharmadealmakers
PUBLISHING TEAM
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Editor
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Profile Writers
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FEATURES
B2 ADVANCES IN NEUROSCIENCE AND SURGING MARKETS MAY SPUR
DEAL ACTIVITY
After a period of setbacks and the exodus of high-profile companies from neuroscience R&D,
industry leaders predict a rebound in neuroscience investment and deal activity in areas such
as pain.
B14 APPROACHES TO AGE-RELATED DISORDERS EVOLVE
Although specific age-related disorders such as Alzheimer’s disease continue to be a focus of
R&D investment and dealmaking activity, companies are also beginning to approach aging in a
broader way.
B17 MANIPULATING THE HUMAN MICROBIOME TO FIGHT
INFLAMMATORY DISORDERS
Big pharma’s interest in the therapeutic potential of modulating the body’s own bacterial
ecosystem is growing, particularly with regard to the treatment of inflammatory disorders.
PROFILES
B5 ASTROCYTE PHARMACEUTICALS
B6 SANFORD BURNHAM PREBYS
MEDICAL DISCOVERY INSTITUTE
B7 BIOASIS
B8 TEVA PHARMACEUTICALS
B9 IMANOVA
B10 INSTITUT PASTEUR
B11 TITAN PHARMACEUTICALS
B12 PROBIODRUG
B16 INTERNATIONAL STEM CELL
CORPORATION
B19 RE-PHARM
B20 BIOPHARMA SNAPSHOT
September 2015
Dedicated to nurturing collaboration and partnerships in the biopharma industry
Neuroscience set for deal spree
Evolving approaches in age-related disorders
Partnering to manipulate the microbiome
As originally published in the September 2015 edition of Nature Biotechnology
and the September 2015 edition of Nature Reviews Drug Discovery as an advertising feature.

B2
biopharmadealmakerswww.nature.com/biopharmadealmakers
Advances in neuroscience and surging
markets may spur deal activity
After a period of setbacks and the exodus of high-profile companies
from neuroscience R&D, industry leaders predict a rebound in
neuroscience investment and deal activity in areas such as pain.
BY CHRIS MORRISON
A
resurgence in venture financing and
merger and acquisition (M&A) activity
alongside advances in clinical trial design,
imaging and biomarkers have added up to
renewed interest in drugs to treat central nervous
system (CNS) disorders. That interest coincides
with the emergence of a variety of innovative
mechanisms of action and technologies such
as gene therapy that are driving early‑stage
dealmaking and investment.
Over the past decade, several large companies
have partially or altogether exited neuroscience
research. Some have spun off assets that have
matured within venture‑backed biotech environ‑
ments. Others remain interested in the space but
are reluctant to make a deal before a drug has
reached human proof‑of‑concept. Risk in neuro‑
science drug development meant that active play‑
ers tended to focus on life‑cycle management of
existing products through reformulation or new
delivery methods.
This retrenchment is at odds with increasingly
dire demographics. CNS disorders are among
the most prevalent causes of death and disabil‑
ity; for example, the World Health Organization
estimates that worldwide more than 350 mil‑
lion people suffer from depression, and the
devastating physical, social and economic con‑
sequences of dementia continue to vex health
systems globally (see “Approaches to age‑related
disorders evolve", page B14).
According to a June 2015 report from the
Biotechnology Innovation Organization (BIO), a
biotech‑industry lobbying group, venture funding
of companies with lead programs in neurology
and psychiatry was about $5 billion in 2005–
2014 (13% of all biotech venture dollars, behind
only oncology). The space was dominated by
venture funding of pain R&D, which accounted
for 42% of that funding over the ten‑year period.
This dwarfed all other neuroscience disease
areas, none of which breached the $500 million
mark (multiple sclerosis, Alzheimer’s disease and
Parkinson’s disease were the most significant
also‑rans in the category). But over that span,
nearly half of pain’s venture capitalist (VC) invest‑
ment haul was not devoted to novel drug R&D but
instead pegged for reformulations of old thera‑
pies and various new routes of administration.
VCs who invest in the CNS and pain areas say
that it can be difficult to syndicate deals because
fewer large pharma companies are interested
in the space, and the odds of striking large
deals that can offset a company’s burn rate are
lower than those in hot areas such as oncology
and immunology.
Neurology and psychiatry also combined to rank
second in R&D‑stage licensing‑deal dollars over
the ten‑year period, with 16% of the total (about
$5.6 billion). The area fared poorly in terms of
racking up M&A dollars, however, accounting for
only about 5% of R&D‑stage acquisitions and 5%
of acquisitions of companies with products on
the market, according to the BIO data.
But in the past two years there has been a
shift toward investing in novel drug R&D and
away from reformulations, as biotechs advance
molecules through the clinic that aim to modulate
new drug targets. New modalities, such as gene
therapy, are also being brought to bear; Sanofi
recently committed $100 million up front in an
alliance with CNS gene therapy specialist Voyager
Therapeutics, for example. In addition, several
large acquisitions, such as Biogen’s January
2015 takeover of the VC‑backed pain‑focused
Convergence Pharmaceuticals ($200 million
up front with up to $475 million in earn‑outs),
Novartis’ June 2015 acquisition of the Australian
pain company Spinifex ($200 million up front plus
earn‑outs) and Teva Pharmaceuticals’ acquisi‑
tion of Auspex Pharmaceuticals for $3.2 billion
in March 2015 to access that biotech’s lead
program in Huntington’s chorea, have sparked
investor enthusiasm. Perhaps the best example
of buy‑side interest in neurological disease
came in July 2015, when Celgene paid $7.2
billion for Receptos, whose lead sphingosine
1‑phosphate 1 (S1P) receptor modulator ozani‑
mod is in phase 3 trials for multiple sclerosis and
ulcerative colitis (Table 1).
“It’s a fascinating time right now,” said Bruce
Booth, a partner at Atlas Venture, based in
Cambridge, MA. “In some ways the evolution of
neuroscience R&D is like the previous evolution
in oncology R&D, in that it’s becoming precision‑
medicine oriented.” Industry research is being
augmented by large public efforts, such as the
EU Human Brain Project and the US National
Institutes of Health’s Brain Research through
Advancing Innovative Neurotechnologies (BRAIN)
initiative. As neurological conditions give up their
genetic secrets, previously heterogeneous dis‑
ease populations can be subtyped, said Booth,
leading in some cases to an ‘orphanization’ of
neuroscience. “We are starting to pick apart
different diseases” in areas such as neuro‑
degeneration, pain, epilepsy and even psychiatry,
said Booth. “We previously thought about these
diseases as large and amorphous, but the biol‑
ogy is providing interesting proof points for drug
discovery campaigns, especially for small com‑
panies” who could not afford to invest resources
in broader disease settings. The Atlas Venture
portfolio, Booth said, comprises about two dozen
companies that are beyond seed stage,and those
companies are engaged in a total of 75 R&D pro‑
jects. Of those projects,40% are in neuroscience.
Table 1. Selected major M&A deals in the neuroscience area (July 2014–July 2015).
Companies Headline Date M&A value (US$ million)
Celgene; Receptos Celgene acquires Receptos and phase 3 multiple sclerosis candidate July 2015 7,200
Teva; Auspex Teva acquires neurology‑focused Auspex in $3.5 billion deal March 2015 3,500
Otsuka Pharmaceutical;
Avanir Pharmaceuticals
Otsuka acquires CNS‑focused Avanir for $3.5 billion December 2014 3,500
Biogen;
Convergence Pharmaceuticals
Biogen acquires pain specialist Convergence January 2015 675
Allergan; Naurex Allergan spends $560 million to buy antidepressant maker Naurex July 2015 560
Acorda; Civitas Acorda acquires neurological drug‑maker Civitas for $525 million September 2014 525
Roche; Trophos Roche buys Trophos to expand portfolio in neuromuscular disease January 2015 515
Novartis; Spinifex Novartis buys pain drug developer Spinifex June 2015 200 (Upfront payment)
Data sourced from BioCentury BCIQ.

B3
“In some ways the
evolution of neuroscience
R&D is like the previous
evolution in oncology
R&D, in that it’s
becoming precision-
medicine oriented.
”BRUCE BOOTH, PARTNER
AT ATLAS VENTURE
and a biomarker to measure whether you’re
engaging with and modulating the target,” said
Brudnick. “That allows you to test in a smaller
patient population and increases your chance
of success, and those are big steps forward”
in neuroscience drug development in the past
decade, he said.
Other players in the Nav1.7 space include
Xenon, who licensed its lead Nav1.7 inhibitor to
Teva for $41 million up front in December 2012
(the small biotech company also has a pain‑
focused deal with Roche’s Genentech, signed
in January 2012 and worth up to $646 million in
total potential payments), and newcomer SiteOne
Therapeutics, which in July 2015 finalized its first
round of financing. “What’s interesting about this
particular target is that there’s partnering interest
at all stages of development,” pointed out Abel,
whose previous companies Corthera, Cerexa
and Peninsula were sold to Novartis, Forest and
Johnson & Johnson, respectively. “I’ve sold three
biotechs, and all have been after phase 2 data,
but this is a target where a deal much earlier than
that might be possible.” Abel notes SiteOne is
open to a variety of partnership structures.
Other new targets, as well as new approaches
to existing targets, are attracting similar atten‑
tion. Afferent Pharmaceuticals, a 2009 spin‑
out from Roche that is focused on developing
drugs for pain and related sensory patholo‑
gies, is developing its lead asset AF‑219 as a
treatment for chronic, pathologic cough that
results when nerves fail to return to a quiescent
state after an acute event such as a respira‑
tory infection. Afferent’s target is an ATP‑gated
ion channel receptor called P2X3 that is often
upregulated after nerve injury or inflammation
and thus may be modulated to treat a variety
of pain and related conditions. “Once we saw
there were P2X3 receptors selectively expressed
by sensory fibers which aren’t involved in funda‑
mental processes but signs and symptoms in
pathology, pain was an obvious way to go,” said
Anthony Ford, CSO. The company published
proof‑of‑concept data for its lead cough program
in The Lancet in November 2014, and it landed
$55 million from a syndicate of crossover inves‑
tors (investors who invest in both privately held
and publicly traded companies) in July 2015,
potentially signaling an impending IPO. “We’ve
validated this target across indications from a
clinical perspective, and that’s caused a lot of
pharmaceutical companies to take note,” said
Afferent CEO Kathy Glaub.
Older targets can be modulated in new ways
to avoid some deleterious effects of older ther‑
apies. G protein‑coupled receptors (GPCRs)
represent an enormously popular class of drug
targets and the largest family of transmembrane
receptors. For years researchers treated the
receptors like switches that could be turned on
or off using agonists or antagonists, said Trevena
scientific co‑founder Jonathan Violin, who runs
the company’s investor relations. But a pair of
discoveries upended that notion. First, GPCRs
were found to couple to more than one signaling
pathway: alongside G protein‑mediated signal‑
ing is a distinct pathway mediated by β‑arrestin.
Second, researchers learned that those distinct
Emerging mechanisms in pain
Various manifestations of pain—postoperative
pain, chronic pain, migraine and many others—
remain largely unchecked. Moreover, most are
treated with drug classes discovered decades
ago, such as nonsteroidal anti‑inflammatories
(NSAIDs) and opioids (and recently approved
abuse‑deterrent versions), although α2δ cal‑
cium channel modulators (for example, Pfizer’s
Neurontin (gabapentin) and Lyrica (pregabalin))
have been introduced for some indications
more recently.
“In pain there’s such a huge unmet need, and
such a huge problem with opioid abuse and addic‑
tion,” said Stan Abel, president and CEO of pain‑
focused SiteOne Therapeutics. The Convergence
and Spinifex deals “are a reflection of how big
these opportunities can be for novel non‑opioid
pain therapies,” he said. What’s more, “there’s
been an unbelievable explosion and advance‑
ment in basic neuroscience over the past few
years,” said Richard Brudnick, VP and co‑head
of business development at Biogen. “That plus
a robust financial market that has reawakened
venture investment and the successes of Biogen
and others in neurology has stimulated a lot of
entrepreneurial activity,” he said.
Advances in ion channel technologies have
allowed researchers to greatly increase the
throughput of screening technologies, and
advances in stem cell technologies have allowed
for much better models of disease, said David
Reynolds, VP and site head of Neusentis, Pfizer’s
specialized unit for pain and ion channel R&D.
“These are tools that had been missing from
our toolbox,” he said. Over time, this increased
bandwidth and unprecedented access to models
of the human nervous system “should increase
our success rate for drugs going into early clini‑
cal trials,” he said. New research is unraveling
the origins of pain and the fundamental mecha‑
nisms that carry those signals to the brain, as
well as how pain becomes permanent, said
Husseini Manji, global therapeutic head for
neuroscience at Johnson & Johnson’s Janssen
Pharmaceuticals unit. “Until now we’ve tried to
make you not feel pain instead of working on the
fundamental mechanisms that cause it, but now
we’re in a position to intervene at the root of what
is going on.”
Biogen’s acquisition of Convergence—a 2010
spin‑out from GlaxoSmithKline (GSK), which
owned a minority stake in the company—landed
the big biotech company a suite of assets for the
treatment of chronic pain that target voltage‑
gated sodium channels. Inhibitors of the Nav1.7
channel are something of a poster child for
genetically informed drug development; naturally
occurring but rare mutations that lead to loss of
function of the channel have been identified in
people who are unable to perceive pain, and rare
gain‑of‑function mutations in SCN9A have been
identified in families with the congenital pain dis‑
order primary erythermalgia, which causes burn‑
ing pain in the extremities. Biogen is preparing
its lead program, CNV1014802, for phase 3 after
positive mid‑stage results in trigeminal neuralgia,
a severe form of facial pain. “In ideal circum‑
stances, you have a genetically validated target

B4
xrender/iStock/Thinkstock
pathways can lead to different pharmacologi‑
cal outcomes. “With the right kind of molecule,
you can activate one pathway or the other,”
said Violin, and in the case of Trevena’s lead
pain program, it could be possible to avoid on‑
target effects associated with μ‑opioid receptor
agonists, such as respiratory depression.
Activating only the G protein‑mediated pathway
would mean “you could get an opioid with a much
better side‑effect profile,” explained Neusentis’
Reynolds, who said Pfizer is among a group of
companies trailing Trevena’s TRV130, an intra‑
venously administered small molecule that has
completed a phase 2 study for use in acute
postoperative pain. A second phase 2 study,
for management of postoperative pain after
abdominoplasty, should read out in the third quar‑
ter of 2015, said Violin. He also said that Trevena
aims to license ex‑US rights for the molecule’s
intravenous formulation, and possibly rights
for other formulations and indications, such as
transmucosal delivery for breakthrough cancer
pain or transdermal delivery for chronic pain.
Ramping up CNS R&D via partnerships
When it comes time for Afferent, Trevena,
SiteOne and others to partner, a larger audi‑
ence may await them than would have been
the case in years past. There will be stalwarts
such as Biogen and Johnson & Johnson, of
course, but also deal‑hungry specialty pharma
companies such as Shire, Teva and Allergan, the
last of which expanded its CNS efforts recently
by bringing Merck & Co.’s oral calcitonin gene‑
related peptide (CGRP) migraine drugs into its
pipeline via a $250 million up‑front deal in July
2015. CGRP is a hot migraine target, but most
of the competition is among antibody drugs from
Amgen, Teva, Lilly and Alder Pharmaceuticals.
Teva’s TEV‑48125 came from its 2014 acquisi‑
tion of Labrys Biologics ($200 million up front).
Similarly, Lilly acquired its compound from
Arteaus Therapeutics in January 2014 (Atlas
Venture‑backed Arteaus had originally licensed
the drug from Lilly, in 2011, taking on the risk
and eventual reward of the drug’s success in a
clinical proof‑of‑concept trial).
Companies that have pulled back in the past
are eyeing the field for opportunities. GSK,
alongside a handful of other large companies,
has committed $25 million in capital to the
Dementia Discovery Fund, a $100 million public–
private UK‑based partnership that will invest in
dementia‑related opportunities. GSK expects to
expand its business development activities in
neuroscience as it embraces advances in the
field’s foundational biology. But at the same time,
said Min Li, SVP and head of GSK’s neuroscience
therapeutic area unit, “each subspecialty in
neuroscience is an area of deep biology, and it’s
certainly unrealistic for us to develop an in‑house
effort with sufficient bandwidth to accommodate
these significant new discoveries; thus external‑
ization through partnering is key to expanding
our coverage.”
Even big companies with long‑standing neuro‑
science R&D commitments are increasingly
looking elsewhere for innovation. “Because
of the magnitude of the problem, the degree of
complexity, it’s necessary to bring together
different groups of people with complemen‑
tary skills, talents and approaches to tackle
problems in neurological disease,” said
Janssen’s Manji.
Manji has high hopes for a renaissance
in neuroscience R&D. “It’s unfortunate that
some companies have pulled back in neuro‑
science. But 15 or 20 years ago, people had
similar concerns about oncology,” said Manji.
A handful of “big breakthroughs” later, he said,
“every company is back in oncology; that’s
exactly what could happen in neuroscience.”
Among the positive signs Manji sees are the
application of ‘big data’ approaches to neuro‑
science problems, and technologies embedded
in smartphones and wearable devices that will
allow researchers to gather signals and data
from people in the real world to better track the
natural progression of neurological disorders.
“We’re also seeing a lot of device companies
moving into the neuroscience space,” he said,
“because there’s a recognition that the brain
is an electrical organ, and there are opportu‑
nities for devices to engage specific circuits.”
These approaches could be complementary to
pharmacological approaches, he said.
Chris Morrison is a freelance analyst, editor
and writer who reports on the biotechnology and
pharmaceutical industries.

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ADVERTISEMENT FEATURE
Astrocyte Pharmaceuticals, Inc.
www.astrocytepharma.com
Harnessing the stars to treat
traumatic brain injuries
New company Astrocyte Pharmaceuticals is pioneering a novel approach to healing a damaged brain that involves
activating energy supplies in astrocytes, the abundant star-shaped brain cells with a central role in repairing CNS injury.
F
ootball impacts and car crashes are just
some events that can cause traumatic
brain injuries (TBIs). Many news stories
from the past few years about TBIs and con-
cussions (a mild form of TBI) have emerged as
researchers have learned more about the disturb-
ing long-term effects of repetitive injuries, which
can trigger age-associated neurodegeneration
resulting in a range of symptoms and disabilities
over decades1
.
Each year, approximately 1.7million people are
diagnosed with a TBI in the United States, accord-
ing to the US National Institutes of Health2
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incidence of this type of injury is even more
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. Despite the growing
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That’s where Astrocyte Pharmaceuticals, Inc.
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rotransmitters or the influx of calcium, our work
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super custodians of the brain.”
Spawned by the research of cofounder James
D. Lechleiter, which was patented in 2013,
Astrocyte’s novel approach targets P2Y1
recep-
tors on astrocyte cells, which are abundant in
the brain. These specialized star-like glial cells
can outnumber nerve cells five to one in many
areas throughout the brain4
and are essential
for vital aspects of maintaining brain health and
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target and small-molecule agonists,” said William
S. Korinek, Astrocyte’s cofounder and CEO.
Brain injury after impact
When the brain endures an impact, often there
is tearing of blood vessels and bruising, as well
as a flood of potassium, which overexcites nerve
cells and triggers the release of toxic levels of
glutamate. Studies have shown that without
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nently damaged under such circumstances5
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Astrocytes have a vital role in removing excess
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controlling brain edema or swelling. Astrocytes
require energy to perform these functions, and
Lechleiter found that boosting ATP production
by using a P2Y1
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activate mitochondria metabolism in astrocytes
is remarkably effective at protecting the brain.
“Normally people want to block pathways to
stop injury,” Lechleiter said. “We’re saying, let’s
stimulate the natural caretakers of the brain, part
of whose job is to help maintain ion homeostasis,
which fundamentally controls edema.” When the
brain swells, it expands against the skull and
puts additional pressure on neurons and tissues.
Edema can result from even mild blows to the
head, and if left untreated, the swelling can cause
many symptoms from headaches to behavioral
changes.
“The sooner you provide treatment, the better,
but we still see improvements when treating
24 hours after the initial trauma,” said Lechleiter.
P2Y1
receptor activation increases neuronal and
astrocyte survival, and it also partially reverses
neuronal and glial damage. Ives emphasized that
the pharmacology of Astrocyte’s lead candidate is
compelling, and he mentioned that the Lechleiter
lab at the University of Texas Health Science
Center at San Antonio has rescued or repaired
neurons that in the past would have been con-
sidered damaged beyond help, even two days
after trauma.
Future development
Astrocyte has conducted a number of initial stud-
ies in mouse models and ex vivo human brain
tissue and is planning further rodent and porcine
studies. “The neuroprotection data to date in
multiple models is quite compelling and promis-
ing,” expressed Ives. These initial steps have
provided a robust data foundation and strong
rationale to expect translation to people, and to
support the move toward clinical trials, which the
company is aiming to start in 2017.
The potential for an efficacious neuroprotec-
tive therapeutic would also extend beyond TBIs,
as neuronal damage or loss is central to many
CNS disorders. “It’s exciting that a new thera-
peutic might not only help themillions of brain
trauma patients but also those with other dis-
orders, such as stroke and neurodegenerative
diseases,” said Korinek. “This urgent medical
need is the driving force behind our commitment
and approach.”
Many other groups, from sports leagues to the
US government, have also shown their support
for more of this type of critical research. Astrocyte
Pharmaceuticals stands out with a fresh and
compelling hypothesis of neuroprotection that
has the potential to reach the ultimate goal of
healing a damaged brain.
References
1. McKee, A.C. et al. Brain 136, 43–64 (2013).
2. National Institute of Neurological Disorders and Stroke.
Traumatic Brain Injury: Hope Through Research. http://
www.ninds.nih.gov/disorders/tbi/detail_tbi.htm (2015).
3. Langlois, J.A., Rutland-Brown, W. & Wald, M.M. J. Head
Trauma Rehabil. 21, 375–378 (2006).
4. Sofroniew, M.V. & Vinters, H.V. Acta Neuropathol. 119,
7–35 (2010).
5. Largo, C., Cuevas, P., Somjen, G.G., Martin del Rio, R. &
Herreras, O. J. Neurosci. 16, 1219–1229 (1996).
CONTACT DETAILS
William S. Korinek, CEO
Astrocyte Pharmaceuticals, Inc.
Cambridge, MA, USA
Tel: +1-617-444-8765
Email: info@astrocytepharma.com
Astrocytes, easily recognized by their stellate
structure with many protrusions branching
radially out from the soma, form a supportive
network throughout the brain.

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Sanford Burnham Prebys
Medical Discovery Institute
www.sbpdiscovery.org
Partnering to advance translational research
Sanford Burnham Prebys Medical Discovery Institute is an independent, nonprofit biomedical research institute that
combines deep expertise in fundamental and translational science to discover innovative medicines and diagnostics.
S
anford Burnham Prebys Medical Discovery
Institute (SBP) is on a mission to advance
translational research that will have a
meaningful impact on human health. The insti-
tute is poised to do this by implementing a model
of drug R&D that focuses on partnerships with
industry and clinics at the translational juncture
of fundamental research and clinical science.
Key to the institute’s strategy is its history
of excellence in fundamental research and its
extensive investment in industry-like, in-house
drug discovery expertise and technology. “Given
my own experience, I know that the optimal
partner for pharma contributes scientists with a
deep understanding of the biology of the target
or pathway of interest, a line of sight to unmet
patient needs, the rigor to conduct experiments
right the first time, a collegial and collaborative
mindset and the ability to create a complete data
package,” said Perry Nisen, CEO of SBP.
This unique academia-industry blend—sup-
ported by well-funded, world-class basic research
and drug discovery expertise—makes SBP the
partner of choice for pharmaceutical and biotech
companies (Box 1).
Conrad Prebys Center for
Chemical Genomics
Since its establishment in 2009, the Prebys
Center has been progressing laboratory dis-
coveries to clinical studies. The center’s state-
of-the-art, high-content and high-throughput
robotic small-molecule screening platform
represents a key capability in the institute’s
translational strategy.
The center, led by Michael Jackson, SVP of drug
discovery and development, deploys a team of
80 scientists with extensive pharma experience,
focused on discovering small-molecule drugs
against disease-relevant targets newly identi-
fied and validated by scientists at the institute.
Equipped with the latest high-throughput screen-
ing technology and large chemical libraries, they
are advancing first-in-class projects from assay
development, through lead optimization, to
clinical-candidate selection. This comprehensive
approach has created a robust asset pipeline of
high commercial interest for potential partners.
Four disease focus areas
The institute’s world-class principal investigators
and industry-trained drug discovery researchers
focus on four therapeutic areas: cancer, autoim-
munity, metabolic disorders and neuroscience.
Cancer. SBP is one of only seven National
Cancer Institute (NCI)-designated Basic Cancer
Research Centers in the United States, and has
held this designation for over 30 years. With
more than 46 faculty and $149million in direct
funding, SBP’s world-class cancer center has
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tions to the understanding of tumor initiation
and maintenance, the tumor microenvironment,
tumor metabolism, apoptosis and the biological
underpinnings of metastasis.
Findings from these investigations have led
to multiple ongoing clinical trials for solid and
hematologic tumors and have served as the
basis for US Food and Drug Administration–
approved cancer therapies.
Autoimmunity. Guided by several world-class
investigators, SBP is pushing the boundaries of
immune research at the intersection of cancer
and the immune system. SBP is a leader in
translating research discoveries regarding cyto-
kine signaling molecules and immune-checkpoint
modulators into new therapies for cancer and
autoimmune disease. The recent announcement
of SBP’s collaboration with Eli Lilly to develop
strategies to target multiple immune-checkpoint
modulators for the treatment of diseases such
as lupus, Sjögren’s syndrome and inflammatory
bowel disease shows SBP’s commitment to this
space and the value its assets represent for
pharma partners.
Metabolic disorders. A particular focus at SBP’s
Orlando campus is the study of the metabolic
origins of disease, including diabetes, obesity
and cardiovascular disease. In addition, scien-
tists at the institute’s NCI-designated Cancer
Research Center are elucidating cell pathways
that disrupt tumor cell survival and proliferation,
tumor response to nutrient deprivation and pro-
inflammatory pathways in cancer progression.
Through a collaboration with Daiichi Sankyo,
the institute also has an opportunity to develop
first-in-class therapeutics for the treatment of car-
diovascular-metabolic diseases. By identifying,
validating and screening new drug targets and
studying new mechanisms of disease, SBP was
able to develop a first-in-class small molecule
that was licensed to Daiichi Sankyo.
Neuroscience. SBP is investing heavily in sci-
entific capabilities and tools in neurobiology,
which has led to collaborations with Mayo Clinic
and the Michael J. Fox Foundation on basic
and translational research in Parkinson’s dis-
ease and with the Tanz Centre for Research in
Neurodegenerative Diseases in Toronto to study
Alzheimer’s disease.
A focus area is the generation of induced plu-
ripotent stem cells from patients with various
neuropsychiatric disorders (e.g., bipolar disorder,
Alzheimer’s disease and ALS) to create disease-
in-a-dish assays that closely reflect the underlying
biology of disease and can be used to search for
effective drugs.
Valuing success
The key value of SBP’s approach is its focus on
translational science. The institute’s unique
blend of basic research and cutting-edge tech-
nology, coupled with a solid financial foundation,
offers pharma and biotech companies a way to
deepen their research portfolios at all stages of
development.
SBP is seeking partners with complementary
capabilities in clinical development and/or as
clinical partners, that is, with access to patient
samples. According to Nisen, “The institute
brings to the table an ability to conduct killer
experiments to enable unequivocal go/no-go
decisions to either proceed with a project or stop
and move on to the next project. At the end of the
day, success needs to be measured by some sort
of external metric—for example, external valida-
tion by ethics committees, institutional review
boards and regulators to support a first-time-in-
human experiment.”
Together with pharma and clinical partners, SBP
will accelerate the pace of R&D to deliver drugs
for the most challenging unmet medical needs.
CONTACT DETAILS
Michael Jackson, SVP,
Drug Discovery and Development
Sanford Burnham Prebys
Medical Discovery Institute
San Diego, California
Tel: +1-858-795-5201
Email: mjackson@SBPdiscovery.org
BOX 1: SBP’S PHARMA AND
CLINICAL PARTNERS
 The Alzheimer’s Association
 Boehringer Ingelheim
 Celgene
 Daiichi Sankyo
 Duke University
 Eli Lilly
 Leukemia & Lymphoma Society
 Mayo Clinic
 Michael J. Fox Foundation for Parkinson’s
Research
 Pfizer
 Takeda Pharmaceuticals
 U.S. Air Force

biOasis
http://biOasis.ca
Transcend: a natural way to cross
the blood–brain barrier
By hijacking one of the body’s own transport methods, biOasis has identified a
natural route to treat disorders of the central nervous system.
F
ew challenges in drug development have
proven to be as tough to overcome as
crossing the blood–brain barrier. Deep-
pocketed pharma companies have tried for
years to come up with a solution to this problem,
yet it remains a significant impediment to the
treatment of diseases affecting the brain. The
irony is that nature may have solved the problem
millennia ago. Now, biOasis Technologies is ready
to share its method with the world.
The blood–brain barrier is hard to cross by
design. It acts as a shield for the brain, stopping
anything that might harm the vital organ from
making it beyond the blood. For drug developers,
this means that 98% of small molecules and
100% of biologics are unable to reach targets
within the brain. With central nervous system
diseases affecting one in six people and the
markets for disorders affected by the barrier
being worth upward of $100billion a year, there
is an open opportunity to improve these figures.
Having seen others try and fail to solve the
problem by disguising drugs with lipophilic
molecules or using compounds to boost the
permeability of the barrier, biOasis struck upon
the idea of hijacking the body’s own transport
system to access the brain. This idea led the
company to melanotransferrin, a protein that
attaches to receptors on the endothelial cells
that form the blood–brain barrier. Upon attach-
ment to a receptor, melanotransferrin is shuttled
through the endothelial cell and into the brain to
deliver iron. Turning this system into a function-
ing delivery route has taken years, but biOasis
now thinks it has an effective approach. Most
important, it has independent validation to back
its claims.
Turning a natural process into
a drug delivery system
biOasis and the researchers at the University
of British Columbia have spent over 20 years
figuring out how to turn melanotransferrin, a large
protein, into an effective drug delivery system.
The work led to Transcend, a method that can
use either melanotransferrin or specifically the
peptide portion of the protein to deliver drugs
across the blood–brain barrier. biOasis discov-
ered that instead of attaching drugs to the large
melanotransferrin protein, it could pair them with
a peptide that is just 2% of the size of its parent
protein. As biOasis tested the peptide further, it
found that it crosses the barrier more efficiently
and persists in the brain longer than its parent
protein.
The data to support these claims are from tests
in animals, but there are reasons to believe that
the performance will be replicated in humans.
First, blood–brain barriers in rodents and non-
human primates are very similar to those in
humans, so it is likely that products developed
by biOasis will behave similarly once in clinical
trials. Second, and unusual for an early stage
biotech, biOasis has a wealth of independent
validation from human-based in vitro and in vivo
models to support its claims. The firm has delib-
erately worked with the likes of the National
Research Council of Canada, pharmaceutical
companies and universities to obtain this valida-
tion and gain credibility.
Having access to an innovative, independently
validated solution to a hoary problem—one that
can also help extend the patent life of existing
drugs—has put biOasis on the radars of leading
biopharma companies. AstraZeneca’s biologics
wing, MedImmune, has entered into a licensing
deal, leading to the generation of more indepen-
dent data to demonstrate the effectiveness of
biOasis’ technology. Others are set to follow.
biOasis expects to sign technology access deals
with multiple companies.
Such arrangements allow companies to
test the technology to confirm what biOasis,
MedImmune and others have already ascer-
tained: that the drug delivery system holds
immense promise. Once other firms have spent
time generating their own data to demonstrate
this fact, biOasis anticipates that they will sign
full licensing deals. “We at biOasis are very
proud of the accomplishments we have made to
date. From concept, through research, to valida-
tion and now into commercialization, we’ve made
the careful steps to ensure that the hopes of
being able to provide a solution to the blood–
brain barrier are now within our grasp,” said Rob
Hutchison, CEO of biOasis.
Making crossing the blood–
brain barrier mundane
The signing of such licensing deals is of the
utmost importance to biOasis, which sees itself
as more of a technology platform provider than
a traditional biotech. Taking this approach will
allow the delivery system to be applied to a far
broader range of therapeutic fields than would
be possible if biOasis kept the technology for
itself. biOasis foresees its science being used
to deliver drugs to treat a wide spectrum of
central nervous system disorders, including
brain cancers, pain and metabolic disorders, and
neurodegenerative diseases. Data are available
to support these ambitions.
MedImmune has shown that fusing an
interleukin 1–receptor antagonist to biOasis’
peptide facilitates transport across the blood–
brain barrier and the induction of analgesia. Such
early indications of efficacy, which have been
demonstrated with multiple drugs, set biOasis
apart from others in the field. These data are
part of a growing pool of independently validated
research showing that Transcend can take biolog-
ics and small molecules across the blood–brain
barrier, keep the active ingredient around the
target cells for a prolonged period of time and
have an effect on hard-to-treat diseases.
This process is a unique discovery in the many
years of research into crossing the blood–brain
barrier. If the next few years go as biOasis hopes,
accessing the blood–brain barrier will become
mundane—a challenge consigned to history.
CONTACT DETAILS
Rob Hutchison, CEO
Richmond, British Columbia, Canada
Tel: +1-604-644-1232
Email: rob@bioasis.ca
biOasis, solving the challenges of the blood–
brain barrier.
“We at biOasis are
very proud of the
accomplishments we
have made to date.
”ROB HUTCHISON

Teva Pharmaceuticals
www.tevapharm.com
Teva Pharmaceuticals: a leader
in CNS specialty medicine
A leader in CNS specialty medicine sales in the United States and in the top five globally,
Teva Pharmaceuticals is actively looking to expand its CNS portfolio further.
T
eva Pharmaceuticals is committed to
developing and improving treatments
for patients suffering from disorders of
the central nervous system (CNS). In 2014,
Teva’s portfolio earned over $6billion globally.
In addition to offerings of established CNS
medicines, the company also boasts a deep
CNS pipeline and is actively seeking to expand
through partnerships, license agreements and
acquisitions. Active development programs
are under way in multiple sclerosis (MS),
various headache and migraine conditions,
pain and neurodegenerative diseases (NDD),
with a high focus on movement disorders
including Huntington disease and tardive
dyskinesia.
MS. Teva is interested in augmenting
the available treatments for MS. In
relapsing-remitting MS, Teva seeks
to d evelop s afer, more toler able
therapies, including once-daily orals and
monoclonal antibodies. In progressive
MS, Teva seeks neuroprotective and
regenerative medicines. The application
of pharmacogenomics and eHealth
technology to improve MS disease
management is also an area of active
research at Teva.
NDD. Teva is interested in assets that
modify disease progression specifically in
Huntington’s, Parkinson’s and Alzheimer’s
disease. Improved symptomatic therapies
for both motor and non-motor symptoms
of NDD are also of interest. Medicines
targeting other movement disorders, such
as tardive dyskinesia, are of strategic fit as
well.
Pain. Pain management continues to
be an area of enormous unmet need.
Teva has a broad interest in therapies
addressing chronic pain and nociceptive
pain associated with conditions such as
painful diabetic neuropathy, post-herpetic
neuralgia, osteoarthritis, and low back pain
and breakthrough pain in cancer, as well as
in formulations and delivery technologies
designed to deter opioid abuse.
Migraine and headache. Globally, nearly
15 % of people suffer migraines, making
it the seventh-highest cause of disability
worldwide. Chronic migraine, episodic
migraine, menstrual migraine and
migraine-related syndromes, trigeminal
autonomic cephalalgias (e.g., cluster
headaches) and post-traumatic headache
are all indications of interest.
An experienced partner in CNS
Teva offers its business partners proven excel-
lence in CNS drug discovery, drug development
and commercialization. According to Michael
Hayden, president of global RD and chief sci-
entific officer, “In our areas of therapeutic focus,
Teva possesses the development and commer-
cialization capabilities that are synonymous
with being leaders in the field. We combine an
entrepreneurial mindset with a scientific- and
innovation-led agile approach that sets us apart
as a partner of choice.”
Teva takes a flexible approach, seeking
solutions that satisfy the needs of both parties.
Reflecting its entrepreneurial outlook, scientific
experts are involved from the earliest discus-
sions to facilitate in-depth exploration of the
value proposition, and as conversations pro-
gress, bureaucracy is minimized to allow rapid
decision making.
When considering business opportunities,
Teva prioritizes improving the lives of people by
addressing unmet needs, while aligning strate-
gically within the current portfolio and pipeline.
Small-molecule medicines, the full spectrum of
biologics and new technologies to improve adher-
ence or compliance are all areas of interest and
synergize well with the company’s broad capa-
bilities. As it expands its portfolio, Teva also
welcomes patient-centric therapies that leverage
its proprietary patient-support programs across
the globe. In this area, Teva is recognized as a
leader in patient safety and transparency1
.
Crafting win-win partnerships
Teva’s continued commitment to expanding its
leadership in treating CNS disorders is reflected
in recent business development activities, with
acquisitions of promising new pipeline agents for
migraine (Labrys Biologics), Huntington disease
and tardive dyskinesia (Auspex Pharmaceuticals),
as well as an innovative technology to improve
adherence with an implantable microchip-based
drug delivery platform (Microchips Biotech).
In the United States alone, over 3 million
people, mostly women, endure chronic
migraine. Teva has cemented its position as a
leader in the development of more efficacious
migraine treatments, such as antibodies that
bind calcitonin gene–related peptide, a well-
validated migraine target.
For patients devastated by a diagnosis of
Huntington disease, new medications cannot
reach the market soon enough. “The acquisi-
tion of Auspex is a significant step in strength-
ening Teva’s leadership position in CNS and
advances us into underserved movement dis-
order markets. We look forward to accelerating
the development and commercialization of the
Auspex portfolio based on our infrastructure,
capabilities and strong commercial and RD
position in CNS”, commented Erez Vigodman,
president and CEO of Teva. The Auspex acqui-
sition has also brought a rich patent portfolio
based on the application of its deuterium-
chemistry platform to create new medicines
with improved pharmacokinetic properties.
In a move designed to enhance patient
outcomes through the use of digitally controlled
drug delivery technology, Teva also recently
announced a partnership with Microchip Biotech.
The Microchip Biotech platform is a programma-
ble microchip implant that can store hundreds of
medicine doses for months or years and allows
medicine release to be controlled via wireless
communications. The deal includes up-front pay-
ments to Microchip Biotech in the form of equity
investment and a technology access fee, with
Teva responsible for clinical development and
regulatory filings beyond phase 1.
According to Timothy R. Wright, Teva’s execu-
tive vice president of strategy, business develop-
ment and innovation, “Teva is transparent about
its desire to do business. We have developed
a clear and focused approach to outlining our
areas of interest, making it straightforward for
potential partners to understand the scope of
opportunity and engage in a more efficient and
fruitful dialogue.”
Reference
1. PatientView. The Corporate Reputation of Pharma in
2014—The Perspective of 165 Neurological Patient Groups.
http://www.patient-view.com/uploads/6/5/7/9
/6579846/patientview_neurology_final.pdf (2015).
CONTACT DETAILS
Rivka Kreitman, Senior Vice President,
Head of Global Search and Evaluation
Frazer, Pennsylvania, USA
Tel: +1-610-727-3222
Email: rivka.kreitman@tevapharm.com
Fernando Sallés, Vice President,
Head of Global Search
North Wales, Pennsylvania, USA
Tel: +1-610-786-7158
Email: fernando.salles@tevapharm.com

Imanova Ltd.
www.imanova.co.uk
Bridging the CNS translational gap
one image at a time
Imanova helps companies accelerate their drug development programs by providing imaging tools
for de-risking lead compounds early in humans, thereby reducing late-stage attrition.
I
maging technologies have long had a key
role in biomedical research and clinical
diagnostics. Because of its noninvasive
nature and exquisite sensitivity, molecular
imaging is of particular relevance when it comes
to translational science and validation of new
targets in both preclinical disease models and
human clinical trials.
A number of technologies, such as magnetic
resonance imaging (MRI), positron-emission
tomography (PET) and computed tomography
(CT), have provided researchers and clinicians
with powerful, noninvasive means to look
inside the human body using a range of
spatial and temporal scales. Although each
of these technologies on its own generates
useful data, the integration of information from
two or more modalities provides invaluable
information on drug-target interactions and
possible pharmacological responses. However,
accomplishing this integration has proven
technically challenging, and thus biomedical
imaging has yet to reach its full potential.
Established in 2011, translational imaging
company Imanova has become a global leader
in the development of processes to help address
this technological challenge for research purposes.
With its deep-rooted expertise in radiochemistry,
PET and MRI, the organization is uniquely
positioned to accelerate innovation in imaging
sciences—from radiotracer design and biomarker
validation to the integrated analysis of information
from multiple platforms—to support the drug
development programs of its partners all the way
from preclinical research to clinical studies.
“A well-designed imaging study saves time
and cost,” said Imanova CEO Kevin Cox. “For
example, molecular imaging provides early
information in man that de-risks decision making
and can help make early clinical trials shorter,
smaller and more targeted, bringing drugs to the
market more quickly and more cost-effectively.”
Imanova has built an extensive catalogue
and strong pipeline of imaging biomarkers
in partnership with academic and industrial
organizations and has developed a range of
integrated imaging services for clients in the
translational science space. At this point,
the company is interested in identifying new
opportunities to in-license compounds to expand
its portfolio of imaging ligands, and to further
move beyond the brain.
Informed decision making
for CNS therapies
Imanova has developed world-leading capabilities
in the application of PET for preclinical and
clinical target evaluation. Combined with MRI,
PET allows the company to address the main
pillars on which the potential success of a lead
compound rests: tissue penetration, target
engagement and pharmacological response.
With PET, a trace compound labeled with
a positron-emitting radioisotope can be
detected while bound to its target, which
allows researchers to determine the exact
location of the compound in the subject,
as well as quantitative aspects such as its
pharmacokinetics. This makes PET a crucial tool
for visualizing drug-target interactions in humans
early in the drug development process, often
at the same time as first-in-human and early
patient trials. Thus, it is an ideal approach for
experimental medicine.
This ability to directly bridge the preclinical
and clinical spaces makes PET a powerful
tool for translational science. By providing
key information on drug penetration and
engagement, optimal dose selection, and the
relationship between target and disease in
humans, PET helps accelerate new therapeutic
concepts into actual treatments.
Imanova has established a PET-tracer
development service, dubbed i-biomarker, to
provide industrial and academic partners with a
seamless solution for the development of new
molecular imaging biomarkers for use in disease
research and drug development for a range of
therapeutic indications.
The company is using i-biomarker to create
a pipeline of broadly applicable tracers, but
it is also positioning this service to allow
collaborations with institutions and pharma
partners on the development of specific
biomarkers of interest, often from pharma
compound libraries, for novel indications.
To date, Imanova has developed and
implemented over 17 i-biomarkers to good
manufacturing practice (GMP) standard and
is looking to in-license new leads. In addition
to CNS diseases, other key therapeutic areas
are candidates for i-biomarker development,
including oncology, inflammatory disorders and
respiratory diseases.
Imaging partnerships
Working to facilitate the translation of academic
research into commercial drug development,
Imanova brings together under one roof a
breadth of world-class capabilities to advance
imaging research in support of both academic
and industrial partners. The company is looking
to further expand its biomarker lead portfolio.
Strong par tnerships with academic
collaborators such as Imperial College London,
King’s College London and University College
London, three of the company’s co-owners,
provide access not only to scientific excellence,
new ideas and innovative concepts but also
to diverse and well-characterized patient
populations for drug development.
By providing a comprehensive suite of imaging-
based solutions, Imanova is driving imaging
research to new levels, with a focus on intelligent
and flexible study designs that can deliver
quantitative endpoints. Cox explained, “We
help clients make data-driven decisions and by
making imaging an integral part of the research
process we can help accelerate advances in CNS
drug development, and shape a collaborative
ecosystem in imaging and biomarker research
to the benefit of all.”
CONTACT DETAILS
Kevin Cox, CEO
Imanova Ltd.
London, United Kingdom
Tel: +44 (0)20 8008 6000
Email: enquiries@imanova.co.uk
Figure 1: Positron emission tomography (PET)
and magnetic resonance (MRI) images of the
human brain. PET images of important
serotonergic proteins involved in synaptic
neurotransmission are shown with [11C]
WAY100635 a marker of 5-HTs1A receptors
(top) and [11C]DASB a marker of the serotonin
transporter (bottom). The middle images
shows a structural T1 MRI image. Each row
contains three orthogonal slices through the
brain of the same individual.

Institut Pasteur
www.pasteur.fr
Unraveling the gut–brain axis
The Institut Pasteur is harnessing a powerful combination of in-house research strengths to explore
the relationship between the microbiome and the brain. The institute is looking for partners eager
to take advantage of this unique opportunity to learn more about the gut–brain axis.
A
dvances in microbiology, immunology
and neurobiology have long hinted at the
role bacteria and other microorganisms
may have in brain disorders and mental
dysfunction. Few organizations, however, have
the breadth of expertise to tackle questions at
the crossroads of these disparate fields. The
Institut Pasteur is an exception and is now
embarking on a comprehensive investigation
into the inner workings of the gut–brain axis.
The Institut Pasteur has established a
strategic plan that includes a ‘Grand Programme
Fédérateur’ (GPF), or major federating program,
that aims to unite forces within the institute’s
Paris campus and across the organization’s
international network. The goal is to earmark
significant resources for studies of the links
between microbes (microbiota and pathogens)
and neurological diseases so far considered
noncommunicable. This will ultimately result
in a better understanding of the interactions
between the microbes and their human hosts.
Since researchers first linked the microbiome to
human health over a decade ago, interest in the
microbiome and its connection to human biology
and disease, including its role in modulating brain
function, has exploded. Researchers from the
Institut Pasteur’s microbiology, immunology and
neurobiology teams have joined forces to better
understand the significance of the gut–brain
axis in the context of age-related neurological
disease. Disorders such as Alzheimer’s disease
and other dementias, Parkinson’s disease,
epilepsy, multiple sclerosis, migraine, tension-
type headache and cerebrovascular disease
together represent 7% of the total global burden
of disease1
. To curb the growth in these figures,
the research and medical communities must
gain a deeper understanding of the factors
responsible for neurodegenerative diseases
and mental disorders. With this goal in mind,
the Institut Pasteur plans to identify internal
synergies, promote innovative and translational
research and train tomorrow’s leaders in the field.
A four-pronged approach
The Institut Pasteur’s effort to combine
microbiology and immunology with neurobiology
makes it uniquely equipped to lead the search
for a new understanding of the causes of
neurological diseases. Recognizing that in
isolation none of these divisions could fully
address the breadth of the challenge, the
institute developed ad hoc collaborations that led
to the establishment of a broader, more formal
collaborative effort focusing on four key topics.
The first question to be addressed was whether
microorganisms can affect brain function through
the release of molecules or other mechanisms.
The second component was to study how
pathogens interfere with brain activity. The third
track will focus on developing animal models and
related tools to tackle these questions. Finally,the
Institut Pasteur plans to translate the outcomes
from the above thrusts into clinical approaches to
test new treatments for depression,schizophrenia
and other psychiatric disorders.
The potential of this research raises the
prospect of extraordinary advances, such as
the ability to reduce the incidence of depressive
states by simply altering the microbiome.
Other areas where the gut–brain axis could
have a role are Parkinson’s disease, obesity
and other conditions originally thought of as
noncommunicable diseases.
The Institut Pasteur is pursuing all of the above
as part of its GPF. An international symposium
took place in early July 2015 to advance the
initiative, and a massive open online course is
set to launch in 2016. The Institut Pasteur has
also initiated several international academic
partnerships around this initiative.
Pierre-Marie Lledo, director of the Department
of Neuroscience at the Institut Pasteur,
explained the significance of the project and
what it aims to achieve: “The vision of how
the human brain and body work together has
continuously evolved over the course of many
centuries. Modern neuroscience has now
entered a realm of quantitative and holistic
methods for measuring how mental states
correlate with brain activity and, consequently,
how brain activity depends on information
relayed from the external world or from our
internal state. At the Institut Pasteur, we seek to
answer these deep questions by reintroducing
the brain into the body, and not as a separate
entity from the body.”
Collaborative breakthroughs
The Institut Pasteur is now looking for partners
to help it accelerate the microbiome–brain
initiative. Potential collaborators could include
industrial partners, nonprofits, venture
capitalists and any other party interested
in advancing basic findings into the clinic.
Currently, the program is supported by a mix of
internal funding and external contributions from
organizations such as the Fondation Daniel
Nina Carasso, and it will continue expanding as
additional partners join.
A comprehensive understanding of the
microbiome–brain axis is perhaps the biggest
unmet need and market opportunity left in
healthcare. New partners will be joining a long
list of organizations that have recognized the
unique combination of capabilities the Institut
Pasteur brings to the table to tackle this
complex challenge.
Reference
1. Chin, J.H. Vora, N. The global burden of neurologic
diseases. Neurology 83, 349–351 (2014).
CONTACT DETAILS
Mallory Perrin-Wolff, Head of Partnerships and
Incentive Research Programs Department
Direction of Development/Grant Office
Institut Pasteur
Paris, France
Tel: +33 (0)1 44 38 93 69
Email: mallory.perrin-wolff@pasteur.fr
Microbes

Brain
With the support of
“The vision of how the
human brain and body
work together has
continuously evolved over
the course of many
centuries.
”
Identification of mechanisms underlying
microbed brain interactions has the potential
to increase our understanding of a broad
spectrum of human disease, and generate
novel therapies for these conditions.

Titan Pharmaceuticals, Inc.
www.titanpharm.com
Long-term drug delivery implant
for select chronic disorders
Titan Pharmaceuticals’ ProNeura implant offers an alternative to oral administration
by providing stable medication levels for up to 12 months.
T
itan Pharmaceuticals is a specialty phar-
maceutical company developing propri-
etary therapeutics utilizing its ProNeura
drug delivery platform. The technology provides
nonfluctuating medication levels over periods of
6–12 months and is ideal for treating chronic
diseases where around-the-clock, stable blood
levels of medication offer advantages over
the inconsistent levels associated with oral
administration.
ProNeura is a biocompatible, nonbiodegrad-
able implant made of a mixture of ethylene-vinyl
acetate and a chosen drug. It is a rod-shaped
solid matrix that is inserted subdermally into the
inner upper arm during a 15–20-min outpatient
procedure with local anesthesia and is removed
in a similar manner. Medication is released con-
tinuously by dissolution, providing a stable blood
level of the drug similar to that achieved with
intravenous administration. ProNeura is suitable
for use with various potent molecular entities,
allowing for long-term low-dose treatment of
chronic diseases such as Parkinson’s disease
and opiate addiction.
“Although daily oral medications for treating
chronic diseases, including CNS disorders, have
greatly benefitted patients, they often come with
some disadvantages. Titan is focused on opti-
mizing long-term treatment with already approved
drugs by using the ProNeura platform,” said Kate
Glassman Beebe, Titan’s executive vice president
and chief development officer. “In many cases,
the stable levels of medication delivered by
ProNeura could offer safety, efficacy or compli-
ance benefits to patients.”
Titan has validated the ProNeura platform
through the development of Probuphine
(buprenorphine implant) for the treatment of
opioid addiction. Addiction is a chronic disease
of the brain circuitry involving cycles of relapse
and remission. In the United States, daily sub-
lingual buprenorphine is the gold standard for
treating opioid addiction; however, it comes
with major challenges, such as poor patient
adherence, fluctuating medication levels in the
blood, diversion, abuse and even accidental
ingestion by children. Probuphine is an implant
formulation of buprenorphine capable of pro-
viding medication for six months after a single
treatment. Probuphine addresses many of
the treatment challenges associated with oral
buprenorphine while providing continuous medi-
cation. Probuphine completed phase 3 clinical
development in mid-2015, and resubmission of
the New Drug Application (NDA) to the US Food
and Drug Administration is expected in the third
quarter of 2015. Titan is now seeking partnering
opportunities for Probuphine outside the United
States and Canada for the treatment of opioid
addiction and potentially chronic pain.
Titan has also commenced the development
of a ProNeura-based product for the treatment
of Parkinson’s disease. Ropinirole, a dopamine
agonist for use in Parkinson's disease, was
evaluated as an implant formulation in a primate
model of Parkinson’s. Results demonstrated
sustained plasma levels of ropinirole for several
months after implantation, and Parkinsonian
symptoms were controlled without triggering
of dyskinesias. Titan plans to complete non-
clinical studies to enable the submission of an
Investigational New Drug (IND) application over
the next several months and to commence a
proof-of-concept clinical study in the second half
of 2016. Evaluation of additional compounds
in other chronic disease settings is also under
way, and Titan continues to seek opportunities
to collaborate with other companies and expand
the use of ProNeura.
CONTACT DETAILS
Sunil Bhonsle, President
Titan Pharmaceuticals, Inc.
South San Francisco, CA, USA
Tel: +1-650-989-2260
Email: sbhonsle@titanpharm.com
PlasmaDrugLevels
Therapeutic
Window
ProNeura
Oral Drug
Figure 1: Probuphine is designed to release sustained therapeutic drug levels in patients with
opioid addiction for up to six months.
Figure 2: ProNeura implants provide stable, nonfluctuating drug levels for 6-12 months v.
daily oral delivery.

Probiodrug AG
www.probiodrug.de
New therapeutic strategy for
treating Alzheimer’s disease
Probiodrug’s novel approach targets a modified form of β-amyloid, which has a key role in the creation of toxic
Aβ oligomers. The company’s lead product is a first-in-class oral small-molecule glutaminyl cyclase inhibitor.
P
robiodrug is a biopharmaceutical com-
pany focused on the development and
commercialization of new therapeutic
products for the treatment of Alzheimer’s dis-
ease (AD). The global burden of dementia is
expected to triple from 44million to 135million
affected individuals by 2050, with an estimated
50%–70% of cases attributable to AD. No new AD
drugs have been approved for nearly a decade,
and current approved drugs only treat symptoms
of the disease, so there is a clear unmet need for
disease-modifying therapies.
β-Amyloid (Aβ) peptides are a hallmark of AD.
The first generation of disease-modifying AD
drugs targets Aβ in general to inhibit plaque
production or reduce existing plaque burden.
Although outcomes from advanced clinical trials
have been disappointing, the lessons learned
have been included in the design of new trials,
which are currently under way. Earlier this year,
clinical scientists reported promising interim
results from a phase 1b study of aducanumab in
patients with prodromal or mild AD. The findings
support the concept of Aβ being decisively
involved in AD pathology.
The original Aβ hypothesis has been modified in
recent years, and it is now thought that soluble,
highly toxic small aggregates called Aβ oligomers,
rather than Aβ plaques, are the key culprit driv-
ing early pathological changes in AD. Probiodrug
has developed a new therapeutic concept linked
to disease initiation and progression that is
based on key research results obtained under
the leadership of Hans-Ulrich Demuth, former
CSO at Probiodrug, in collaboration with various
academic groups.
The scientists corroborated earlier findings
that Aβ plaques contain high levels of a post-
translationally modified Aβ species known as
pyroglutamate-modified Aβ (pGlu- Aβ). pGlu-Aβ
seeds Aβ oligomers, and the hypertoxicity of
these oligomers seems to be brought about
by changes in the secondary and tertiary Aβ
structure conferred by pGlu- Aβ1
. An important
cornerstone of this concept is Probiodrug’s dis-
covery and characterization of an enzyme called
glutaminyl cyclase (QC), which is essential for the
formation of pGlu-Aβ. It cyclizes the glutamate
of N-terminally truncated Aβ species that carry
glutamate at positions 3 and 11 (ref. 2).
Taken together, these findings formed the basis
of Probiodrug’s innovative disease-modifying
therapeutic concept to target pGlu-Aβ via two
modes of action: inhibiting its formation with
QC inhibitors, and increasing pGlu-Aβ clearance
with specific pGlu-Aβ antibodies (Fig. 1). The
company’s drug discovery program resulted in
highly selective first-in-class and first-in-indication
inhibitors of QC. The lead molecule, PQ912, is
currently being evaluated in a phase 2a clini-
cal trial. Probiodrug’s preclinical pipeline also
includes a monoclonal antibody designed to
remove existing pGlu-Aβ from the brain (Fig. 2).
Significant investment is needed to conduct
clinical trials and overcome the regulatory
challenges involved in bringing a new AD drug to
market. Probiodrug is currently seeking financing
to continue clinical development of PQ912 and
carry out preclinical work for its other product
candidates in preparation for future clinical
studies.
Scientific understanding
Headquartered in Halle, Germany, Probiodrug
already has a successful track record of
discovering and validating a new concept and
bringing it into drug development. Demuth and
Konrad Glund, who is the CEO, founded the
company in 1997 on the basis of Demuth's
scientific research about the enzymology and
physiology of dipeptidyl peptidase-4 (DPP-4) and
the discovery that inhibition of DPP-4 normalized
high blood glucose levels. A medical use patent
was granted for this newly discovered therapeu-
tic target, and the results paved the way for the
development of a new class of oral antidiabetic
agents, DPP-4 inhibitors (also known as gliptins).
The company sold the diabetes program in
2004. After that, Probiodrug started work on its
AD research program, which led to the concept
of targeting pGlu-Aβ. The company performed
extended target validation, addressing questions
about how the presence of pGlu-Aβ correlated to
and influenced AD pathology in animal models
and what the effect would be of either preventing
the formation of pGlu-Aβ or increasing its clear-
ance. New animal models were developed to
study the pGlu-Aβ hypothesis.
It is now known from analysis of postmortem
brain biopsies from AD patients that pGlu-Aβ
increases with disease severity, as does
expression of QC. Data from animal models
have shown that higher expression of QC
increases pGlu-Aβ levels and the severity of
the behavioral deficits, whereas knockout of
QC has a protective effect3
. Beside this genetic
proof of principle, Probiodrug has shown that
treatment with QC inhibitors reduces pGlu-Aβ
and attenuates behavioral deficits in various
transgenic AD-like animal models. Validation of
the concept has been published4
. Toward the
end of 2010, Probiodrug nominated PQ912 as
its lead product candidate and embarked on the
next steps toward clinical development.
QC inhibitors: a new class of drugs
The first-in-class small-molecule QC inhibitor
PQ912 was safe and well tolerated in a com-
prehensive single and multiple ascending dose
phase 1 study in healthy young and elderly vol-
unteers5
. The maximum tolerated dose was not
reached. QC activity in the cerebrospinal fluid
(CSF) was inhibited in a dose-dependent manner.
Analysis of pharmacokinetic-pharmacodynamic
correlations showed that with safe doses, an
average of 90 % QC inhibition in the CSF was
achieved.
The safety and tolerability of PQ912 over a
12-week treatment period are now being evalu-
ated in a phase 2a clinical trial in nonhospitalized
subjects with early AD (the SAPHIR study). This
randomized, double-blind, placebo-controlled
study plans to enroll 110 patients with a diag-
nosis of early AD (prodromal and mild AD) from
around 20 sites across Europe. The first patient
was enrolled in March 2015, and initial data are
expected mid-2016. Main inclusion criteria are
a baseline Mini Mental State Examination score
of 21–30, no other symptomatic medication,
and an AD-positive signature in screening CSF
samples at randomization (reduced levels of
Aβ42
and increased levels of t-tau or p-tau) or a
positive amyloid positron-emission tomography
(PET) image, if available, within 18months prior
to baseline. The CSF screening and/or PET scan
should ensure that only patients with dementia
caused by AD are included in the trial, thereby
reducing the risk of enrolling patients with other
forms of dementia, which would confound the
results.
The study is also evaluating efficacy through a
set of exploratory outcome measures compris-
ing cognitive tests using the Neuropsychological
Test Battery, assessments of brain functional
connectivity that rely on resting-state functional
magnetic resonance imaging analysis and elec-
troencephalography to capture changes in syn-
aptic activity. The study also includes measure-
ments of a panel of new molecular biomarkers in
CSF designed to evaluate the effect of PQ912 on
disease pathology. Ultrasensitive assays will be
used to quantify levels of pGlu-Aβ and Aβ oligo-
mers, which have been shown to be present in
higher amounts in the CSF of patients with AD
compared with that of age-matched controls.
A pivotal phase 3 clinical trial is likely to fol-
low if results from the phase 2a exploratory
outcome measures are favorable. If results are

biopharmadealmakerswww.nature.com/biopharmadealmakersinconsistent, a phase 2b proof-of-concept study
will be carried out to evaluate efficacy over a lon-
ger treatment period.
Probiodrug’s pipeline includes a second QC
inhibitor, PQ1565, which has an attractive pre-
clinical profile, and the company is preparing
regulatory toxicology studies.
Complementary approach
Alongside the QC inhibitors that prevent the
production of pGlu-Aβ, Probiodrug is pursuing
an immunotherapy approach to selectively clear
the brain of existing pGlu-Aβ and leave nontoxic
forms of Aβ untouched. PBD-C06, the lead candi-
date, is a monoclonal antibody with high specific-
ity for pGlu-Aβ. Data from preventative and thera-
peutic studies in animal models have shown that
PBD-C06 reduces soluble and insoluble pGlu-Aβ
as well as total Aβ, and also rescues behavioral
deficits6
. PBD-C06 has been successfully human-
ized and deimmunized to avoid detection by the
patient’s immune system, and toxicology studies
are expected to start in 2016.
The two modes of action for targeting pGlu-Aβ
could be complementary, and Probiodrug is
exploring combinations of PQ912 and PBD-C06
in animal models. There is also rational for using
anti–pGlu-Aβ strategies with β-secretase inhibi-
tion in combination. The anti–pGlu-Aβ approach
may also have potential in other indications,
such as Down’s syndrome, age-related macular
degeneration and Huntington’s disease. Recent
data have shown that QC inhibition efficiently
reduced mutant huntingtin and rescued the
Huntington’s disease phenotype, probably by
increasing levels of the small heat shock protein
αB-crystallin, which points toward a potential
additional mechanism of action in pathologies
caused by misfolded proteins.
Since 2011, Probiodrug has transformed itself
from a research and discovery entity into a devel-
opment business, a process that culminated in
its shares being listed on Euronext Amsterdam
in October 2014. As a result of the restructuring,
the company now works on a virtual basis, out-
sourcing most of its RD activities. Probiodrug
gains and retains access to global development
and scientific expertise through consulting
contracts.
The company is also expanding and strength-
ening its intellectual property position by filing
composition-of-matter and medical use patent
applications in major jurisdictions. Probiodrug
was the first company to link QC to AD, and it has
been granted broad medical use patents in major
markets for the use of QC to treat and prevent
neurodegenerative disorders, including AD.
Product candidates available
for partnering
Probiodrug is looking to enter into partnerships
to develop PQ912 beyond phase 2a and advance
other product candidates, and it is open to dis-
cussions with biotechnology and pharmaceutical
companies. “The attractiveness for a company
choosing to partner with Probiodrug would be
access to highly innovative drug candidates,”
said Glund. “The targets pGlu-Aβ and QC have
been intensively validated preclinically, show-
ing disease-modifying effects. The frontrunner
PQ912 is well tolerated in human subjects and
shows a high level of target engagement in the
cerebrospinal fluid of humans. It has the poten-
tial to be a next-generation Alzheimer’s asset.”
There are currently no treatments available that
stop or reverse the progression of AD. If QC inhibi-
tors prove successful, they could provide patients
with a leading therapy in the market. “We expect
to make a difference to the patient with a solution
to treat this devastating disease,” said Glund.
References
1. Nussbaum, J.M. et al. Nature 485, 651–655 (2012).
2. Schilling, S. et al. FEBS Lett. 563, 191–196 (2004).
3. Jawhar, S. et al. J. Biol. Chem. 286, 4454–4460 (2011).
4. Schilling, S. et al. Nat. Med. 14, 1106–1111 (2008).
5. Weber, F. et al. Neurodener. Dis. 11, [Supplement 1], 1453
(2013).
6. Frost, J.L. et al. Neurodegener. Dis. 10, 265–270 (2012).
CONTACT DETAILS
Konrad Glund, CEO
Probiodrug AG
Halle/Saale, Germany
Tel: +49 345 55599 00
Email: contact@probiodrug.de
Figure 1: Probiodrug’s differentiated approach targets the formation of toxic soluble Aβ oligomers
in AD.
Figure 2: Probiodrug’s pipeline. The company is targeting pGlu-Aβ via two modes of action:
(i) inhibiting the production of pGlu-Aβ (PQ912 and PQ1565) and (ii) clearing existing pGlu-Aβ
from the brain (PBD-C06).

B14
Approaches to age-related disorders evolve
Although specific age-related disorders such as Alzheimer’s disease
continue to be a focus of RD investment and dealmaking activity,
companies are also beginning to approach aging in a broader way.
BY SUZANNE ELVIDGE
T
he world’s population is aging. According
to the World Health Organization, the
global population of people aged over
60 is predicted to be around 2 billion by 2050,
or 22% of the population, an increase from
11% in 2000. The concomitant increase in the
prevalence of age-related diseases—such as
Alzheimer’s disease, age-related macular degen-
eration, osteoporosis, cardiovascular disease,
diabetes and cancer—is placing a growing
and substantial strain on healthcare budgets.
Thus, the need for new approaches to treat
or prevent such disorders is high, particularly
for diseases such as Alzheimer’s disease, for
which the effectiveness of current treatments
is very limited.
Persistence with Alzheimer’s disease
Alzheimer’s disease, the most common form
of dementia, is the focus of two of the top five
aging deals from the past 12 months (Table 1),
with companies persisting despite the catalog of
expensive late-stage clinical failures in the field.
A recent study found that the industry invested
in 1,120 unique pipeline drugs for Alzheimer’s
disease from 1995 to 2014, but the overall suc-
cess rate in reaching approval was just 0.5%
(Nat. Rev. Drug Discov. 14, 161–162; 2015).
Furthermore, the drugs that were approved
only treated disease symptoms, as opposed to
modifying disease progression.
Such failures may be dampening investment
and dealmaking activity in the field. “Failure
rates are high, and pragmatically, the money
spent on an Alzheimer’s trial could fund a num-
ber of oncology trials. It’s not that companies
don’t want to work in the area, but there is a
penalty, and it takes investment away from
somewhere else,” said Eric Karran, director of
research strategy at Alzheimer’s Research UK.
Many putative disease-modifying drugs in devel-
opment for Alzheimer’s disease are based on
the amyloid hypothesis, which proposes that the
accumulation of a fragment of amyloid precursor
protein (APP), β-amyloid, is behind the neuronal
loss and neurodegeneration associated with the
disease. One of the key deals of 2014, an agree-
ment between Eli Lilly and AstraZeneca that could
be worth up to $500 million for AstraZeneca,
focuses on preventing the production of β-amyloid
by targeting β-secretase cleaving enzyme (BACE).
The 50:50 partnership to develop AZD3293,
AstraZeneca’s BACE inhibitor, brought Lilly—a
long-term investor in the field—back into the race
to develop a BACE inhibitor after it had to drop
its own BACE inhibitor, LY2886721, owing to liver
toxicity (Nat. Rev. Drug Discov. 13, 804; 2015).
A phase 2/3 trial of AZD3293 is planned, with
Lilly leading the clinical development.
Some researchers have questioned the amy-
loid hypothesis, however, pointing out inconsis-
tencies between β-amyloid levels and normal
cognition, and suggesting that research on
Alzheimer’s disease needs to expand beyond
a focus on β-amyloid plaques (Alzheimers Res.
Ther. 6, 37; 2014). Another approach to treat-
ing Alzheimer’s disease involves targeting the
tangles of tau protein that develop in the brain.
An agreement between Johnson Johnson
and the Swiss biotech company AC Immune
focused on ACI-35, AC Immune’s therapeutic
vaccine targeting tangles of tau protein, as well
as on other tau vaccines. Johnson Johnson’s
Janssen has gained rights to ACI-35, which was
the first vaccine for Alzheimer’s disease to enter
clinical trials and is now in phase 1b. This is
AC Immune’s third major collaboration involving
drugs targeting the tau protein.
Uncertainty over the optimal approaches for tar-
geting Alzheimer’s disease will remain high until
a clinical trial clearly demonstrates a disease-
modifying effect. Recently, however, there
have been tentative suggestions of such
an effect in trials of Lilly’s solanezumab, an
antibody to β-amyloid. Although the primary
endpoints were missed in two phase 3 trials,
an extended subgroup analysis suggested that
solanezumab has a positive effect in mild dis-
ease (Alzheimers Dement. (NY) doi:10.1016/
j.trci.2015.06.006; 2015), and another phase 3
trial is ongoing.
“If it is successful, this could transform the
field as the first disease-modifying drug for
Alzheimer’s disease, and tell us a lot about the
disease process,” said Karran. “This could bring
companies back into the area.”
A broader approach for age-related
disorders?
Although the focus at the moment is still
largely on treating individual diseases such
as Alzheimer’s disease, more researchers and
companies are beginning to look at aging over-
all, with interest in a potential central mecha-
nism leading to progressive decline and a focus
on healthy lifespan, or ‘healthspan’.
“Many big pharma companies, including
AbbVie, Pfizer and Johnson Johnson, have
programs in aging and healthspan,” said
George Vlasuk, president and CEO at Navitor
Pharmaceuticals, a company focusing on the
mTORC1 signaling pathway as a target for
intervention in age-related diseases. “While
previous overhyping about drugs for aging led
to skepticism, there is now a recognition of real
science behind the mechanisms of aging and
aging-related diseases.”
Part of the skepticism might originate from
investments in the area that have appeared
to fail, at least in the short term. For example,
back in 2008, GlaxoSmithKline (GSK) invested
$720 million to buy Sirtris, a biotech company
that developed drugs targeting sirtuins, which
have been implicated in age-related diseases
such as type 2 diabetes and cancer. But after
little apparent progress, GSK shut down Sirtris
in March 2013 and moved its projects in-house.
“Sirtris was a trailblazing effort to look at an
overall mechanism of action for aging. It was
the first real aging-based company, but I believe
it was ahead of its time, and its story got lost
Table 1. Top three aging deals by value (July 2014–July 2015).
Companies involved Headline Deal value
(US$ million)
Date announced
Calico; AbbVie Calico will create an RD facility
focused on aging and age-related
diseases in the San Francisco Bay
Area. To fund the facility, AbbVie and
Calico will each provide up to $250
million, with the possibility to both
contribute a further $500 million.
1,500 September 2014
Johnson Johnson
(Janssen
Pharmaceuticals);
AC Immune
Johnson Johnson to develop AC
Immune’s tau-targeted therapeutic
vaccine against Alzheimer’s disease,
ACI-35, from phase 2 onward in a
$509 million deal.
509 January 2015
Eli Lilly; AstraZeneca Eli Lilly and AstraZeneca enter
into a partnership to develop
AZD3293, a BACE inhibitor for
Alzheimer’s disease. Lilly will take
the lead on the phase 2/3 trials.
500 September 2014

B15
selvanegra/iStock/Thinkstock
behind the hype because the deal with GSK fell
way short of its expectations, leaving a wari-
ness about the area,” said Vlasuk, who was
previously Sirtris’ CEO.
One sign that the skepticism about broad-
based strategies for targeting age-related dis-
orders could be abating is the biggest deal of
the past year, between Calico and AbbVie. This
deal, signed in September 2014 and poten-
tially worth up to $1.5 billion, is to create an
RD facility in the San Francisco Bay Area that
will focus on aging and age-related diseases,
including neurodegeneration and cancer. Calico,
established in 2013, is focused on age-related
diseases and has the might of Google behind it,
as well as a leadership team that includes Art
Levinson and other key figures from Genentech.
Another intriguing recent development is
an effort to tackle a major outstanding ques-
tion in the field: could it be possible to design
clinical trials and gain regulatory approval for
a therapeutic to intervene in aging, rather than
treat a specific age-related disorder such as
type 2 diabetes?
According to Nir Barzilai of the Albert Einstein
College of Medicine in New York, treating one
disease might mean simply exchanging it for
another; for example, reducing the incidence of
cardiovascular disease might mean that more
people will die from another age-related illness
such as Alzheimer’s disease.
“It’s aging that makes people ill. The new
paradigm is to develop drugs that delay aging
and therefore delay the onset of aging-related
diseases, rather than treating the individual dis-
eases,” explained Barzilai. “Delaying aging by
just two years could lead to huge savings in
healthcare and social costs.”
One potential therapeutic in this field is met-
formin, an oral antidiabetic drug that has been
available since the 1950s. It is safe and well
tolerated, and it delays aging in animal models.
Barzilai and his colleagues are planning a clini-
cal trial dubbed Targeting Aging with Metformin
(TAME), which will involve thousands of people
who have or are at risk of one or two of the follow-
ing diseases: cancer, heart disease and cogni-
tive impairment (Nature 522, 265–266; 2015).
The aim is to see whether the metformin delays
death, onset of diabetes or the development of
diseases that the subjects do not already have.
“The metformin trial is an intriguing opportunity,
and makes a great start,” said Vlasuk.
The next step will be to get the regulatory
bodies to accept therapeutics that delay aging
rather than treat individual diseases. The US
Food and Drug Administration (FDA) seems open
to the idea, having held a meeting to discuss the
TAME trial in June 2015.
“We are really glad to see dialogue happen-
ing at the FDA, as this area has previously
been seen by some as pseudoscience,” said
Vlasuk. “Delaying aging and therefore reduc-
ing age-related diseases will be well worth
the investment.”
Suzanne Elvidge is a freelance writer who covers
the biotechnology and pharmaceutical industry.
“Many big pharma
companies, including
AbbVie, Pfizer and Johnson
Johnson, have programs
in aging and healthspan.
”GEORGE VLASUK,
PRESIDENT AND CEO
AT NAVITOR
PHARMACEUTICALS

International Stem Cell Corporation
www.internationalstemcell.com
A new approach to Parkinson’s disease
Regenerative medicine company International Stem Cell Corporation (ISCO) leads the way in developing
new treatments for Parkinson’s disease and other clinical conditions using a unique stem cell approach.
C
alifornia-based ISCO is a clinical-stage
biotechnology company developing
novel stem cell–based therapies, with
revenues of over $7million in 2014 from its two
subsidiary businesses: Lifeline Cell Technology,
a leading manufacturer of purified primary human
cells and optimized reagents for cell culture, and
Lifeline Skin Care, which develops, manufactures
and markets dermatological products containing
stem cell extracts. The company’s therapeutic
pipeline includes programs in neurology, ophthal-
mology and metabolic liver diseases (Fig. 1).
ISCO’s proprietary stem cell platform is based
on parthenogenesis and produces pluripotent
stem cells from unfertilized human eggs, a
method the company has patented in the United
States, Japan and the European Union (EU).
Importantly, in the EU, where embryonic stem
cells (ESCs) are unpatentable, the company has
successfully prosecuted its patents, thereby gain-
ing a significant competitive advantage.
Against the backdrop of a cell-therapy renais-
sance across multiple clinical areas, ISCO
provides unique partnering opportunities from
preclinical to later stages of development.
Tackling Parkinson’s disease
Recently, ISCO began a phase 1/2a clinical study
in Parkinson’s disease (PD). The trial breaks
new ground: despite years of research into cell
therapy for PD, this is the first time cells derived
from a pluripotent stem cell source have been
transplanted into people with the disease.
PD is a progressive neurodegenerative disor-
der resulting from a gradual loss of the neurons
responsible for producing dopamine, and it is
characterized by symptoms including tremors at
rest, rigidity and impaired movement. According
to the Parkinson’s Disease Foundation, an esti-
mated 7 to 10 million people worldwide live with
PD, with as many as 1 million of those in the
United States alone—more than the combined
total of people diagnosed with multiple sclerosis,
muscular dystrophy and Lou Gehrig’s disease.
ISCO’s PD program builds on earlier clinical
work showing that transplanted fetal cells can
be effective in treating the symptoms of PD.
Indeed, transplanted cells have been shown to
persist and provide symptomatic relief for more
than 18 years1
, offering the tantalizing possibility
that, if the disease is caught early enough, a cell
transplant may effectively ‘cure’ a patient (Fig. 2).
One of the major problems with these earlier
trials was the availability and supply of fetal cells
for transplant. ISCO has solved this problem by
using its proprietary stem cell platform to gener-
ate stem cell–derived human parthenogenetic
neural stem cells (hpNSCs). The company has
shown in its preclinical research that neural stem
cells—self-renewing, multipotent cells that have
the ability to differentiate into dopaminergic neu-
rons and express brain-protecting neurotrophic
factors—are a viable alternative to fetal cells and
therefore offer a new possibility for the treatment
of PD and other neurological disorders.
ISCO has assembled a significant body of pre-
clinical data on hpNSCs and has evaluated the
cells’ safety and tolerability in different animal
species, including non-human primates2
. Data
presented at the annual meeting of the Society
for Neuroscience in November 2014 showed
that the company’s hpNSCs have a clean safety
profile, with no evidence of teratoma formation
or ectopic tissue up to 12 months after trans-
plant. Proof-of-concept studies, in which hpNSCs
were transplanted into animals with induced PD
symptoms, validated the postulated mechanism
of action. Data showed that the cells migrated to
the damaged area of the brain, created dopamine
fibers and increased dopamine levels, leading
to improved motor function. Evidence was also
found to support the hypothesis that the trans-
planted cells protect the native neuron population
by expressing neuroprotective trophic factors.
The phase 1/2a clinical trial is ongoing under
the direction of Andrew Evans, director of the
Movement Disorders Program at the Royal
Melbourne Hospital in Australia. The trial is a
single-arm, dose-escalating 12-month study
designed to evaluate the safety and efficacy of
ISCO’s clinical product in 12 subjects with PD.
Results are anticipated in 2016.
The platform’s edge
ISCO’s proprietary stem cell technology uses
human parthenogenesis to produce stem cells
(hpSCs) that are similar to ESCs: they have the
potential to differentiate into all the specialized
cells of the human body and, like ESCs, have the
capacity to divide an almost unlimited number
of times, providing an essentially inexhaustible
supply of cells for transplantation. Unlike ESCs,
ISCO’s hpSCs do not require the destruction of
human embryos and, importantly, unlike other
allogeneic cell therapies, can be made in a way
that may obviate the need for immune suppres-
sion in patients receiving stem cell treatments.
ISCO collaborates with researchers at institu-
tions including the Scripps Research Institute,
Sanford-Burnham Stem Cell Research Center and
the University of California, San Diego.
With its novel stem cell platform having a clear
intellectual property advantage in the EU and
first results for its phase 1/2a clinical trial in
PD expected in 2016, ISCO is now beginning a
systematic outreach program to find licensees or
co-development partners.
References
1. Kefalopoulou, Z. et al. JAMA Neurol. 71, 83–87 (2014).
2. Gonzalez, R. et al. Cell Transplant. 24, 681–690 (2015).
CONTACT DETAILS
Ruslan Semechkin, Chief Scientific Officer
International Stem Cell Corporation
Carlsbad, California, USA
Tel: +1-760-940-6383
Email: ras@intlstemcell.com
Figure 1: ISCO’s pipeline covers a range of therapeutic conditions. IND, investigational new drug.
Figure 2: ISCO’s PD treatment paradigm is
unique in two regards: the neural stem cells
are created from human parthenogenetic stem
cells, and the cells are transplanted in three
locations of the patient’s brain—the substantia
nigra, the putamen and the caudate.
Product Indication Preclinical IND track Phase 1/2a Phase 2b/3
Neural stem cells Parkinson's disease
Ischemic stroke
CytoHep Metabolic liver diseases
RPE cells Retinal blindness
CytoCor Corneal blindness

BioPharma Dealmakers_September 2015

BioPharma Dealmakers_September 2015

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