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 2015www.nature.com/biopharmadealmakers

PUBLISHING TEAMHead of Publishing ServicesRuth Wilson

EditorRaveena Bhambra

Editorial AssistantChristine Janssen-Seijkens

Business Development TeamClaire ThompsonSamia BurridgeVeronica Zacatenco

Profi le WritersSofi e BosmaEmma DoreyJackie KellyDolly KoltchevMary Lee MacKichanKaren de SeveGaspar Taroncher-OldenburgNick Taylor

Feature WritersRachel BrazilSuzanne ElvidgeChris Morrison

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MarketingVirginia Lee

Note: Companies that appear in this table of contents have paid for their advertisement features and have fi nal approval of their content. If you would like to appear in the next Biopharma Dealmakers please contact: Claire Thompson | [email protected]

FEATURES

B2 ADVANCES IN NEUROSCIENCE AND SURGING MARKETS MAY SPUR DEAL ACTIVITYAfter 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 EVOLVEAlthough 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 DISORDERSBig 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.

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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.

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Advances in neuroscience and surging markets may spur deal activityAfter 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 co incides with the emergence of a variety of innova tive mechanisms of action and technologies such as gene therapy that are driving early‑stage d ealmaking 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 global ly (see “Approaches to age‑related disorder s 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‑phosphat e 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.

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“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 painVarious 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

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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 abdomino plasty, 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 trans mucosal delivery for breakthrough cancer pain or transdermal delivery for chronic pain.

Ramping up CNS R&D via partnershipsWhen 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 neuro science therapeutic area unit, “each subspecialty in neuro science 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 p harmacological approaches, he said.

Chris Morrison is a freelance analyst, editor and writer who reports on the biotechnology and pharmaceutical industries.

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Astrocyte Pharmaceuticals, Inc.www.astrocytepharma.com

Harnessing the stars to treat traumatic brain injuriesNew 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 1.7 million people are diagnosed with a TBI in the United States, accord-ing to the US National Institutes of Health2. The incidence of this type of injury is even more widespread when those who are not treated in a hospital or emergency department are included, with up to 3.8 million concussions occurring each year in the United States3. Despite the growing need, there are no approved therapeutics for the treatment of TBI.

That’s where Astrocyte Pharmaceuticals, Inc. may be on to something exciting and very prom-ising. Historically, neuroprotective approaches have focused on nerve cells or just one mecha-nism involved in a brain injury. “Our approach is different,” said Jeffrey L. Ives, an independent director at Astrocyte. “Instead of trying to help neurons directly by regulating the release of neu-rotransmitters or the influx of calcium, our work focuses on activating astrocytes, which are the 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 function, from adjusting blood flow to regulating neurotransmitter transport and uptake to provid-ing energy. Astrocyte’s compounds trigger mul-tiple intrinsic protective pathways in the brain, increasing the chances for success. “This is an exciting pleiotropic mechanism, and our goal is to harness the neuroprotective and neuroregenera-tive support of astrocytes through our proprietary target and small-molecule agonists,” said William S. Korinek, Astrocyte’s cofounder and CEO.

Brain injury after impactWhen 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

astrocyte intervention, nerve cells are perma-nently damaged under such circumstances5. Astrocytes have a vital role in removing excess glutamate and other neurotransmitters, regulat-ing calcium release, restoring ion balance and controlling brain edema or swelling. Astrocytes require energy to perform these functions, and Lechleiter found that boosting ATP production by using a P2Y1 receptor agonist to selectively 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 developmentAstrocyte 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 the millions 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 DETAILSWilliam S. Korinek, CEOAstrocyte Pharmaceuticals, Inc.Cambridge, MA, USATel: +1-617-444-8765Email: [email protected]

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 PrebysMedical Discovery Institutewww.sbpdiscover y.org

Partnering to advance translational researchSanford 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 GenomicsSince 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 areasThe 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 $149 million in direct funding, SBP’s world-class cancer center has revealed new insights into the molecular mecha-nisms of cancer, including significant contribu-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 successThe 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 DETAILSMichael Jackson, SVP,Drug Discovery and DevelopmentSanford Burnham Prebys Medical Discovery InstituteSan Diego, CaliforniaTel: +1-858-795-5201Email: [email protected]

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

P� zer

Takeda Pharmaceuticals

U.S. Air Force



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biOasishttp://biOasis.ca

Transcend: a natural way to cross the blood–brain barrierBy 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 $100 billion 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 systembiOasis 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 mundaneThe 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 DETAILSRob Hutchison, CEORichmond, British Columbia, CanadaTel: +1-604-644-1232Email: [email protected]

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



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Teva Pharmaceuticalswww.tevapharm.com

Teva Pharmaceuticals: a leader in CNS specialty medicineA 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 $6 billion 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 t reatments for MS. In relapsing - remit t ing MS, Teva seeks t o d e ve l op s a f e r, mo r e t o l e r ab l e therapies, including once-daily orals and monoclonal antibodies. In progressive MS, Teva seeks neuroprotective and regenerative medicines. The application of pharmacogenomics and eHeal th technolog y to improve MS d isease 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 mig r a ine, mens t r ua l m ig r a ine and migraine-related syndromes, trigeminal autonomic cephalalgias (e.g., cluster headaches) and post-traumatic headache are all indications of interest.

An experienced partner in CNSTeva offers its business partners proven excel-lence in CNS drug discovery, drug development and commercialization. According to Michael Hayden, president of global R&D 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 partnershipsTeva’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 R&D 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 DETAILSRivka Kreitman, Senior Vice President, Head of Global Search and EvaluationTeva PharmaceuticalsFrazer, Pennsylvania, USATel: +1-610-727-3222Email: [email protected]

Fernando Sallés, Vice President, Head of Global SearchTeva PharmaceuticalsNorth Wales, Pennsylvania, USATel: +1-610-786-7158Email: [email protected]



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Imanova Ltd.www.imanova.co.uk

Bridging the CNS translational gap one image at a timeImanova helps companies accelerate their drug development programs by providing imaging tools for de-risking lead compounds early in humans, thereby reducing late-stage attrition.

Imaging 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 therapiesImanova 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 partnershipsWorking 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 DETAILSKevin Cox, CEOImanova Ltd.London, United KingdomTel: +44 (0)20 8008 6000Email: [email protected]

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.



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Institut Pasteurwww.pasteur. f r

Unraveling the gut–brain axisThe 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 approachThe Institut Pasteur’s effor t 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 par tners, 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 DETAILSMallory Perrin-Wolff, Head of Partnerships and Incentive Research Programs DepartmentDirection of Development/Grant Office Institut Pasteur Paris, FranceTel: +33 (0)1 44 38 93 69Email: [email protected]

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.



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Titan Pharmaceuticals, Inc.www.t i tanpharm.com

Long-term drug delivery implant for select chronic disordersTitan 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 DETAILSSunil Bhonsle, PresidentTitan Pharmaceuticals, Inc.South San Francisco, CA, USATel: +1-650-989-2260Email: [email protected]

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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.



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Probiodrug AGwww.probiodrug.de

New therapeutic strategy for treating Alzheimer’s diseaseProbiodrug’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 44 million to 135 million 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 understandingHeadquartered 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 drugsThe 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 18 months 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



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inconsistent, 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 approachAlongside 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 R&D 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 partneringProbiodrug 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 DETAILSKonrad Glund, CEOProbiodrug AGHalle/Saale, GermanyTel: +49 345 55599 00Email: [email protected]

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).

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Approaches to age-related disorders evolveAlthough 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.

BY SUZANNE ELVIDGE

The 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 e ffectiveness of current treatments is very limited.

Persistence with Alzheimer’s diseaseAlzheimer’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 m odifying 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 t argeting 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 solanezu mab 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 R&D 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

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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 R&D 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 t rials 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 o pportunity, 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



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International Stem Cell Corporationwww.internat ionalstemcel l .com

A new approach to Parkinson’s diseaseRegenerative 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 $7 million 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 diseaseRecently, 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 edgeISCO’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 DETAILSRuslan Semechkin, Chief Scientific OfficerInternational Stem Cell CorporationCarlsbad, California, USATel: +1-760-940-6383Email: [email protected]

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

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Manipulating the human microbiome to fight inflammatory disordersBig 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.

BY RACHEL BRAZIL

F ortune declared 2015 “the year of the microbiome.” The clinical success of fecal microbiota transplants (FMTs)

for treating Clostridium difficile infections and studies linking changes in the composition of the gut microbiota to various disorders have moved the therapeutic manipulation of the body’s bacterial ecosystems into the spotlight.

“The microbiome space, unlike any other that I have seen in life sciences, has quickly captured the public’s imagination with its thera-peutic potential,” said Peter DiLaura, CEO of Second Genome, one of the pioneering biotech companies in the area. This is mainly because of the unconventional nature of FMT therapy, which involves introducing healthy bacterial flora through infusions of donor stool. In 2013, a randomized, controlled trial showed that FMT was more effective than antibiotics for treating recurrent C. difficile infection (N. Engl. J. Med. 368, 407–415; 2013). Dramatic improvements in sequencing technology in recent years have also enabled studies that compare the com-position and characteristics of the microbiota in healthy subjects with those seen during disease at multiple levels, including bacterial gene expression and metabolite profiles.

There is still substantial uncertainty about the best way to therapeutically target the microbiome, particularly for indications beyond C. difficile infection. Nevertheless, the amount of evidence showing that the gut microbiota

can contribute to inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn’s disease (Gastroenterology 146, 1489–1499; 2014) is rapidly growing, catalyzing a wave of interest and dealmaking in the field (Table 1).

Early moversIsabelle de Cremoux, CEO of the venture capital fund Seventure Partners, has been interested in the area longer than most. “We identified this field in 2006,” she said. Earlier this year, Seventure set up a first-of-its-kind €120 million (~US$130 million) fund, Health for Life Capital, dedicated to microbiome-based innovations.

De Cremoux said that since the June initial public offering of Seres Health, which grossed about $134 million, investors have started to pay attention. Seres is one of the first compa-nies to move from FMTs to the development of a tablet-sized capsule of bacterial spores, dubbed SER-109, to prevent recurrent C. dif-ficile infection. Several other leading funds are investing in the area, such as Flagship Ventures, an early investor in Seres, and Woodford Investment Management, which has invested in 4D Pharma, a company that is developing a microbiome screening platform for autoimmune and inflammatory disease therapeutics. The company plans to commence clinical trials with two microbiome-based IBD therapies in 2015.

The pharmaceutical company that has taken the greatest interest in the area over the past

five years is Janssen, a division of Johnson & Johnson. The company has a number of partnerships and projects that it has recently complemented by establishing the Janssen Human Microbiome Institute, headed by Dirk Gevers (Nat. Rev. Drug Discov. 14, 305; 2015). Via email, Gevers explained that the institute aims “to build an internal team of expert scientists and match such capabilities with external collaborators.” Janssen is also “focusing on pioneering the space and becom-ing the go-to partner for innovative micro-biome projects and talent,” he added. In addi-tion to deals with several startups, Janssen has academic partnerships with the University of California, San Francisco, the University of Michigan and the James Cook University in Brisbane, Australia.

Other early adopters with significant micro-biome research programs include Novartis, Pfizer, AbbVie and AstraZeneca. But many more companies are keeping an eye on the field. “We are well aware of what’s going on. I think it’s a matter of watching and seeing what other types of advances are made, in particular with respect to clinical proof of concept,” said James Brown, who coordinates microbiome and i nfectious disease support at GlaxoSmithKline.

“You would be hard pressed today to find a pharmaceutical discovery executive that doesn’t list microbiome science as one of the top two or three areas of emerging science that they are watching very closely,” said DiLaura.

Table 1. Selected recent major microbiome deals (2013–2015).

Companies involved Headline Date announced

Second Genome; Janssen Biotech Second Genome and Janssen Biotech partner on microbiome-based drug discovery in ulcerative colitis

June 2013

Second Genome; Pfizer Pfizer partners with Second Genome to research the role of microbiomes in metabolic diseases

May 2014

Synthetic Biologics; Enterome Microbiome collaboration between Synthetic Biologics and Enterome June 2014

Mayo Clinic; Seres Health Mayo Clinic to collaborate with Seres Health on microbiome-based therapies June 2014

Mayo Clinic; Second Genome Mayo Clinic to develop Second Genome’s microbiome therapeutics October 2014

Enterome; AbbVie Enterome and AbbVie to develop novel microbiome-based therapies for Crohn’s disease November 2014

Vedanta Biosciences; Janssen Biotech Vedanta and Janssen Biotech to accelerate research between the human microbiome and the immune system

January 2015

Alimentary Pharmabiotic Centre (APC), The University College Cork; Janssen Biotech

APC Microbiome Institute and Janssen Biotech to explore the role of viruses in shaping the human microbiome and potential uses in inflammatory bowel disease

March 2015

Evotec; Second Genome Second Genome and Evotec to discover and develop small-molecule therapies for microbiome-mediated diseases

March 2015

Alimentary Pharmabiotic Centre, The University College Cork; Second Genome

Second Genome to develop anti-inflammatory bowel disease therapies with the APC Microbiome Institute

April 2015

Data sourced from Thomson Reuters Cortellis.

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ock DiLaura agreed that focusing not on the bac-

teria directly but on the bioactive compounds that are secreted is the strategy that is drawing in big pharma. “I think it has catalyzed an interest and provided a road map to bridge from this incredibly important new understanding of the role of the microbiome in human health and disease to clear drug discovery efforts.”

Second Genome is using this approach, and its small-molecule IBD drug candidate SGM1019, for which the target has not been disclosed, is currently in phase 1 trials, with phase 2 trials planned for early 2016. In 2013, the company inked a deal with Janssen to iden-tify microbes and their metabolites with causal roles in ulcerative colitis and ultimately develop new therapeutics.

Another microbiome-based biotech com-pany working on the small-molecule approach is Enterome, founded in 2012. CEO Pierre Belichard said that in addition to developing its own small-molecule drug candidate for Crohn’s disease (which it hopes will reach the clinic in 2016), the company is working with three different large pharma companies. He did not disclose details of all three deals, but Enterome partnered with AbbVie in 2014 to develop a rapid and noninvasive test for Crohn’s disease based on fecal bacterial DNA analysis.

DiLaura said that microbiome science can also bring a new view to patient stratifica-tion. “By bringing a biomarker-centric view of a patient population that includes the micro-biome to both the diagnosis and the monitor-ing of patients, we can get to a more targeted therapeutic population.” This is the backdrop for another Second Genome collaboration, with Pfizer, which began in 2014. Together, the com-panies are carrying out a 900-patient study of the relationship between microbiomic profiles and metabolic phenotypes to better understand disorders such as obesity.

Beyond the gutAlthough activity so far has focused on the role of the gut microbiome in C. difficile infection and IBD, the microbiome in the gut and beyond could have a role in a much wider range of inflamma-tory diseases, including the liver disorder non-alcoholic steatohepatitis, airway diseases such as asthma and chronic obstructive pulmonary disease, skin disorders such as psoriasis, and other autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

The next two to three years will be a crucial time for accelerating efforts to realize the prom-ise of manipulating the microbiome, with an increase in partnerships and involvement from major pharmaceutical companies. Belichard expects 2017 to be the year for significant deals in the space. “[Big pharma] will not move until someone else is really showing that they have a drug in clinical development…But then you will see; they are going to move.”

Rachel Brazil is a freelance science writer who covers the biotechnology and pharmaceutical industries.

Manipulating the microbiomeScientists are testing several distinct approaches to therapeutically manipulate the microbiome, and it is not yet clear which of these will prove successful. Apart from FMT, the most advanced approaches make use of bacterial cocktails with the aim of restoring and rebalancing the micro-biome; these are being used by companies such as Vedanta Biosciences. In January, Janssen announced that it was investing up to $241 mil-lion to license and develop Vedanta’s potential IBD therapy, VE202, which is expected to reach the clinic within a year or so. VE202 is a cocktail of Clostridia subspecies that studies suggest encourage the proliferation of regulatory T cells (Nature 500, 232–236; 2013).

The microbiome space has also captured the interest of the food industry, and several com-panies are developing partnerships in the medi-cal food area. In January 2015, Seres Health announced a further $65 million investment from Nestle Health Science, a subsidiary of Nestle, which increased its total investment to $110 million. The deal will fund phase 3 trials of SER-109 to prevent recurrent C. difficile infection, as well as advance Seres’ pipeline, which includes treatments for inflammatory disease. Danone is also a key investor in Seventure’s Health for Life Capital fund.

But the “bugs as drugs” approach, as DiLaura calls it, has some drawbacks for big pharma. “There are concerns about regulatory frame-works, manufacturing processes and intellectual property protection,” he said.

De Cremoux highlighted similar concerns. “There is an environment of uncertainty where big pharma are not comfortable…They don’t like products that are not well characterized and identified as unique components.”

Charles Mackay, CSO of Pfizer’s Inflammation and Immunology Research Unit, said that Pfizer is unlikely to enter the probiotics busi-ness. “I think we are much more interested in understanding the pathways whereby beneficial bacteria work and replicating those using a small-molecule drug.”

“The microbiome space ...has quickly captured the public’s imagination with its therapeutic potential.”PETER DILAURA, CEO OF

SECOND GENOME



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Re-Pharmwww.re-pharm.com

Smart drug reprofilingUsing a unique combination of computational chemistry, pharmacology and cheminformatics methods, Re-Pharm is successfully reprofiling marketed compounds as early stage candidates ready for partnering.

S ir James Black, winner of the 1988 Nobel Prize in Physiology or Medicine, famously stated, “The most fruitful basis for the dis-

covery of a new drug is to start with an old drug.” With the cost and risks associated with devel-oping new chemical entities at an all-time high, many companies are finding that repositioning existing pharmaceuticals for new medical uses is leading to real therapeutic and business returns.

Enter Re-Pharm, an early stage drug discovery and development company dedicated to repur-posing compounds to address areas of unmet medical need. Re-Pharm combines outstand-ing chemistry and pharmacology expertise with the software solutions of its parent company, Cresset, to repurpose drugs currently on or near the market or that have been pulled from development for commercial reasons. Because these compounds have already undergone full or partial clinical testing and may be in active use, their safety and pharmacokinetics are gen-erally well understood. Developers can build on existing data, significantly reducing the risks, cost and time involved in taking such drug can-didates to market.

Cresset’s computational chemistry tools offer unique insight into the molecular characteristics behind biological activity, taking the 3D shape and electrostatic properties of molecules into account to produce a ‘protein’s-eye view’ of how a compound interacts with a target. “In essence we’re trying to look at the skin of the molecule rather than the skeleton,” explained Mark Mackey, CSO of Cresset. “If you look from that viewpoint, you find that molecules that are very similar have the same biological effect.” Cresset software condenses the surfaces of the molecules to field points, making it possible to rapidly compare thousands of chemically diverse structures and fragments on the basis of biological similarity.

“Applying these computational methods to reprofiling is a way of identifying alternative tar-gets for candidate compounds and suggesting alternative compounds for known targets,” said Robert Scoffin, CEO of Re-Pharm.

A winning workflowSuccessful repurposing requires a well -understood target with good commercial and pharmacological potential. Robust biological assays must also be readily available to rapidly and cost-effectively determine potential new activity for any lead.

To assess whether any existing drugs are likely to be active against a new target, Re-Pharm chemists typically build a template (essentially a complex pharmacophore) on the basis of known

ligands and, where available, crystal structures, that incorporates the essential characteristics a candidate compound must possess to bind the target. The template is then screened against a database of several thousand marketed and late-stage drugs to pinpoint compounds that are biologically similar and therefore likely ligands. By comparing the possible matches, Re-Pharm can rapidly identify promising reprofil-ing opportunities.

Compounds of interest are then subjected to a robust triage process, which includes not only wet screening for activity but also filtering for key features that could impact future develop-ment, such as existing intellectual property, publications that reveal off-label use, side-effect problems and so on.

Intellectual property issues are a major factor in reprofiling; for potential compounds to have real commercial opportunity, it is essential that they be clear of prior art. To ensure solid patent protection, the dose, formulation and/or route of administration of the original compound may have to be altered to target the new indication.

Re-Pharm’s rigorous validation process ensures that resulting candidate compounds have well-understood disease biology, robust pharmacology and a promising commercial posi-tion. “This leads to a rapid and cost-effective approach to proof of concept, and a clear and straightforward development path to clinic,” confirmed Scoffin. “This gives the best chance for success.”

A commercially valuable pipelineThrough its compelling strategy, Re-Pharm has built a pipeline of commercially valuable early stage assets in a variety of therapeutic areas.

All have an excellent combination of decreased cost, lowered risk and faster development pathways.

The company’s lead compound, RP0217, has almost completed preclinical development for a variety of inflammatory conditions with large market potential, which strongly validates Re-Pharm’s approach. Currently a widely pre-scribed high-dose oral drug for non-inflamma-tory conditions, RP0217 resulted from a search for an existing drug that could be repurposed for a newly identified enzyme target. Evaluation of 50 candidates discovered through Cresset’s software, followed by further testing of 12 of those compounds, identified RP0217 as an effective new agent.

“Our streamlined method made it possible to move efficiently through pharmacological assessment, computational chemistry work and initial testing in order to demonstrate novel anti-inflammatory activity for an existing drug,” said Scoffin.

Time for partneringPreclinical testing of topical and inhaled formu-lations of RP0217 has been completed for oph-thalmic and respiratory inflammatory conditions and is under way for irritable bowel disease. Re-Pharm is looking for one or more partners to develop RP0217 into new non-steroidal treat-ments for these disorders. The company is also interested in operating its virtual screening and molecular-design platform on a fee-for-service basis and in acquiring early stage assets that require further validation.

“We believe that there are a wealth of unmet medical needs that can be profitably treated by using a smart approach to drug reprofiling,” said Scoffin. “Our virtual platform transforms molecular design and discovery, enabling the rapid identification of reprofiling opportunities for swift and successful development.”

CONTACT DETAILSRobert Scoffin, Chief Executive OfficerRe-PharmCambridgeshire, United Kingdom Tel: +44 (0)1223 858890Email: [email protected]

Sildenafil as rendered by Cresset’s Forge software. This is an example of a compound that was reprofiled from hypertension to erectile dysfunction.



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BRAINWAVE-DISCOVERY LTDwww.brainwave-discovery.com

Non-mammalian Alzheimer’s, Parkinson’s and Huntington’s neurodegeneration testsEarly-stage drug screening. Brainwave-Discovery provides medium throughput drug screening in early stage drug discovery for Alzheimer’s, Parkinson’s and Huntington’s diseases. The Drosophila and human systems have been shown to have great similarity, and our in-house humanised models include hAPP/htau, htau, hAbeta42, halpha synuclein and hLRRK2, with familial mutant forms. This is a fast and cost effective way to find new active chemicals or test chemicals between HTS and mammalian studies. We can provide these screens as a service or as a co-development opportunity.Personalised neurodegeneration models. Key Alzheimer’s and Parkinson’s genes have many variants with potentially different neurodegenerative mechanisms. Our established humanisation approach offers a way of testing candidate drugs against a much wider range of disease alleles, increasing the likelihood of clinical success by matching to patients with the particular mutation. Other CNS diseases. Brainwave-Discovery offers a custom human-ised model production service for many human CNS diseases.

Contact detailsDr. Joanna Young (Europe, Asia) or Matt Mahoney (Americas) | Email: [email protected] | [email protected]

HITGEN LTDwww.hitgen.com

HitGen – OpenDEL

Making encoded library technology a viable alternative to HTS

HitGen’s new OpenDEL encoded library of over 145 million small molecules, all with drug-like properties, can be screened using only 2 mg of target protein, at costs comparable to HTS on much smaller decks. The OpenDEL library is based on 70 different templates and is designed for high diversity within drug-like space.

OpenDEL is just one of the encoded library collections available for screening at HitGen; the other libraries, including the Macrocycle Lead-Finder library, have demonstrated the ability to generate exciting hits even for challenging targets such as PPIs.

Contact detailsJin Li, CEO | F7-10, Building B3, Tianfu Life Science Park,88 South Keyuan Road, Chengdu 610041, Sichuan, ChinaTel: +86 288 519 7385 | Email: [email protected]

Harnessing the power of Encoded Library Technology for your new targets

CELONICwww.celonic.com

Celonic SEFEX: A GMP CHO-K1 cell line kit for drug developers and service providersSEFEX is a royalty-free cell line kit based on CHO-K1 cells. The ready-to-go kit includes cells, plasmids and detailed protocols for the handling, selection and screening process of drugs. Celonic provides the full service; from technical support and regulatory advice, through to process development and GMP manufacturing, Celonic is there for you.

The powerful SEFEX platform can be used throughout the entire product development process from laboratory cultures to production scale. SEFEX is robust, highly performing, and easy to implement. By using SEFEX you are guaranteed maximum productivity, substantial cost savings, and scale-up stability for increased project safety. Celonic also warrants that SEFEX-based production cell lines can be transferred to GMP environments.

Celonic’s SEFEX delivers to you a scalable, highly efficient cell line kit to decrease your biologics development risk. Contact us today to learn more about how to access SEFEX.

Contact detailsOle Fuetterer, Senior Director Sales & MarketingEulerstraße 55, 4051 Basel, SwitzerlandTel: +41 (0)61 56 49 159 | Email: [email protected]

CELLECT BIOMEDwww.cellectbio.com

An innovative technology for the functional selection of stem cellsCellect Biotechnology is developing a platform technology for the functional selection of stem cells based on their resistance to apoptotic signals. Extensive lab studies on bone marrow, cord blood and fat cells have demonstrated a significant increase in stem cell concentration while eliminating toxic mature cells. Tested in vivo, these results represent improvements to the safety and efficacy of transplantations. Cellect’s functional stem cell selection also improves the efficiency of any stem cell based treatment, while reducing the toxicity, resulting in better productivity during the manufacturing process for stem cell based products.

The company’s first product line is a series of unique biocompatible cell selection containers internally coated with molecules that create an apoptosis-inducing microenvironment. These containers will be targeted for use in bone marrow transplants for cancer patients. Cellect also intends to market its containers to research laboratories and companies that manufacture stem cell based products.

Contact detailsShai Yarkoni, CEO | 20 Ha’Taas Street, Kfar Saba 4442520, IsraelTel: +972 (0)9 974 1444 | Email: [email protected]

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BioPharma Dealmakers_September 2015

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