Seven alternative opportunities to overcome the “Valley of Death” for CNS drug candidates developed by academic researchers

Pierre Guertin ＊

1 Department of Psychiatry and Neurosciences, Faculty of Medicine, Laval University, Quebec City, QC, Canada

2 Nordic Life Science Pipeline Inc., Quebec City, QC, Canada

SIGNIFICANT BASIC SCIENCE BUT JUST A FEW DRUG PRODUCTS THAT REACH MARKET

Scientists worldwide, from all biomedical areas and all sectors (public and private), have published more than 500,000 articles in PubMed last year (http://www.ncbi.nlm.nih.gov/pubmed). However, in the meantime, they obtained Food and Drug Administration (FDA) approval (New Drug Approval-NDA) for only 45 new drug treatments in 2015(U.S. Food and Drug Administration, 2016). Those approved therapies include new molecular entities (NMEs) but also drugs for which innovation is limited - e.g., expanded indication, new formulation (e.g., oral tablet vs. injection),or combinatorial approaches (e.g., fixed-dose combinations constituted for so-called off-patent old drugs) (U.S. Food and Drug Administration, 2016).

THE “VALLEY OF DEATH” IS DEVASTATING FOR ACADEMIC RESEARCHERS AND THE INDUSTR

The question is - Why do governments in U.S., Europe and Canada, agree to spend 80 billion dollars each year into public research if discoveries and innovation emerging from this investment do not translate ef ficiently into approved therapies for the population? The answer is unclear and undoubtedly complex. However, most experts in drug development would agree that a devastating phenomenon often called the Valley of Death is signi ficantly contributing to this lack of ef ficiency (Yu, 2016). That phenomenon normally refers to a gap in financing (public or private sources) for research activities associated with final preclinical activities - also called IND-enabling studies. It includes toxicology and safety pharmacology as well as first-batch manufacturing and corresponding CMC work (chemical,manufacturing, & control) contracted to GLP/GMP (Good Laboratory Practice/Good Manufacturing Practice)-accredited Clinical Research Organizations (CROs). Around the world, most public agencies that financially support academic research generally do not provide grants for preclinical studies. Instead, they provide researchers with monies to conduct basic, mechanistically-driven projects,typically in animals in order to (1) further understand the pathophysiology of diseases, and (2) identify/discover new therapies (National Institutes of Health, Canadian Institutes of Health Research). Although these agencies claim to also support clinical studies, in most cases, allocated amounts per grant do not suf fice to meet the complex regulatory and financial needs of drug development today. Indeed,according to Forbes, developing NMEs in 2014-2015 had cost on average, from bench-to-bedside, up to 2.6 billion dollars for each single product (Matthews, 2015), although discrepancies exist (Morgan et al., 2011).

The next question is then - how can academic researchers overcome this critical lack of public support desperately required to achieve technological transfer and to reach levels of development that are legitimately expected by industrials for partnering (typically proof-of-ef ficacy data in patients)?Well, prior to the biotech bubble bursting in 1992 (and the smaller burst in 2000), seed financing from private investors(i.e., venture capital firms - VCs, individual angel investors,etc.) was abundant in North America and Europe. Academic researchers simply needed to create a spin-off biotech company to get access to signi ficant private equity financing -the first millions- enabling preclinical IND-enabling studies to be completed (Frank, 2001). Things have changed. In recent years, most VCs, even those that take the risk of investing at an earlier stage (e.g., proof-of-concept in vitro or in vivo animal models), generally seek for proof-of-concept data in patients prior to commit themselves. That is after the Valley of Death! Therefore, to reach that level of development and thus to overcome the Valley of Death, academic researchers have to find alternative sources of financing. As of today,only a few North American opportunities, listed below, were identi fied for scientists based in U.S., Canada and abroad.

SEVEN ALTERNATIVE OPPORTUNITIES FOR ACADEMIC RESEARCHERS

(1) The National Center for Advancing Translational Sciences (NCATS), one of 27 National Institutes of Health(NIH) Institutes and Centers, aims at transforming the translational process so that new treatments and cures can be delivered to patients faster (National Center for Advancing Translational Sciences). Through programs such as BriDGs (formerly RAID), it offers support to academic researchers around the world as well as to small U.S.-based companies. In-kind support is essentially provided for conducting IND-enabling work. As of last year, NCATS-BrIDGs/RAID has generated data to support 18 investigator-initiated INDs that have been cleared by the FDA and one clinical trial application cleared by Health Canada (National Center for Advancing Translational Sciences).

(2) The Canadian Institutes of Health Research (CIHR)through its programs called POP I and POP II, have been providing financial support (up to 750,000 dollars) for intellectual property (IP) protection, proof-of-concept of ef ficacy in animals and some preclinical studies for promising clinically-relevant technologies. However,it has been recently abolished despite a critical need of Canadian researchers, as clearly pointed out by the scientific of ficer and chair of the POP program (Marsman and McKerracher, 2015). Efforts have apparently been made by CIHR to continue supporting comparable research activities through its new program called Scheme(Marsman and McKerracher, 2015).

(3) The Congressionally Directed Medical Research Programs (CDMRP), an internationally-open program supported by the U.S. army, provides different levels of funding (typically ＜ 1 million dollars) normally for clinical trials addressing the needs of a wide variety of pathological conditions that affect their soldiers (CDMRP). Greater amounts may be granted in some cases- e.g., 2.07 million dollars in 2009 to Dr. Schnitzer for a clinical study in spinal cord injury with a novel combinatorial approach (CDMRP. Search Awards).

(4) The NIH-Small Business Innovation Research (SBIR)program may help academic scientists moving forward their technology given that a spin-off or small biotech company is created in the U.S. That special program encourages indeed domestic small businesses in conducting drug development activities for technologies with great potential for commercialization (SBIR and STTR). Researchers from Canada or abroad may also have access if the sponsor is a U.S.-based company. For instance, Dr. Lisa McKerracher, an adjunct professor at McGill University who founded Bioaxone Biosciences a few years ago obtained more than 1 million dollars in seed funding from SBIR (Bioaxone Biosciences, Inc.).

(5) For scientists based in Canada, Amorchem (formerly GeneChem) a VC based in Montreal may support your academic research activities (i.e., without having to create a spin-off company) at a very early stage of development - e.g., proof-of-concept in in vitro or in vivo models(AmorChem). In 2015, Amorchem lead by Dr. Elizabeth Douville provided support to Dr. Claude Perreault and Dr. Denis Claude Roy at the Maisonneuve-Rosemont Hospital (Montreal) for the development of new diagnostic tools (Institute for Research in Immunology and Cancer).

(6) The Centre for Drug Research and Development(CDRD), founded 10 years ago in British Columbia helps Canadian researchers, somehow like the NIH-BriDGs program, by providing in-kind work capable of advanc-ing a discovery closer to clinical trials or market. Their rate of success in undertaking a project is about 14% (134 distinct technologies out of 1,052 projects assessed). In contrast with BriDGs, they can also help in creating a spin-off company or in filing IP (The Centre for Drug Research and Development).

(7) Finally, social financing (e.g., crowdfunding, angels, Bill Gate foundation) may constitute other potential sources of funding although applicants from all areas (not only from healthcare/biomedical research) are lined up for support from these alternative sources (Osakwe and Rizvi, 2016). Since risks associated with the development of new drugs are typically greater than those associated with devices, electronic, web-based technologies, it is probably more dif ficult for biomedical scientists to compete for this kind of support.

CONCLUSION

Identifying or discovering a new drug candidate is difficult. But, developing that product, speci fically a CNS candidate from bench-to-bedside is undoubtedly harder.Many groundbreaking findings are made routinely in research institutions across North America, Europe and Asia although just a few technologies each year end up successfully overcoming all the challenges (mainly financial) that lead to approval by regulatory authorities.

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