Pharmas are likely to support NCATS’ drug repurposing program based on economic interest, hoping to justify the millions they’ve spent on shelved compounds. [© Xuejun li - Fotolia.com]
NIH’s National Center for Advancing Translational Sciences (NCATS) is days away from disclosing its list of molecules for repurposing under a recently announced agency-industry pilot program. On or about June 12, NCATS will issue a request for applications, with a link to summaries for each compound in its pilot program, Discovering New Therapeutic Uses for Existing Molecules.
The number of compounds available may rise well above the approximately two dozen discussed when NCATS announced the pilot program, as might the number of participating pharmaceutical companies. “We are in active, real time negotiations with several companies,” Kathy L. Hudson, Ph.D., NIH’s deputy director for science, outreach, and policy, told GEN.
“Depending on how everything works out, the number of compounds will increase markedly.” The three pharmas that have already committed are Pfizer, Eli Lilly, and AstraZeneca.
AstraZeneca is the sole pharma partner of the U.K.’s Medical Research Council (MRC) in a similar collaboration launched in December. MRC has solicited proposals by academic researchers to study 22 AstraZeneca compounds for effect on human disease mechanisms as well as development of possible new therapies.
The 22 include zibotentan, a prostate cancer therapy that failed a Phase III trial in 2010, and saracatinib, which was developed for solid tumors but generated disappointing results in several trials. The 22 AstraZeneca compounds most commonly covered solid tumor, diabetes, and analgesia (three each).
How successful will NCATS' new pilot program prove in reviving at least some shelved compounds?
Comparing U.S. and U.K. Programs
Wisely, NCATS expanded participation to multiple drug developers, since more pharmas will mean more compounds for researchers to study. Also, NCATS will review applications from researchers from academia, industry, and nonprofit institutes, while MRC’s program is limited to academic and research institute applicants.
NCATS reasons that working with industry offers a greater chance of advancing the compounds. “The goal is simple: To see whether we can teach old drugs new tricks,” said U.S. Health and Human Services Secretary Kathleen Sebelius.
MRC’s applications may include collaborations with commercial third parties under agreements that must be in place before submission of full applications. Over eight weeks, MRC received more than 100 proposals from researchers at 37 institutions, said Donald Frail, vp of science within AstraZeneca’s new opportunities innovative medicines unit.
MRC’s program will award up to £10 million (about $15.6 million) in two- or three-year grants, with announcement of awards to come in October. Where MRC has said its awards will not be value limited, NCATS envisions awards of more than $2 million each—eight awards totaling $20 million—during the pilot program’s first year. NCATS awards will be announced in April or May 2013.
The $20 million sum is likely to rise over the second and third years, Dr. Hudson said, reflecting the expectation that some of NIH’s 27 institutes and centers will contribute additional research funding for projects affecting their specialties and the greater expense of clinical vs. preclinical studies.
NIH will be challenged to maintain, let alone increase, spending, however. Congress faces two sobering options soon after the November presidential election: Cut at least $1.2 trillion in spending over the coming decade or absorb across-the-board spending cuts of 7.8% or more for NIH.
Even if budget were no issue, NCATS faces another challenge in ramping up the new-therapeutic-purpose program: the willingness of NIH’s other centers and institutes to help the translational medicine center. As late as 2007, NIH acknowledged an agency culture where “research projects are normally managed by an individual institute or center.” Then-director Elias A. Zerhouni, M.D., sought to reverse this culture by creating interdisciplinary research consortia.
While the new program is disease-agnostic, NIH director Francis S. Collins, M.D., Ph.D., said that neurological disorders “would certainly be an area where we would hope there would be a lot of activity.” Four of the MRC program’s 22 compounds have neuro indications: two for schizophrenia, and two for anxiety, one of which was also indicated for depression.
The CNS disease focus for NCATS could reverse years of retrenchment by big pharma in CNS disease. AstraZeneca, Pfizer, GlaxoSmithKline, and Novartis closed research facilities, while Merck & Co. and Sanofi reduced research spending. Those moves followed the failure of numerous clinical trials.
NCATS Research Set-Up
Like MRC, NCATS has established a two-stage process. Interested researchers must complete pre-applications subject to NIH peer review. Researchers whose applications pass muster must then complete an application showing that they have access to the compound in question, through the signing of a collaborative research agreement.
To speed up the start of research, NCATS has developed template agreements: Memoranda of understanding will govern NIH’s dealings with drug developers, which will sign collaborative research agreements with researchers, who in turn will be expected to sign confidential disclosure agreements with the companies.
None of the templates address how much in royalties researchers can expect from companies in return for generating new intellectual property. Those will have to be worked out case by case, Dr. Hudson said, with companies having a first right of refusal to license back the IP generated by the researchers and their institutions.
Researchers will be compensated by NIH as part of their grant agreements with the agency. Researcher milestones are expected to include validating their compounds in year one, moving to clinical studies in year two or three. Dr. Hudson said success will be defined by:
- how effective template agreements prove in facilitating or accelerating better, faster, and cheaper collaborations.
- what science emerges from the collaborations. “If we’re able to advance knowledge on a specific disease pathway and yet the molecule doesn’t advance as a drug candidate, that’s still a success because we’re contributing to the overall knowledge of that pathway in that disease,” Dr. Hudson remarked.
- whether the compounds advance into new indications and how well.
“I don’t anticipate that our success rate will be any different than anybody else’s. The advantage we have is that we have leapfrogged over five or six or seven years and $30 million or so” in development, she added.
Compounds in the pilot program have already been tested in humans, with acceptable safety profiles in dosing, pharmacologics, and toxicity, but failed to show efficacy or were abandoned for business reasons. “Initial data from human volunteers will be available and probably also testing in some patients where the outcome wasn’t enough to be sufficient for progress into Phase III,” Jan Lundberg, Ph.D., president of Lilly Research Laboratories.
Potential for Success
In the NCATS program’s favor is the likelihood of support from pharmas based on economic interest. Drug developers hope to finally justify the millions they spent on shelved compounds by reviving discontinued research projects, eager to generate new revenue through a new indication.
“Too many times, these compounds end up sitting on shelves, or they end up in somebody’s freezer,” noted Rod MacKenzie, Ph.D., group svp and head of pharmatherapeutics R&D for Pfizer. “We may be able to connect with some great ideas and generate together some kind of data sets that may allow us to make further investments and take those drugs all the way to the market.”
That will depend, however, on what extra knowledge researchers develop from the compounds and whether it justifies costly new trials. Investigators and their pharma partners will be challenged to advance not only the sure-fire home run treatments but also the incremental gains in understanding disease pathways that may not yield new drug revenues for years. Partners will also have to decide the value of their new IP and how to monetize it. Answers to these questions will determine whether Dr. Collins was right when he predicted the pilot program would be “not just a win-win, but a win-win-win.”