|Bridging the Valley of Death: How Can Academia and Pharma Best Work Together?|
The National Institutes of Health (NIH) calls the process of translating basic research into a viable product the "Valley of Death." They define it as the period of transition when a developing technology is seen as promising, but is too new to validate its commercial potential and unable to attract the necessary funding for its continued development.
Map of the Valley of Death
Illustration courtesy of FasterCures
The Valley has been the subject of many articles in journals as well as a cover story in Newsweek by journalist Sharon Begley titled “Desperately Seeking Cures: How the road from promising scientific breakthrough to real-world remedy has become all but a dead end.”
In her article, Begley writes "from 1996 to 1999, the U.S. Food and Drug Administration approved 157 new drugs. In the comparable period a decade later—that is, from 2006 to 2009—the agency approved 74. Not among them were any cures, or even meaningfully effective treatments, for Alzheimer’s disease, lung or pancreatic cancer, Parkinson’s disease, Huntington’s disease, or a host of other afflictions that destroy lives." She notes that "the chance of FDA approval for a newly discovered molecule, targeting a newly discovered disease mechanism, is a dismal 0.6 percent. Diseases are complicated, and nature fights every human attempt to mess with what she has wrought. But frustration is growing with how few seemingly promising discoveries in basic biomedical science lead to something that helps patients, especially in what is supposed to be a golden age of genetics, neuroscience, and biomedical research in general."
And although many advocacy groups and politicians have blamed pharmaceutical companies for being more concerned about their stock price than discovering new drugs, Begley says that "the barriers to exploiting fundamental discoveries begin with science labs themselves. In academia and the NIH, the system of honors, grants, and tenure rewards basic discoveries (a gene for Parkinson’s! a molecule that halts metastasis!), not the grunt work that turns such breakthroughs into drugs. If we are serious about rescuing potential new drugs from the valley of death, then academia, the NIH, and disease foundations will have to change how they operate."
In a recent article in Pharmalot, it is noted that the number of new drug applications and therapeutic biologics filed under Original Biologic License Applications (BLAs) declined last year from the previous two years and that since 2001, the Center for Drug Evaluation and Research (CDER) has averaged 22.9 approvals a year. The author of the article, Ed Silverman writes “if the number of applications does not increase, CDER does not expect to see much of a year-to-year increase in approvals. And so, drug makers and biotechs may complain the FDA is not moving quickly enough, but then, neither are they."
The FDA Says Don’t Blame Us!
The FDA disputes that they are part of the problem. In November they issued a news release saying that they have approved 35 new medicines in 2011, but note that they considered only two of the approved drugs to be breakthroughs.
So where will the next blockbusters come from? In an article in Nex Paradigm, Jason Chew writes that "drug discovery often begins in academic research labs; many of today’s best selling and leading edge products have their roots in academia. These include Byetta, Copaxone, Geldanamycin, Emtriva, Alimta, Taxol, and Rapamycin. But the process of translating a laboratory discovery into a drug is fraught with difficulties. There is a tremendous gap between the time of the original discovery and the time to market." In addition, he points out that universities don't have the resources and marketing skills of pharmaceutical companies, and are faced with cutbacks of their own in research dollars from the NIH and private foundations.
Where Have All the Venture Capitalists Gone?
Another barrier to new drug discovery is that the number of venture capitalists (VC) willing to fund basic research is fading due to the high risk of failure. As noted by Chew, "only 0.03% of VC funding goes into the seed stage due to the very high risk of failure. For many researchers, the initial source of funding for discovery work often comes from the NIH in the form of small business innovation research (SBIR) grants. In bioscience research, the initial phase I grant can be around $150,000 for pilot research. The number of applicants for these grants has grown significantly in the past decades. In 1983, fewer than 1,000 grants were sought; by 2006, there were more than 3,000 applications; in that time period the percent approved remained between 20% and 30%, leaving an increasing number of applicants looking for alternative funding sources."
The Valley at SLAS2012
To address these issues and discuss ways that academia and pharma can better work together, SLAS is bringing together some of the finest minds from both worlds at SLAS2012 in San Diego, CA. A Track 1 Drug Target Biology session entitled “Bridging the Valley of Death: How Can Academia and Pharma Best work Together?” will be presented on Monday, Feb. 6, from 10:30 a.m. to 12:30 p.m. Chairing the panel are William P. Janzen of the University of North Carolina at Chapel Hill and Michelle Palmer of the Broad Institute. Derek Lowe, the author of the In the Pipeline blog will moderate the panel. The panelists are John Luk of the National University of Singapore; Rudy Juliano of the University of North Carolina; Mao Mao of Pfizer; Alan D. Palkowitz of Eli Lilly and Company; and John Reed of Sanford-Burnham Medical Research Institute.
SLAS President and Panel Co-Chair Michelle Palmer, Ph.D., the platform leader for Screening at the Broad Institute in Cambridge MA, says she is looking forward to a lively discussion. "This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease. To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations that have the capacity to tackle ambitious challenges."
SLAS Board Member and Panel Co-Chair William P. Janzen, is director, Assay Development and Compound Profiling in the Center for Integrative Chemical Biology and Drug Discovery at the University of North Carolina at Chapel Hill. He has had articles published this year in Nature Chemical Biology, Nature Reviews and the Journal of Medicinal Chemistry, and says that big pharma and academia are working together better than ever. "I believe that there is a growing mutual respect for each group's capabilities. Both groups see that there are growing numbers of collaborations that have worked well. Each success strengthens these bonds and benefits not only the drug companies and academic centers but the public. I believe it will help usher in the era of personalized medicine that we have been talking about for so long."
Mao Mao, Ph.D., research fellow at Pfizer Oncology Research in San Diego, CA, says that 60 to 90 percent of his work is with collaborators from academia. Mao is also the president of the Asian Cancer Research Group, an independent not-for-profit organization jointly established by Eli Lilly, Merck and Pfizer.
He and his colleagues at Pfizer are working on hundreds of tumor samples from hepatocellular carcinoma, gastric, breast, and colon cancer patients for next-generation sequencing, including whole genome, whole-exome, and transcriptome sequencing. The goal is to use next-gen sequencing to characterize tumors in the studies and identify cancer mutations and structural changes for target discovery and cancer molecular classification.
Mao is co-author of several articles with fellow panelist John Luk, Dr. Med.Sc., an associate professor, Department of Pharmacology, Yong Loo Lin School of Medicine of the National University of Singapore. Luk received his Doctorate in Medical Science from the Karolinska Institute, Stockholm, Sweden and also did a two year fellowship in Immunology and Pathology at Harvard Medical School. Mao and Luk are co-authors of a recent paper in BMC Cancer and have manuscripts under review at Nature Genetics.
"Dr. Luk and I have collaborated together for five years resulting in several publications in the field of biomarkers." Mao points to the discovery of EML4-ALK fusion gene in non-small-cell lung cancer, which was the featured article in Nature in 2007, as an example of what can result when academia and big pharma work together. "In 2011, the FDA approved crizotinib, for patients with late-stage, non-small cell lung cancer with this rare genetic abnormality under the trade name Xalkori. To bring a drug to market in less than five years is a remarkable and rare achievement."
Rudy Juliano, Ph.D., is the Boshamer Distinguished Professor, Department of Pharmacology, Division of Molecular Pharmacy at the University of North Carolina at Chapel Hill in Raleigh, NC. Together with his colleagues Stephen Frye and Marina Crosby, and Teresa Edwards of the University of North Carolina, he published the first survey on academic and non-profit drug discovery entities in the United States in Nature Reviews.
Juliano says the survey finds that while academia is perceived to be much stronger than industry in disease biology expertise and innovation, and is considered to be better aligned with societal goals, industry is perceived to be much stronger in assay development and screening, and particularly in medicinal chemistry." To Juliano, the big question is whether academic centers can go further down the line and push toward the next level of actually helping bring drugs to market. "Our survey showed that most small molecule academic drug discovery is in the early stage and has not yet contributed much to marketed drugs. With the expansion of academic interests in small-molecule drug discovery, perhaps the coming decade will see a similar impact on innovation in this domain as well."
Their survey was the topic of a blog by SLAS2012 Panel Moderator Derek Lowe, Ph.D., who says that Juliano et al. did everyone a great service. "What they found was 78 centers of academic drug discovery (in one form or another) in the U.S. cancer and infectious diseases are the most widely worked-on, but tropical and orphan diseases make a strong showing (and I'm glad to see this; they should). Another interesting stat: 49% of targets being investigated are based on unique discoveries that had little validation in the literature." Lowe's blog, In the Pipeline, is regarded as "one of the Top 10 Blogs to Make Sense of the Pharmaceutical Industry" by the authors of the website, blogs.com.
John C. Reed, M.D., Ph.D. has testified before Congress on the economic impact of NIH-funded research. He is the chief executive officer of Sanford-Burnham Medical Research Institute in La Jolla, CA, where he has worked as scientist and leader for over 20 years. He is recognized by the Institute for Scientific Information as the world’s most highly cited scientist for his research publications during the decade 1995-2005 in the broad field of cell biology and also in the field of general biomedicine.
Reed says that personalized medicine needs a new business plan that has creative solutions. "We need a hybrid between universities and the pharmaceutical industry,” Reed offers. He believes that the NIH’s proposed National Center for Advancing Translational Medicine (NCATS) may be just the shot in the arm basic research needs to reach forward across The Valley. He says that "to understand how NCATS will help further catalyze drug development, consider just one of the ongoing NIH programs slated to move into this new center: the Molecular Libraries Probe Production Centers Network (MLPCN). Created as part of the 2004 NIH Roadmap for Medical Research, MLPCN established the first federally funded network to facilitate drug discovery by producing early-stage small molecule leads." He says another step in the right direction is that pharmaceutical companies are realizing they should build stronger partnerships with academia. For example, Pfizer announced it is expanding research operations near the Massachusetts Institute of Technology (MIT), with construction of a new complex in Kendall Square. The company will move into a 230,000-square-foot building that MIT is building where it will conduct research on drugs for type 2 diabetes, Alzheimer’s, and schizophrenia, among other illnesses.
In 2009, Eli Lilly and Company announced the Lilly Phenotypic Drug Discovery Initiative (PD2) that uses Lilly-developed disease-state assays and a secure web portal to evaluate the therapeutic potential of compounds synthesized in university and biotechnology laboratories. The PD2 initiative is designed to provide a more convenient point of entry for global external researchers into Lilly's drug discovery and development process. By doing so, PD2 allows for the establishment of productive relationships with institutions and organizations that may not previously have worked with Lilly.
"Each year, researchers throughout the world design and synthesize compounds in university and biotechnology laboratories that are never fully evaluated as potential drug candidates," said Alan D. Palkowitz, Ph.D., vice president of discovery chemistry research and technologies at Lilly. "Increasingly, innovation depends on a broad network of relationships outside our walls."
The SLAS LabAutopedia wiki is a collaborative compilation of the world's laboratory technology knowledge. It is continually grown and updated online at SLAS.org. SLAS Member Nicola Tolliday is creating a Medicinal Chemistry Facility Directory for LabAutopedia, which she believes will be helpful to many SLAS members as well. "Historically follow-up and medicinal chemistry resources have been limited in academic screening. Modeled after the highly successful SBS Academic Screening Facilities Directory, the new SLAS Medicinal Chemistry Facility Directory will provide a central listing of known academic and commercial entities supporting follow-up and medicinal chemistry. Having a consolidated resource will enable the successful progression of academic screening and probe development programs," Tolliday said. "The new directory is currently in the pilot phase and is scheduled to launch by the time SLAS2012 starts. I think it will be a great service to SLAS members."