The “Pathways to Cures: Translational Science Research Day” on June 13 showcased the work of UC Irvine Institute for Clinical and Translational Science (ICTS) in accelerating translation of laboratory research to the clinic, partnering with industry to improve patient therapies, and promoting preventive medicine in the community. One of more than 50 medical research institutions throughout the U.S., ICTS is funded by the National Institutes of Health (NIH) under the Clinical and Translational Sciences Award (CTSA) program.
Dan Cooper, M.D., a pediatric pulmonologist and associate vice chancellor for clinical and translational science, opened the day by sharing a recollection from his residency at Oakland Children’s Hospital when he watched a child die at 2 a.m. from cystic fibrosis. There was no treatment available at the time. Cooper resolved to work in drug discovery to make a difference for his patients.
Pramod Khandeghar, Ph.D., UCI vice chancellor for research, and distinguished professor of electrical engineering and computer science discussed research priorities. “I think we are positioned to be national leaders in how to do team science right,” said Khandeghar.
Next, Enrique Lavernia, Ph.D, UCI provost and executive vice chancellor, reviewed ICTS accomplishments. “You not only advance research and clinical application of health cures but you also touch people at their most vulnerable,” said Lavernia. Since ICTS received the 2012 NIH Clinical Translational Award, the ICTS team’s “amazing advancements” included developing novel data and analytics in flow cytometry, proteomic diagnostics for pediatric encephalitis, and partnering with the community on cost-effective delivery of prenatal care to low-income Orange County mothers. In addition, ICTS has:
- helped to support over 2000 research projects;
- funded 53 new pilot awards of which 78% led to at least one new extramural research grant;
- supported 21 campus community incubator awards to foster regional development;
- mentored and funded 12 translational research career development “K” awards, of which 100% of awardees continued a career in science;
- funded 18 pre-and post-doctoral trainee fellowships; and
- collaborated with other centers to compete for the NIH Center for Accelerated Innovation.
Charles Theuer, M.D, Ph.D, founder and CEO of TRACON Pharmaceuticals, gave the keynote speech: “An Academic Surgeon’s Journey from Campus to Corporation”. A former surgeon at UCI, with a stint at the National Cancer Institute, Theuer worked at IDEC Pharmaceuticals Corporation, Pfizer, TargeGen, and TRACON Pharmaceuticals. He cited a 2013 Tufts Center for the Study of Drug Development estimate that the average approved drug costs an aggregate $2.5 billion. “There is about a 60% chance your drug fails phase 1 testing.” Theuer said. While a drug takes an average of 10-12 years to move from concept to full approval, the real “Valley of Death” is phase 2 efficacy trials. Only a third of drugs make it to Phase 3 trials and only one in 10 new drugs survives through phase 3 trials to approval. Since drug development is so expensive and risky, a key pharma strategy is to get a drug approved for any indication possible.
Theuer shared some key drug development principles from industry:
- Reduce cost and time in the drug development pipeline by getting accelerated approval, in any indication. Full FDA approval typically requires demonstrating a patient survival benefit in phase 3 trials based on surrogate endpoints. A surrogate endpoint is a measure or biomarker that substitutes for a clinical endpoint but may not improve clinical benefit for patients. For a drug to take advantage of an accelerated approval pathway, it has to be “a superstar”, meaning it has modest toxicity and shows a strong response rate (20% or higher) in a population with unmet needs. Superstar drugs like rituximab, gemicitabine for non-small cell lung and pancreatic cancer, imatinib for chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST) were approved on the basis of phase 2 studies using a limited number of patients because they showed robust response rates in populations with unmet needs.
- Use an incrementalist approach for phase 2 and phase 3 studies if agent is suspected to inhibit cell growth and division. “Incremental” drugs require more time and money to obtain approval than superstar drugs. These drugs will need either a phase 3 head to head randomized trial against another drug or to be combined with other drugs. “Because a drug is incremental does not mean that it is not going to be meaningful to patients,” Theuer noted. For example, Genentech’s Avastin was an “incredibly effective” incremental drug that was never approved as a single agent. It was approved as an add-on for chemotherapy across four major tumor types. Avastin was actually more successful than Sutent, a drug which Theuer helped to develop that was a “superstar” but only in one indication.
- Highlight unmet need. “If you help your patient, you are going to help your drug.” Theuer said. “Pursue the highest unmet need; this the first-to-market indication most suitable for single agent accelerated approval.” According to Theuer, taking interferon alpha, the former first-line therapy for certain GIST-driven renal cell cancers, is “like giving yourself the flu every day.” But combining sunitinib with interferon as a second-line therapy was easier on the patient.
- Segment the precision patient population. Use genetics, first focusing on the segment that has the highest response rate. For example, the developers of the cancer drug Herceptin got approval by focusing on the 10% to 15% of cancer patients who responded best to their drug. “Once the drug is approved you can always expand to other indications,” said Theuer.
- Combine the new drug with existing therapy. “Can you combine a new drug with existing therapy, for instance, imatinib and sunitinib in GIST rather than waiting for a patient to fail therapy?” Theuer asked. According to Theuer, imatinib was incredibly effective, but sunitinib could be second line therapy for patients who had flunked imatinib therapy.
- Engage with cooperative groups for trials. Theuer advised engaging cooperative groups to defray trial costs. For example, Genentech got the U.S. government to pay for most of the clinical trials for Avastin.
- Absent superstars, divide up the pie incrementally. “Drug development is about a pie,” says Theuer. “Everybody wants a piece of that pie.” Using Avastin for age-related macular degeneration (AMD) was still true innovation, but a “me too” therapy for other indications.
- There is always risk in the pipeline, even with a positive phase 3 trial. Theuer told a cautionary story of TargeGen’s fedratinib, a JAK2 kinase inhibitor for myelofibrosis, in which proliferating red cells and platelets cause bone fibrosis. There was an unmet need, a driver mutation that could be inhibited for clinical benefit. Sanofi purchased the company and started pivotal phase 3 studies. But a few patients in the phase 3 trial developed Wernicke’s encephalopathy, caused by insufficient dietary thiamine. In vitro studies showed that fedratinib inhibited oral absorption of thiamine, an effect not shown by the approved JAK inhibitor on the market. Sanofi abruptly shelved fedratinib.
In the afternoon panel, “Think Tank: Bridging the Gap in Research Translation; Academia and Industry”, moderated by Dr. Dan Cooper, Theuer was joined by Bruce Tromberg, Ph.D., director of the UCI Beckman Laser Institute, Michael Artinger, Ph.D., managing director of the Research Translation Group at Applied Innovation, and Bill Boyle, Ph.D., associate professor of medicine at the UCLA David Geffen School of Medicine.
Boyle recounted that the collaboration Dr. Dennis Slaymon at UCLA conducted with Genentech on the HER2 monoclonal antibody resulted in Herceptin—a breakthrough breast cancer drug that earned $120 billion over its patent lifetime. “He made that happen through his clinical research,” said Boyle. “If you ask how much of it came back to him or to UCLA, it was nothing. This was because it was transferred by a material transfer agreement that had a royalty-free clause.” Even a small percentage of return could have funded a lot of university research, Boyle added.
According to Boyle, industry holds an “academic bias” against university medical research, translating into lower valuations. But de-risking drug development through clinical trials could increase expected value of IP, as translation potential and commercial viability are valued by industry. However, universities are not good at offering assets supported by data that show value to industry.
According to Tromberg, the journey from blackboard to benchtop to bedside means traversing the following phases of technology translation:
- Phase 0: Design, calibration, testing—the comfort zone for researchers
- Phase 1: The friends and family study
- Phase 2: Standardization and validation
- Phase 3: Reproducing results in multiple centers
- Phase 4: Becoming standard of care
Successfully commercializing technology means balancing innovation, impact, and risk. “We need committed clinical champions,” said Tromberg. “We need problems that are worth solving. It comes together best when you have the right experts working on a team. We need accessible enabling technologies.”
Theuer added that an issue with academic assets is getting the IP. After 20 years, the patent expires, making it unattractive to industry. So academic institutions need to issue IP promptly. But industry can keep IP hidden behind closed doors until the last minute because they don’t need to disclose it. He cautioned that academia needs to be more efficient about pushing a molecule from target to a true druggable clinical candidate, and then advertising their innovations.