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Research Development & Clinical Trials Replenishing Pipelines By Repurposing And Rescuing Pharmaceuticals By Fred Olds A bout 80% of drug candidates fail in phase 2 trials because they don't reach endpoints for efficacy. Of those drugs that get FDA approval, little is known about possible applications outside the narrow science of their original indication. Repurposing marketed drugs or rescuing compounds that failed in clinical trials offers entrepreneurs the potential to replenish pipelines with reduced risk and time in drug development. Yet these potential advantages may be moot if one can't overcome the main barrier of repurposing — intellectual property exclusivity. Seth Lederman, M.D., co-founder, president, and chairman of TONIX Pharmaceuticals, says the risk of abandoning repurposing projects is lower than trials with new chemical entities (NCEs). "Looking back at the past 15 years," he says, "there's been a credo in early-stage research, 'fail fast.' You don't want to end up in late-stage trials and fail. It's just too expensive." He feels this led to a bias toward early discontinuance of trials with NCEs that might have succeeded otherwise. With repurposing, research starts with defined pharmacokinetic (PK) data and a compound already proven safe through possibly millions of human exposures. If an apparent safety issue arises, investigators are more likely to approach it as an anomaly rather than to consider dropping the project. TONIX is developing the muscle relaxant cyclobenzaprine (CBP) in a sublingual form (CBP SL) for use in fibromyalgia and post-traumatic stress 44 LifeScienceLeader.com disorder (PTSD). Lederman says, "Even if a toxicity signal arises in an animal model during our research, we wouldn't be discouraged. We can't shrug it off; you have to take every piece of data seriously; but we may go and test in two other species." A company may shave years off R&D; by repurposing, and the savings can affect the strategic positioning of the compound. A new drug application (NDA) can be submitted under the 505(b)2 provision. This allows a company to support its application using the existing safety and PK data the FDA sanctioned for the drug in its original indication. Lederman says, "It's hard to say, but I think the provision helped TNX-102 SL (CBP SL) shorten R&D; by as much as five years because we were able to go directly to dose finding." Michael Coffee, chief business officer of MediciNova Pharmaceuticals, says having the pharmacokinetic and safety data saved a year or two of research repurposing the anti-asthmatic ibudilast for chronic neuropathic pain and drug dependency. He says, "These advantages can move a project's priority up significantly when you're looking at six or seven potential projects you could invest in." May 2013 MAKING THE DISCOVERY Historically, new uses for existing drugs were found by practitioners observing patient reactions to medications and linking those observations to an unmet need. TONIX is advancing the research of Dr. Iredell Iglehart, who noticed CBP had a positive effect on his fibromyalgia patients. Lederman says, "This kind of practice: a careful doctor, making a clinical observation, and then expanding on it, I think really goes back to Edward Jenner and cowpox. But, it is not necessarily reproducible in a systematic way." Advances in science and technology now make systematic approaches feasible. Using high-throughput technology, like phenotypic drug screening, investigators can screen libraries of compounds against banks of cellular assays to uncover potential therapeutic links. Millions of assays can be tested, and the results reported within days, that might have taken months or years to find by manual laboratory methods. Eli Lilly's proprietary phenotypic drug discovery system (PD2) screens human cells with a known diseaserelated biology or defect against a battery of compounds to see if there