LAUSR

Wouldn’t it be great to be able to develop a completely new drug for less than $60 million in 6 years or less? And to solve a problem associated with significant morbidity (intraoperative hypothermia) during and following major surgery with inhalation anesthetics? Or does someone think I’m dreaming or smoking something? Well – maybe not. One of the most promising new ways to initiate drug development may be to find ways to repurpose “failed” compounds into new drugs. And my new company, Catalina Pharma Inc., has a plan to do just that by using the perceived “adverse event” profile of transient receptor potential cation channel subfamily V member 1 (TRPV1) antagonists (hyperthermia) for prevention of anesthesia-induced hypothermia while potentially retaining their intended therapeutic action (analgesia) as an adjunct to postoperative analgesia. This editorial is a story about starting a new pharmaceutical company with an academic anesthesiologist who identified a critical need for preventing or treating hypothermia that occurs with high prevalence in multiple types of major surgeries (Amol Patwardhan, MD, PhD), an academic preclinical pharmacologist who has extensive experience in pain medicine and specifically with TRPV1 antagonists (Frank Porreca, PhD), an integrative physiologist with extensive experience in body temperature regulation (Andrej Romanovsky, MD, PhD), and me, a preclinical and clinical pharmacologist and entrepreneur who has spent a career in the pharma-biotech industry and more recently as an independent consultant to big pharma, medium pharma, startup companies, and academic laboratories around the world primarily in the area of pain medication development. And, I should mention that I’ve had experience repurposing “failed” drug in the past for an entirely new purpose that achieved approval by the U.S. Food and Drug Administration (FDA) several years ago. It would be difficult, time consuming, and expensive to approach this problem by searching for an entirely new pharmaceutical agent to control intraoperative hypothermia. According to the Tufts Center for the Study of Drug Development, the cost of developing a new prescription drug to marketing approval is $2,558 million in 2013 dollars. Some people may argue that the actual cost for a specific drug approval may be only $200 million, but the rest of the development cost is the amortized waste of funds for drugs that fail during clinical development. In a recent study of 4235 pharmaceuticals entering development between 1995 and 2011, Davis et al. reported that only 11% had succeeded to approval, 2.6% were still active in development, and 86% had failed. More importantly, a review of data from Davis et al. shows that 61% of failures occur between the time that a compound enters preclinical development and the end of Phase 1 clinical trials. What if we had a way to skip that 61% failure rate, and the time and cost of early failures, and start directly into Phase 2 clinical trials? And to develop a drug that would be used only in a hospital setting for acute care, and hence not require long-term clinical studies or preclinical safety data? Well, I’ve done it before and I think it’s possible to do this again. Research on the potential use of TRPV1 antagonists as analgesics started in the year 2000 with the first description of synthetic TRPV1 antagonists that could block the irritating effects of capsaicin in mice. Later studies described increasingly potent and specific small molecule inhibitors of TRPV1 that could be administered parenterally or orally in experimental animals and that produced analgesic activity on their own, in the absence of capsaicin effects in animals. As of the writing of this article in April 2017, there have been more than 670 publications describing the potential analgesic activity of TRPV1 antagonists (Fig. 1).