Turning up the heat on surgical cold

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.¹ 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.² 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).

Figure 1.

PubMed citations describing analgesic activity of TRPV1 antagonists.

However, Amgen, Inc., in collaboration with Dignity Health, later identified hyperthermia as a risk factor for TRPV1 antagonists in laboratory animals³ and in humans.⁴ Multiple TRPV1 antagonists were abandoned following the identification of hyperthermia as a significant adverse effect in early clinical studies with both healthy volunteers and pain subjects. Only three TRPV1 antagonists are known to still be in clinical trials (Table 1). PAC-14028 is being evaluated as a topical cream in atopic dermatitis, possibly to avoid significant systemic uptake. NEO6860, thought to be less likely to produce hyperthermia in humans, is being evaluated in human proof-of-concept trials for osteoarthritis. XEN-D0501 is currently being evaluated in human proof-of-concept trials for Type 2 diabetes after earlier clinical trials with a different sponsor evaluated its efficacy for treatment of idiopathic cough and chronic obstructive pulmonary disease (COPD) cough.

Table 1.

Examples of TRPV1 antagonists in clinical development. (Current status determined from sponsor's website and/or press releases or publications.)

Compound	Sponsor	Clinical phase	Current status	Last reported clinical results
ABT-102	Abbott	1	Discontinued	2013
AMG 517	Amgen	2	Discontinued	2008
AZD1386	AstraZeneca	2	Discontinued	2014
GRC-6211	Lilly-Glenmark	2	Discontinued	2008
JNJ-39439335 (Mavatrep)	J&J	1	Discontinued	2009
MK-2295 / NGD-8243	Merck-Neurogen	2	Discontinued	2011
NEO6860	NeoMed	2	Ongoing	2017
PAC-14028	AmorePacific	2	Ongoing	2017
SB-705498	GSK	2	Discontinued	2014
Unnamed	Evotec	1	Discontinued	2009
V116517	Purdue Pharma	2	Discontinued	2016
XEN-D0501	Pila Pharma (Xention)	2	Ongoing (diabetes)	2011

So, this brings us to a new concept: Would it be possible to use the hyperthermic potential of TRPV1 antagonists to prevent and/or treat intraoperative hypothermia associated with inhalation anesthetics? As readers of this journal are probably already aware, anesthesia impairs thermoregulation and hypothermia is common during major surgeries lasting 2 h or longer. Changes in core body temperature may exceed −3°C, putting patients at significant risk for adverse effects on the cardiovascular system (myocardial ischemia, hypertension, tachycardia, and deep vein thrombosis), coagulation (decreased platelet activation and coagulopathy), the immune system (increased incidence of wound infection), and various electrolyte and endocrine-metabolic changes. Current techniques to control surgical hypothermia include increasing the temperature of the operating theater (often used in pediatrics, to the detriment of the surgical staff who may experience increased sweating and fatigue) or use of warming blankets that may have varying degrees of effectiveness depending on the type of surgery and that may bring their own potential complications. There is no current pharmacological method to control surgical hypothermia.

Combined research by Drs. Patwardhan, Porreca, and Romanovsky confirmed that TRPV1 antagonists could reverse and prevent intraoperative hypothermia in animal models. With the help of their respective institutions (University of Arizona and Dignity Health), they filed a provisional patent on “Compositions and Methods for Treatment, Amelioration, and Prevention of Anesthesia-Induced Hypothermia” in December 2015. And then they started looking for someone to join their team who knows something about pharmaceutical development.

Some years ago, I too had an idea for repurposing a failed compound, a peripherally acting mu opioid antagonist, LY246736, which had once been part of Eli Lilly's GI (gastrointestinal) product portfolio. I first learned about LY246736 when I was chairing a meeting on novel analgesic drugs in San Diego in 1994. Dennis Zimmerman, the Lilly chemist who initiated a highly successful program on opioid-related analgesic and antagonist drugs, confided with me after his brilliant lecture that Lilly was going to discontinue their GI diseases program that included his portfolio of compounds that Lilly thought could be useful in treating irritable bowel syndrome (IBS).

I had another idea. When I joined Adolor Corporation in 1998, a conversation I had with the Chief Executive Officer (CEO) during my very first day on the job took me back to Dennis's lecture – but with the idea that a drug with this profile could be useful in treating opioid-induced constipation. The CEO was intrigued, and in further discussions with the executive team, we decided that it could be valuable to pursue two indications: opioid-induced constipation, which would be a chronic indication requiring extensive clinical trials, and postoperative ileus, a hospital-based indication where the use of the drug would likely be limited to in-hospital usage immediately before and for several days following major abdominal surgery. We too filed a patent application, and then licensed LY246736 from Roberts Pharmaceutical Corporation that had acquired the drug along with other IBS assets from Eli Lilly.

To our good fortune, Lilly had already conducted a Phase 1a clinical trial with LY246736 and had transferred their Investigational New Drug (IND) application along with about 6 ft of preclinical efficacy and safety information to Roberts. But even more importantly, they also sent Roberts a freezer filled with 1 kg of Good Manufacturing Practice (GMP) clinical quality material that was ready for clinical trial formulation development. Within 11 months of the day that I contacted Roberts, we initiated new clinical trials with LY246736 and in 2008 we received FDA approval for Entereg® (alvimopan), which is “indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis.” I had to smile when a subsequent publication of patients outside of a clinical trial setting reported that alvimopan not only reduced time for patients to consume solid food and to regain bowel function, as we expected, but it also led to earlier hospital discharge (by about a day), reduced hospitalization costs, and, most importantly, “On the average, alvimopan-treated patients had a lower incidence of mortality and most incidents of morbidities.”⁵ All of this with a so-called “failed” drug that had been discontinued from development by one of this country's largest pharmaceutical companies.

And this opportunity may now repeat itself. Catalina intends to license a “failed” clinical-phase TRPV1 antagonist and initiate clinical studies to assess its potential in reducing or preventing intraoperative hypothermia, all in 6 years or less and for a budget of less than $60 million.