CEO Remi Barbier said Pain Therapeutics Inc. will ask for a special protocol assessment (SPA) with regard to new trials demanded by the FDA's third complete response letter (CRL) for extended-release, abuse-deterrent Remoxy (oxycodone). "We can't, as a company, just keep doing studies ad infinitum" when the agency asks for something new, he said. "That's just insanity."

Barbier, although plainly surprised and unhappy, held back his opinion about whether Remoxy was evaluated justly by U.S. gatekeepers this time around. "Was the review really fair, neutral and equitable? I'm not going to answer that question," he said. "You're free to ask it, but I cannot answer it, at least not in public." He added that the CRL represents "a speed bump, not a death blow. Some might call it a low blow, but it's not a death blow."

Austin, Texas-based Pain, licensee of Durect Corp., also couldn't explain why U.S. regulators in July cancelled the advisory panel meeting slated for early August, deeming such scrutiny unnecessary – but then sent a CRL. Nor was anyone certain why the FDA didn't simply grant an extension of the PDUFA date (as done for Pfizer Inc. with its oxycodone), allowing the company to finish the new trials, which Barbier said could be done briskly. As things stand, "we have to go through the whole rigmarole of begging for an appointment, an audience with the Pope, and then being granted [an audience], and so forth," he said. "All that takes time. How long I don't know, but typically three months is realistic."

Pain's stock (NASDAQ:PTIE) closed Monday at $1.33, down $1.40, or 51.3 percent. Durect, of Cupertino, Calif., ended the day (NASDAQ:DRRX) at $1.16, down 54 cents, or 31.8 percent.

During a conference call with investors, analyst Jim Molloy of Laidlaw asked Barbier whether the time has come "for someone else to take the torch from failing hands and carry on," and he wanted to know if Pain had conducted "any discussion around potentially offloading Remoxy to a third party." At this, the CEO bristled. "First of all, there's no such thing as offloading a very good drug," he said. "You offload a dog you don't want. You offload old food in the fridge. This is none of the above. Would we get full value right here, right now? Of course not. No one's going to pay us the big bucks for Remoxy" with more studies ahead, he said. "I would say there's a viable market for Remoxy. [To find out] what the market is, stay tuned."

Meanwhile, the CRL delineates what Pain needs to do in order to win approval with label claims on three routes of would-be abuse: injection, inhalation and snorting. Studies would compare the product with one or more already available extended-release oxycodone version.

TWO IS 'ALL YOU GET'?

To support a claim against abuse by injection, the FDA wants Pain to repeat an injectability and syringe-ability study using thin films of drug, smaller volumes of solvents, and additional mixed solvents, along with alternative extraction methods and syringe filter. For the abuse-by-inhaling claim, a volatilization study needs to be completed using the same thickness for each drug to increase the surface area. And for the claim against abuse by snorting, Pain must conduct an intranasal abuse-potential study in human volunteers, with drug applied directly inside the human nasal cavity. "We have done a large animal study, which is a standard way and commonly accepted method," but no study was done in humans, Barbier said. "The thought of putting Remoxy, which is kind of a like a cross between Vaseline and Super Glue, up someone's nose . . . we just didn't think we would get the institutional review board's approval. But somehow we'll find a way to do it," he said. "To our knowledge, there's no such thing as an SPA for an abuse-deterrent study. We intend to ask the FDA for exactly that. I have to say it does seem every time we put a fresh pack of batteries in Remoxy, it comes back to us with a short circuit. At some level, that's troubling." (See BioWorld Today, May 13, 2013.)

Unlike previously, the CRL contains no questions about manufacturing, stability, or bioequivalence. "All those things, the bugaboos that had been the subject of a prior CRL, are behind us," Barbier said. "Those are gone." The longest and most challenging of the mandated trials is the intranasal experiment. In all, Pain guessed that pulling together the new data would take about a year and cost about $5 million. The company has "the cash, perseverance, endurance and knowledge to move forward," he said, although "we may have to compromise," getting injection and inhalation out of the way and doing the intranasal study post-approval. Maybe "two is all you get" from the FDA for an abuse-deterrent, long-acting version of the pain drug, judging from past wins. Of the four abuse-deterrent routes requested by Pain for Remoxy, he said, New York-based Pfizer's product, Troxyca (formerly ALO-02) won a claim on oral and snorting, but not on injection and smoking. Oxycontin, from Purdue Pharma LP, of Stamford, Conn., bears label claims on injection and snorting, but not on oral or smoking, like Xtampza, from Canton, Mass.-based Collegium Pharmaceutical Inc. (See BioWorld Today, April 28, 2016.)

Laidlaw's Molloy wrote in a research report on Durect earlier this month that, "after circling FDA approval for two putts, we believe Remoxy is on track to finally get the tap in on the third go at FDA approval. Durect's management believes that all the manufacturing/stability issues that caused the two prior CRLs have been resolved, and that the FDA canceling the August advisory committee [adcom meeting] shows the FDA's comfort with the Remoxy NDA." Rodman & Renshaw's Raghuram Selvaraju shared Molloy's opinion. "We believe [canceling the adcom] suggests that the efficacy and safety profile of Remoxy has been well presented in the NDA package, from the FDA's perspective, and additional application material is unlikely to be requested," he wrote in a July report. He predicted Remoxy's approval by the PDUFA deadline, which fell on Sunday.