EP Vantage interview – Pain mulls path forward as Remoxy revived

In deciding to keep faith with Pain Therapeutics’ oxycodone project Remoxy, Pfizer is betting that it can convince the FDA of its safety and abuse-resistant bona fides on the third time of asking. Pfizer's handing back the rights to three of Pain’s other opioids looks like a safer decision, especially in light of the FDA’s move yesterday to reclassify hydrocodone pills as Schedule II.

If Remoxy gains US approval it will become a blockbuster, potentially even exploiting the FDA’s guidelines on opioids to force all other oxycodone formulations, including Purdue’s OxyContin, off the market. “Our belief, and certainly our strategy, is that upon approval Remoxy becomes the gold standard of abuse resistance,” Pain’s CEO, Remi Barbier, tells EP Vantage.

Tweaking the dials

The history of Remoxy is, ironically, rather painful. Its first FDA rejection, in 2008, came simply because the FDA did not know what it was dealing with, Mr Barbier says. “When you’re the first to introduce a new concept to the FDA, you suffer the curse of the pioneer. The FDA was not quite sure how to treat it.”

The second complete response letter, in 2011, was due to a manufacturing issue, he says. “Because it’s an abuse-resistant formulation it is very difficult to manufacture and you have to test it in very different ways to an ordinary drug. The FDA told us to stabilise the manufacturing process and then refile.”

In May, Pfizer said it was considering backing out of the Remoxy deal (FDA delivers crushing blows to abuse-deterrent opioids, May 13, 2013). Now, though, it is conducting further trials on a new formulation of the pill in which the proportions of some of the excipients have been changed. This is aimed at making the manufacturing more reliable, Mr Barbier says. “It’s tweaking the dials, it’s not a major shift.”

Studies of the new form’s pharmacokinetics and other aspects will be complete in around a year, potentially allowing for a PDUFA date in late 2015. “The good news is we know exactly why it was not approved. The bad news is that it has taken Pfizer some time to stabilise the manufacturing process. Pfizer has now reached a point where they are confident that the manufacturing platform is 100% stable, so now it’s off to the races.”

In a funk

Unless a company can prove abuse resistance, it is now impossible to get a long-acting opioid approved in the US.

In April the FDA said it would not approve any generic opioids that were not abuse-deterrent, and in September restricted their labelling and laid out the requirements for longer and more thorough trials (Further FDA crackdown on opioids could close market to generics, September 11, 2013). OxyContin, relaunched in a new abuse-resistant formulation in 2010, remains the only drug to gain the FDA’s specific abuse-resistant designation.

Pain believes that all these boxes have already been ticked – and this is why the Remoxy process has taken so long. “We’ve all been in a funk about how long it’s taken to move Remoxy forward. But there are very good reasons why it’s taken forever and a day for Remoxy to cross the finish line,” Mr Barbier says.

He explains that there are six common routes of opioid pill abuse – chewing, crushing, vaporising, snorting, injecting and finally diluting it in fluid. Remoxy is the only long-acting oxycodone with published data against all six methods, Mr Barbier says, making it the gold standard for abuse resistance.

“The flip side of that is that because it’s so resistant to all these different methods is has been difficult to manufacture. That’s why it’s taken all these years.”

The potential for Remoxy to eclipse all other oxycodone formulations, including OxyContin, is what has persuaded Pfizer to stay with the partnership, Mr Barbier says. If the pill does gain approval, and is provably better than OxyContin at defying addicts’ attempts to abuse it, there will then be an impetus for the agency to remove OxyContin from sale.

And, as Mr Barbier remarks, “the stakes are huge. Right now [opioid painkillers] is over a $3bn market in North America alone, so we’re talking about a very, very significant race, both in terms of clinical impact but also in terms of dollars and cents.”

Healthy cash position

Regarding Pfizer’s walking away from three of its other abuse-resistant opioid programmes, Pain seems fairly sanguine – perhaps it is relieved that the Remoxy partnership is still viable. “Whereas Remoxy is clearly a multibillion dollar target, the other three opioids in development are not – instead they’re probably between $200m and maybe $500m in market size. A market size of a few hundred million does not move Pfizer’s needle,” Mr Barbier says.

Two of the candidates, PTI-721, a formulation of hydrocodone, and PTI-202, a version of hydromorphone, are in phase I. The third is an oxymorphone pill in preclinical testing.

Mr Barbier says that Pain has the option of either taking them forward in-house or licensing them out to a new partner, but the strategy has not been decided.

“We have a very healthy cash position – we have over $50m in cash and a very low burn rate. Like anything else, the first time is the hardest. Remoxy took around $100m of R&D expenditure to get it to where it is. The second and third [products] will take a fraction of that. We have the cash to develop them. The question is, do we develop them on our balance sheet or someone else’s?”

For one of these products at least, it may not have a choice. The FDA’s plan to designate hydrocodone as a Schedule II drug, thereby restricting its use, could scare potential partners off ‘721. Indeed, the situation here could end up echoing that with Remoxy.

Drug development is always a matter of balancing risk and reward. With Remoxy, and perhaps with the rest of Pain’s pipeline, both are greater than usual.

To contact the writer of this story email Elizabeth Cairns in London at elizabethc@epvantage.com or follow @LizEPVantage on Twitter

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