At a time when opioid painkiller misuse is putting pressure on the US FDA to approve abuse-deterrent drugs at least one company might feel aggrieved that its own efforts to tackle this crisis have fallen on stony ground.
Kempharm is in the middle of an appeal against the FDA’s refusal to grant its hydrocodone prodrug Apadaz abuse-deterrent labelling. The company’s chief executive, Travis Mickle, insists that real patient behaviour does not fit the regulator’s measures: “Are they trying to make the clinic match the real world, or are they trying to make the real world match the clinical results?”
“The agency only has a number of endpoints or tools that they’re able to look at, like drug-liking and ‘take drug again’,” Mr Mickle tells EP Vantage. “Apadaz ... wasn’t able to hit those endpoints.”
Kempharm was relying on the fact that the hydrocodone prodrug in Apadaz is by definition inert, and indeed the agency agreed that there was no additional risk to patients or abusers. Mr Mickle argues that current drugs are being abused because of early drug liking, which an inert prodrug might not elicit.
However, the FDA simply had no well-trodden precedent to rely on, he says, and issued a complete response letter based on an adcom vote against including abuse-deterrent wording on Apadaz’s label.
Fundamentally this could call into question not only Apadaz but also the rest of Kempharm’s pain portfolio, including prodrugs of hydromorphone, oxycodone and oxymorphone. A decision on the group’s appeal against the US complete response letter could come by the end of 2017, Mr Mickle says.
Meanwhile, Kempharm is hedging its bets, and last year licensed an additional formulation-based technology from Acura. Just in case Apadaz is a no-go this is already being developed in KP201 (comprising hydrocodone without the acetaminophen that Apadaz also contains), a project that is difficult to inject and has nasal aversion properties.
“We’re also watching the broader market for abuse-deterrent opioids, for regulatory tailwinds and headwinds,” says the chief exec, who also stresses the importance of a changing political situation and new FDA commissioner.
A sign of the shifting climate occurred last month when a US panel voted against the safety of Endo International’s Opana ER, though whether this drug will be pulled from the market is unclear. At issue was the formulation, which was actually contributing to safety fears (Event – FDA panel to re-examine Opana ER, March 9, 2017).
Curiously, Endo too had been pursuing an abuse-deterrent label for Opana ER, but shelved this to gather more data.
Mr Mickle stresses that, for now at least, Kempharm is a company focusing not on formulation technology but on prodrugs: “re-engineered forms of existing actives ... to change the properties of the older molecule”.
He insists that many more attributes can be altered by developing a prodrug than by formulation work. Moreover, abuse deterrence is just one application, he says: “We’ve just touched the surface of what the technology can do and where we can take it.”
While the appeal over the abuse-deterrence issue rumbles on this has enabled the group to put Apadaz on the back burner while shifting focus to KP415, a methylphenidate prodrug for ADHD. An efficacy trial in just 100 patients is due to start at the beginning of the school year, and could suffice for approval.
With KP415 Mr Mickle has returned to his roots: he and many of the Kempharm team were key movers behind New River Pharmaceuticals, a company that developed Vyvanse, the prodrug that as part of Shire now generates blockbuster revenue in ADHD.
This kind of limited clinical programme, and abbreviated regulatory pathway, are some of the advantages of the prodrug approach, says Mr Mickle, and Kempharm’s $82.1m of 2016 year-end cash – the group raised $56m in a flotation the previous year – is expected to last to mid-2019, well beyond the KP415 readout.
That said, Mr Mickle stresses that Apadaz remains a key long-term focus. Whether it and the rest of Kempharm’s painkiller prodrugs have a future is in the lap of the FDA.