US regulator sails into treacherous opioid waters

Public criticism fails to derail approval of Acelrx’s opioid painkiller, but not without a lengthy apologia from Scott Gottlieb.

Rarely does a US drug approval elicit a detailed public explanation from the FDA commissioner himself. Then again, if the drug in question is, like Acelrx’s Dsuvia on Friday, an opioid analgesic the agency’s apologia can be seen as a rational way of limiting another public outcry.

No such luck for Trevena, whose own opioid asset, oliceridine, was hit with a complete response letter. The lesson for applicants is that to have a chance of success you need to make a strong case for limiting potential for abuse; you should certainly not take the highly dubious step of completely ignoring FDA advice on phase III design.

That latter move was employed by Trevena, whose stock was hammered by 32% on Friday – the last of a triple whammy of setbacks. The first was occasioned by adcom briefing documents that spelled out the FDA’s displeasure with a proposed pivotal design – Trevena had characterised its regulatory interaction as “successful” – while the second came on the 8-7 negative adcom vote for oliceridine.

Thumbs up

Conversely, Acelrx’s stock is today basking in a 16% climb on the FDA’s thumbs up for Dsuvia. That said, the company’s market cap stands at an undemanding $290m, suggesting that turning Dsuvia into a profitable product might be even trickier than securing its approval.

For a start, Dsuvia looks to be limited to very specific situations. One reason why the sublingual product passed regulatory scrutiny was that it may only be delivered by a healthcare professional in hospitals, surgical centres and emergency departments.

This will likely curtail Dsuvia’s market potential, as will the fact that it is being positioned specifically for military battlefield use. The drug is particularly suited for this thanks to its stable formulation, making it “ideal” for patients unable to swallow or where the is no access to IV pain relief, the FDA says.

EvaluatePharma’s consensus of sellside analysts sees Dsuvia selling $204m in 2024. Trevena’s oliceridine, an IV agent that like Dsuvia is a mu-opioid agonist designed as a more powerful alternative to morphine, is expected to generate just $98m of 2024 revenue.

Trevena’s problems stem from the FDA disagreeing with oliceridine’s proposed phase III dosing, and lack of regulatory agreement on the trial’s primary endpoint and non-inferiority margin for comparison versus morphine. Friday’s complete response letter apparently calls for additional clinical data on QT prolongation, a broader safety database and further preclinical studies.

Criticism

The path to approval for Dsuvia was not straightforward, either. As Ed Silverman wrote in Pharmalot, the FDA had faced extensive criticism in the run-up to regulatory action on Dsuvia, with the Public Citizen group claiming that a painkiller so much stronger than morphine would constitute a threat to public health.

This is clearly why Mr Gottlieb, the FDA commissioner, took the unusual step of publishing a detailed commentary on the decision, beyond the usual agency statement that an approval had taken place, tackling the criticism and explaining the FDA’s action.

The need is raised for a new formulation of sufentanil, Dsuvia’s active ingredient, an especially potent form of fentanyl that has been available IV and epidurally for 34 years. Ultimately, the fact Dsuvia is a high priority for the Pentagon, along with its very tight restrictions – “it won’t be available at retail pharmacies for patients to take home” – seem to have swung the balance.

Interestingly, Mr Gottlieb stressed the need to evaluate opioids not just as a class or as independent review decisions, but in the context of what is available to patients and providers. This looks to be a somewhat novel regulatory stance, though clearly it will provide little solace for Trevena.

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