FDA panel backs Sage’s novel antidepressant but turns down Alkermes’

Sage’s Zulresso (brexanolone) is on course for approval for postnatal depression in the US after a positive vote from an FDA advisory committee at its meeting last week, but the same panel had bad news for Alkermes’ two-drug therapy for major depressive disorder.

The committee voted 17-1 on Friday that the benefit-risk profile for Zulresso (brexanolone) supported approval of the drug as an injectable therapy for post-partum depression (PPD) – provided it is delivered on an inpatient basis, by qualified staff, in a clinic licensed to prescribe the drug.

If the FDA follows its panel’s advice, Zulresso will become the first drug specifically approved for PPD, which is estimated to affect around 400,000 women every year in the US. The regulator is due to deliver a decision by 19 December, setting up a launch in the new year for what could be an important new women’s health drug.

The panel unanimously voted that Zulresso was effective in PPD and given that the drug represents a whole new class of antidepressant, much of the discussion centred on labelling, how to make sure the drug was used appropriately, and patient monitoring.

Brexanolone is a GABAA receptor modulator given as a 60-hour infusion, and has been shown in trials to start working within days of dosing, sometimes as quickly as 14 hours later, while traditional antidepressants can take weeks to exert their effects.

In Europe, Sage has said it hopes to have feedback from the EMA before the end of the year which will "guide our future plans in the EU as well as the timing of the build of our EU footprint," according to recent comments by the company’s chief business officer Michael Cloonan.

The verdict puts Sage on the brink of commercialising its first product, a big achievement for the company which was hit hard by the failure of brexanolone as a therapy for super-refractory status epilepticus (SRSE) – a severe type of epilepsy – last year.

Meanwhile, the company is also planning to extend the use of brexanolone into the depressive phase of bipolar disorder, with phase II trials at the planning stage and due to start before year-end.

As Sage’s follow-up drug SAGE-217 is also a GABAA receptor modulator – in trials for major depressive disorder (MDD) – analysts at Stifel said the outcome also reduces the risk in that project, which is in phase III testing.

The verdict has also reignited speculation that a larger company may decide the time is right to buy into Sage’s pipeline. The company featured high on a list of potential takeover targets in the US biotech sector published earlier this year.

Alkermes setback

Alkermes’ bid to get its new antidepressant ALKS 5461 approved in the US took a big knock a day earlier when the advisory committee voted 21-2 that the drug’s benefit-risk profile is not adequate to support its approval for treatment-resistant MDD.

The once daily drug – due for an FDA verdict by 31 January – combines buprenorphine, a mixed mu opioid receptor agonist/kappa opioid receptor antagonist already used to treat pain and opioid addiction, with an opioid antagonist called samidorphan. Buprenorphine is thought to have an antidepressant effect via the kappa receptor, but its stimulation of the mu receptor means it has abuse potential which Alkermes says can be overcome by giving it alongside samidorphan.

Alkermes was already labouring under the weight of one failed trial out of three submitted in support of the drug, and the panel was critical of the design deployed in trials, specifically a format known as sequential parallel comparison design (SPCD) that is designed to correct the placebo effect which can be a big factor in depression studies.

SPCD – which involves re-randomising placebo non-responders to either the drug or placebo again – has never been used in an FDA submission before, and the agency’s reviewers were sceptical about its benefit in briefing documents filed ahead of the meeting. On the day, that scepticism was shared by the panel, which also had concerns about a decision to change the endpoint in one study mid-way through.

The committee voted 20-3 that the company had not provided sufficient evidence to support the efficacy of ALKS 5461, but concluded it was safe – just – by a margin of 13 to 10.

Jefferies analysts said the vote resulted from "poor choice in statistical methods and an unsupported change in clinical endpoints," adding that the big question now is whether an ongoing phase IIIb trial (study 217) – not due to read out until August 2021 – will be able to meet the regulator’s concerns.

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