Yesterday’s US refusal-to-file letter for Alkermes’s heavily hyped pipeline hope, ALKS 5461 for depression, shows the FDA making a welcome return to the application of rigorous standards after earlier approving several drugs with limited evidence of efficacy.
Little wonder that Intra-Cellular Therapies, another company seeking a CNS green light based on questionable data, lost 8% yesterday in sympathy with Alkermes, which fell 22%. The setback is particularly embarrassing for Alkermes, which had long promised the markets that ALKS 5461 was a goer; the group is now set for a clash with the regulator – a strategy that rarely works out well.
Alkermes has made it clear how strongly it disagrees with the FDA, spelling out on an analyst call that no further study of ALKS 5461 was necessary. This was despite the agency clearly having demanded “additional well-controlled clinical trials” and a bioavailability bridging study.
Asked whether Alkermes would carry out additional trials if the FDA stuck to its guns, the company’s chief executive, Richard Pops, told analysts: “The smart thing to do is to wait until we see the whites of the FDA’s eyes in a type A meeting.”
The problem likely comes down to ALKS 5461’s repeated clinical failures during its tortured development path; indeed, the pivotal programme comprised three studies, Forward-3, 4 and 5, only the last of which was positive.
Forward-4 was claimed to have delivered a sufficiently positive signal only after a post hoc analysis of the data (Alkermes might finally move Forward, October 21, 2016). In initiating a rolling filing last summer Alkermes appeared to have been relying on guidance that one adequate study plus supportive evidence would suffice.
However, the FDA has likely taken the view that the clearly negative Forward-3 trial, and the data mining of the Forward-4 results, is insufficient evidence of efficacy.
|Win some, lose some: ALKS 5461’s failures and successes|
|Phase II||NCT01500200||142||8/8mg, 2/2mg, placebo||Succeeded|
|Forward-4||NCT02158533||385||2/2/mg, 0.5/0.5mg, placebo||Failed, but post hoc analysis showed signal with 2mg/2mg dose|
|Forward-5||NCT02218008||420 (from 350)||2/2mg, 1/1mg, placebo||2/2mg succeeded|
|Phase III '217 study||NCT03188185||325||?||Ongoing|
Despite its apparent confidence in existing data, Alkermes began a new phase III study, coded '217, in June 2017, suggesting that it knew it might need an insurance policy even with the positive Forward-5 results in hand.
Evercore ISI analyst Umer Raffat had already speculated that '217 data might be needed for approval, but now says even this might not be enough, given the FDA's request for additional trials.
For its part, Alkermes said this request was "surprising and troubling", since the agency had already seen efficacy results without expressing concerns. The company also claimed that it had addressed the need for a bridging trial in the pre-NDA meeting documents.
The FDA’s decision to reject ALKS 5461 spooked Intra-Cellular investors, who apparently saw a parallel with that company’s schizophrenia project lumateperone, which is also relying on mixed phase III data (Intra-Cellular bounces back in schizophrenia, August 24, 2017).
Leerink analysts brushed off any concerns, noting that lumateperone had only failed in one pivotal trial versus ALKS 5461’s two, and adding that there was a greater unmet in schizophrenia versus depression.
Intra-Cellular’s latest update claimed a “positive” pre-NDA meeting with the regulator, and the Alkermes debacle illustrates the danger of taking these kinds of announcements at face value; as recently as February Alkermes had touted the blockbuster potential of ALKS 5461, a fixed-dose combination of buprenorphine and samidorphan.
The company’s hopes of establishing a new category of depression drugs based around the modulation of the brain’s endogenous opioid system have been severely dented. Other novel projects now have a chance to claim the advantage including two NMDA modulators set to yield phase III data this year: Johnson & Johnson’s esketamine, which is due to report results this quarter, and Allergan’s rapastinel.
But, if the FDA’s stance over ALKS 5461 is anything to go by, these groups might need more than one positive pivotal trial to gain approval.
|Selected depression pipeline candidates|
|Project||Company||Mechanism||2022e sales ($m)||Trial(s)||Primary completion|
|ALKS 5461||Alkermes||Mu opioid partial agonist & kappa & mu opioid antagonist||247||Forward-3, 4, 5||Reported|
|Esketamine||Johnson & Johnson||NMDA antagonist||652||Transform-1 (NCT02417064); Sustain-1 (NCT02493868)||Both April 2018|
|Rapastinel||Allergan||NMDA modulator||297||RAP-MD-01 (NCT02932943); RAP-MD-02 (NCT02943564); RAP-MD-03 (NCT02943577)||Nov/Dec 2018|
|SAGE-217||Sage Therapeutics||GABA A modulator||353||NCT03000530||Reported|