A week after expressing optimism about its major depression candidate replicating its Phase II results in Phase III, Alkermes PLC is putting on a positive face after revealing that ALKS-5461 failed to meet its primary endpoint in two of its three Phase III trials.

Alkermes announced Jan. 21 that '5461 failed to meet the primary endpoint in the FORWARD-3 and FORWARD-4 studies. Based on topline data from those two studies, the Dublin-domiciled firm said it would add patients and revise the statistical analysis plan for the ongoing FORWARD-5 trial.

Hoping for positive results from the final Phase III study – expected by the end of the second quarter or early in the third quarter – Alkermes plans to combine those in a new drug application (NDA) with its Phase II data and a post-hoc analysis of one of the failed Phase III studies; FORWARD-4 showed a trend toward statistical significance in the primary endpoint – change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score.

ALKS-5461 – which combines Alkermes' proprietary mu opioid antagonist samidorphan (ALKS-33) with the partial mu agonist buprenorphine as a first-in-class opioid modulator – is being investigated as adjunctive therapy in depression patients for whom treatment response with traditional therapies has been inadequate.

FORWARD-3 tested a 2 mg/2 mg dose of '5461 against placebo in 429 patients but found no treatment response and a greater response in the placebo arm. Negative trials for investigational antidepressants are common, however, the company said.

In FORWARD-4, which tested both the 2 mg/2 mg and a 0.5 mg/0.5 mg dose in 385 patients, the primary endpoint failed, but Alkermes said it saw a trend toward efficacy with the larger dose and that a post-hoc analysis yielded a statistically significant change from baseline on MADRS across the 2 mg/2 mg dosing group. FORWARD-5 is studying 1 mg/1 mg and 2 mg/2 mg doses of '5461, which has been dosed once-daily across all the pivotal trials.

In a same-day note, Credit Suisse analyst Vamil Divan called the results a major step backward for Alkermes and said the chances of '5461 gaining FDA approval now are very low.

"With FORWARD-5 being similar in design to FORWARD-4, management plans to modify the statistical analysis plan and increase patient size population in the hopes of increasing the likelihood of success for that trial," Divan said. "We are skeptical but look forward to seeing detailed analyses of the FORWARD-4 data and also further commentary from management on their upcoming earnings call. While there is some precedent for an antidepressant being approved based on single positive Phase III trial, the big overhang remains on whether FDA will be receptive of the package Alkermes will present for ALKS-5461 approval, even if FORWARD-5 is positive."

Also offering a negative take was Jefferies Equity Research analyst Biren Amin, who said he had hoped Alkermes could mitigate the placebo effect often seen in depression studies with the Sequential Parallel Cohort Design it chose for the Phase III program. That approach had enabled Alkermes to produce impressive efficacy results in Phase II, he pointed out in a Jan. 21 note.

Perhaps most pessimistic was UBS Investment Research analyst Marc Goodman, who called the '5461 development program all but dead. He pointed out that Alkermes' strategy had been to run three pivotal trials, hoping at least two would succeed. Goodman, however, rates Alkermes' shares "neutral," while Divan and Amin take a rosier view of the company overall: Credit Suisse rates the company "outperform," while Jefferies calls the stock a "buy" candidate.

"Management indicated in the press release that it believes there is still potential to file if the third study is successful. We disagree," Goodman said in his Jan. 21 note. "The FDA requires two placebo-controlled studies for approval. Alkermes has two failed studies. We don't think management will be able to convince the FDA to approve the drug even if FORWARD 5 is successful, and when that happens, we think management will probably kill the drug. We are now assuming this drug is dead and taking all sales out of the model."

However, Jefferies' Amin pointed out that Otsuka Pharmaceutical Co. Ltd. obtained FDA approval in 2015 for Rexulti (brexpiprazole) on the basis of one successful and one failed Phase III trial ([A#00150720004]).

Optimism Expressed At JPM Does Not Bear Out

Alkermes CEO Richard Pops spoke optimistically about '5461's clinical prospects while addressing the J.P. Morgan Healthcare Conference in San Francisco Jan. 12. In the past, he has referred to '5461 as a "future blockbuster," along with the firm's ALKS-3831 for schizophrenia and ALKS-8700 for multiple sclerosis Also see "Alkermes Says New Aripiprazole Is Just The Start Of A Blockbuster Streak" - Pink Sheet, 3 March, 2015..

At the conference, Pops said data from the Phase III program were imminently expected and that success in the first two could hasten the submission of an NDA.

"This is a rich dataset," he told the conference. "It's maturing quickly. And we couldn't be more excited to start opening the envelopes and seeing what the data show and sharing it with you, so wish us luck. With positive data from two of these three studies, we'll begin to file the NDA for this product."

He said opioid modulation is at the forefront of new mechanisms being tested to improve depression therapy. Alkermes' expectation was that '5461, if approved, would be positioned as the next option for patients who started on generic selective serotonin reuptake inhibitor (SSRI) therapy and did not get an adequate response.

"When they fail, rather than moving to the next, more invasive level of modalities, superimpose adjunctively the treatment with '5461, a well-tolerated oral medication with positive and strong datasets supporting its use," the exec explained. "This is how we conceptualized the product. This is how we tested it in Phase II, and this is exactly how we're testing it in Phase III as well."

The combination of the two agents is intended to work by normalizing the body's own production of opioid, Pops said. "It's not about flooding the system with more opioid or taking the opioid away, but it's creating a functional clamp that maintains hemostatic levels of the opioid," he added. "This is a beautiful theory, but the nice thing, it's now borne out by data in multiple studies showing efficacy in patients refractory to other treatments."

In the aftermath of the FORWARD-3 and FORWARD-4 failures, Pops said Jan. 21 that Alkermes will await the results from the remaining trial to see if they can provide a path forward.

Alkermes Strategy After Antidepressant Failures Doubted By Wall Street

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