With plans to land a new drug application for its treatment-resistant depression candidate, ALKS-5461, on FDA's doorstep before year's end, Alkermes plc is launching a phase IIIb trial intended to bolster its case for approval. Called study 217, the trial will evaluate whether or not adding '5461 to standard antidepressant therapies helps improve both depressive symptoms and participants' moods, a new facet not closely measured in earlier studies. Efficacy outcomes in earlier phase III studies of the candidate have been mixed.

Analysts last year discounted the candidate's chances of approval after it missed efficacy endpoints in two phase III trials that the Dublin-based company ran under the banner of its pivotal program, FORWARD (Focused On Results With A Rethinking of Depression). To close the program out, Alkermes buckled down to run FORWARD-5, a fifth phase III trial in which the higher of two dosages of the drug tested — a combination of 2 mg of samidorphan, an oral opioid modulator formerly known as ALKS-33 and 2 mg of the opioid buprenorphine — met the prespecified primary endpoint of significantly reducing depression scores compared to placebo. (See BioWorld Today, Jan. 22, 2016.)

All five late-stage FORWARD study measured efficacy outcomes based on the Montgomery-Åsberg Depression Rating Scale. Study 217 will use the same instrument for its primary endpoint, but will also incorporate new design features.

"There has been interest in better understanding the potential for ALKS-5461 to impact specific mood domains of depression that are less affected by currently available antidepressant medicines and are known to be regulated by the body's endogenous opioid system," Alkermes spokeswoman Jennifer Snyder told BioWorld.

To meet that interest, study 217 will seek to evaluate its Connor-Davidson Resilience Scale, a measure of stress coping ability; the Snaith-Hamilton Pleasure Scale, an instrument designed to assess a person's ability to experience pleasure; the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form; the Brief Pain Inventory-Short Form; and the Clinical Global Impression-Severity and Clinical Global Impression-Improvement scales.

Should it succeed, Alkermes still may face a significant number of challenges. ALKS-5461 targets the kappa opioid receptor, which is more familiar to regulators for its role in pain and addiction pathways, but not widely known as an antidepressant mechanism. Because it contains an opioid, DEA scheduling may also be required.

"The trouble with opiates, of course, is that they are addictive, and only a very, very small number of physicians in very, very severe cases will use opiates to treat depression, because you're basically just asking for future problems," Alkermes CFO Jim Frates, said during the recent Jefferies Global Healthcare Conference, according to a transcript of the event. "What we set out to do with this program is to see if we could divorce the treatment effect of opiates in depression from their seeking effect, or their addictive effect, and we believe we have been able to do that."

Another challenge will be that atypical antipsychotics such as Seroquel (quetiapine) and Abilify (aripiprazole), are already used in treating resistant depression, mostly in adjunctive therapy. However, it's clear that the company is already thinking about how to frame the issue. Those are "very, very powerful drugs," Frates said at the Jefferies conference. "Nobody wants to be labeled as a psychotic."

Despite all the activity to lay the groundwork for '5461 to move ahead, news of Alkermes' plans for the new study were overshadowed Monday by a front-page New York Times story that chronicled criticism of the clinical evidence supporting Vivitrol (naltrexone), a treatment of alcohol dependence and relapse to opioid dependence, as well as the company's approach to marketing the drug.

Alkermes shares (NASDAQ:ALKS) lost $2.19 on Monday, closing at $59.47.