As investors await data from phase III trials with ALKS 9070 (aripiprazole lauroxil) in schizophrenia, Alkermes plc is starting its pivotal program with once-daily, oral ALKS 5461 for major depressive disorder (MDD).

Dubbed FORWARD (Focused On Results With A Rethinking of Depression), the MDD effort involves a dozen studies, including three phase III efficacy experiments and nine supportive trials.

The company could not be reached, but CEO Richard Pops said late last month in the company’s most recent conference call on earnings that the phase II results offered last year with ALKS 5461 have lately been bolstered by data on remission, “specifically, 50 percent of patients treated with ALKS 5461 in [the second stage] of the study had sufficiently low depression scores that they no longer qualify as depressed.” Pops called the outcome “striking,” and “an example of the human aspect of the benefit that ALKS 5461 has the potential to offer.”

The first FORWARD study in about 60 patients is under way, and the trio of efficacy studies is expected to begin around the middle of this year. ALKS 5461 consists of an opioid agonist and antagonist components, plus the new opioid modulator, samidorphan, discovered by Alkermes.

A key element is the sequential parallel comparison design (SPCD), which splits the trial into two stages and uses patients who are placebo nonresponders in both, as a way to minimize placebo response.

Maurizio Fava and David Schoenfeld at Massachusetts General Hospital came up with the SPCD model more than 10 years ago. Rather than a placebo run-in, which clinical investigators would know about, everything is blinded in the first stage, and becomes part of the statistical analysis later. (See BioWorld Today, Oct. 9, 2013, and Oct. 10, 2013.)

Last summer, the FDA told Dublin-based Alkermes that it could skip the customary end-of-phase-II meeting and move directly into phase III trials with ALKS 5461, and the company – with plenty of irons in the fire – is nicely fixed for cash, thanks to January’s haul of $248.4 million in a new share offering directed at two Invesco Perpetual funds managed by UK investment management firm Invesco Ltd. (See BioWorld Today, Jan. 14, 2014.)

“This is a market characterized by multiple blockbusters that are household names – Lexapro, Zoloft, Prozac, Paxil, all blockbusters with common mechanisms of action,” Pops said. “The issue is that millions of patients do not receive adequate response from these therapies, even after second- or third-line treatment.”

ALKS 5461 has a long phase III road ahead, but ALKS 9070 is expected to yield data soon. Pops called the schizophrenia therapy “a major opportunity” built on Alkermes’ experience with long-acting injectable antipsychotics (LAIs). Aripiprazole is the active ingredient in Abilify, from Bristol-Myers Squibb Co., of New York.

“The atypical antipsychotic market is a $20 billion market worldwide, and it’s the largest therapeutic class in the U.S.,” he noted. “We see this market shifting away from the orals and toward LAIs, which we believe is going to have two important applications. One is that more LAIs are going to be used, based on the quality of the data supporting their use. The second is that they’re going to be used earlier in treatment.”

SPRING FLOWERS

Regarding ALKS 9070, previous outcomes turned up encouraging. “All systems are ‘go,’ and as I always say, that plus a positive result will be good,” Pops said. “We’re very pleased with the design and pleased with the execution, and it actually helped to develop a theme that you’ll see repeating with [ALKS 5461], which is that we will trade time for quality, because we believe these drugs really work. The secret in the [central nervous system disorder] studies is to enroll the right patients at the right sites and be careful about doing it. Hopefully, that will become manifest when we have the data.”

Also in the pipeline, Alkermes has the first phase II trial of ALKS-3831 in schizophrenia under way and expected to complete enrollment by the end of the year. Another phase II study is testing the oral compound in schizophrenia, as well as in alcohol abuse, and will start before then. In January 2013, Alkermes reported promising phase I results in attenuating antipsychotic-related weight gain. ALKS 3831 combines a drug molecule called ALKS 33 (a mu-opioid antagonist, intended as non-addictive) with Zyprexa (olanzapine, Eli Lilly and Co.).

ALKS 3831 “starts with the pharmacology of olanzapine, which is one of the most efficacious drugs for the treatment of schizophrenia,” Pops said, and then “builds onto it additional pharmacology to address two subpopulations of schizophrenia: patients who have significant weight gain on olanzapine and those with schizophrenia that is exacerbated by alcohol use. Our hypothesis is that what links these two patient populations is a fundamental aberration in the reward system that is part of their disease pathology.”

Though Alkermes calls them “subpopulations,” he noted, “these groups represent millions of patients with schizophrenia, who have real unmet medical needs.” Farther back in development, Alkermes has the monomethyl fumarate prodrug ALKS 8700 for multiple sclerosis, which should enter the clinic around the middle of this year, and the opioid analgesic ALKS 7106 for pain, also due for clinical testing before 2014 is done.

The biggest catalyst for Alkermes’ shares this year could be the ALKS 9070 phase III data, which J.P. Morgan analyst Cory Kasimov predicted will happen in the spring. In a research report last month, Kasimov said data from the big phase II trial with ALKS 3831 will be important, too, when they roll out early next year.

Shares of Alkermes (NASDAQ:ALKS) closed Thursday at $46.51, down 85 cents.