On Aug. 21, 2017, Alkermes initiated a rolling application that will allow it to market ALKS-5461, its potential antidepressant that has already failed to gain approval twice. The rolling application will allow the company to submit sections of the NDA separately for review, rather than submitting it all at once.

At a pre-New Drug Application (NDA) meeting with the FDA in July, Alkermes presented a dataset of over 30 clinical trials that show a consistent efficacy and safety profile for the drug, leading to the decision to submit a rolling application. An estimated 17 million people suffer from major depressive disorder (MDD) in the U.S., the majority of whom are not adequately treated. Therefore, ALKS-5461’s novel mechanism of action (MOA), which has not been seen in the MDD space before, will make it a viable alternative when current therapies fail. 

ALKS-5461 is a proprietary, oral, investigational, fixed-dose combination (FDC) drug composed of samidorphan (formerly ALKS-33) + buprenorphine (Subutex). The combination of buprenorphine with the potent µ-opioid receptor antagonist samidorphan is intended to yield a novel, potentially non-addictive opioid modulator. The drug was granted Fast Track Designation by the FDA in 2013 as an adjunctive therapy for patients who have failed to respond to 1-3 medications. It was studied in the FORWARD clinical trial program, which consisted of three Phase III efficacy trials: FORWARD-3, FORWARD-4, and FORWARD-5. While the results of FORWARD-5 were positive, the drug failed to meet its primary endpoint in FORWARD-3 and FORWARD-4. Alkermes stated that these failures were due to a high placebo response rate rather than a drug safety or efficacy failure, and as such, suggested that they should be ignored completely.

With its novel MOA targeting opioid receptors, ALKS-5461 has the opportunity to become an alternative treatment option forpatients with depression, instead of the currently used atypical antipsychotics, which MDD patients have a negative view towards. It is estimated that approximately 30 percent of patients do not adequately respond to the current treatments. As such, GlobalData expects that the uptake of ALKS-5461 will predominantly occur in this patient population.

The competitive landscape for adjunctive therapies will become more crowded over the next decade with four other adjunctive therapies entering the depression market during the forecast period: Allergan/Gedeon Richter/Mitsubishi Tanabe Pharma’s Vraylar (cariprazine), Axsome Therapeutics’ AXS-05, Janssen’s esketamine, and Allergan’s rapastinel. ALKS-5461 will face strong competition if it demonstrates a comparable efficacy and safety profile to the other adjunctive therapies. GlobalData forecasts that MDD sales for ALKS-5461 will reach approximately $153.1M by 2025 in the seven major markets (7MM; U.S., France, Germany, Italy, Spain, U.K., and Japan).

Moving forward, Alkermes is looking to submit the dataset for ALKS-5461 — including information from 30 different clinical trials, in order to show the consistent efficacy and safety of the drug throughout the whole clinical program — to the FDA by the end of 2017. If the FDA review proves successful and the drug is approved, the medication could enter the U.S. market by the end of 2018.

However, whether the drug will be approved remains to be seen. While the FDA has accepted the rolling application from Alkermes, there is no guarantee that it will be able to overlook the drug’s two failed clinical trials. If ALKS-5461 is accepted by the FDA, it will be interesting to see the impact it will make on the market; the drug’s novel mechanism of action bodes well, but physicians may be hesitant to prescribe it given its public failures. The most likely scenario, if the drug is approved, is that it will experience a slow uptake, with physicians growing more comfortable prescribing it only after more studies have been conducted.