An investigational drug that targets the opioid system for major depressive disorder will be reviewed in an , and briefing documents from agency staff suggest the product won't have an easy time.
The safety and efficacy of ALKS 5461, a combination of buprenorphine and samidorphan intended to be used as adjunctive therapy to established antidepressants, will be voted on by the FDA Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee that day.
If it were to be approved by the FDA, the oral buprenorphine/samidorphan combination would be the first in an entirely new class of drugs -- and the first opioid -- for major depressive disorder.
Buprenorphine is an approved treatment for opioid use disorder; samidorphan is a new molecular entity and is not currently marketed in the U.S. or elsewhere. Both are active at opioid receptors.
Major depressive episodes affect an estimated in the U.S. and approximately two-thirds of patients being treated do not respond to currently approved therapies. The rationale for using an opioid to treat major depression is based on prior studies that show the .
To date, only three drugs have an indication for adjunctive treatment of major depressive disorder: aripiprazole (Abilify), quetiapine XR (Seroquel XR), and brexpiprazole (Rexulti). Unlike these atypical antipsychotics, the new oral drug combines a mu-opioid receptor partial agonist and kappa-opioid receptor antagonist (buprenorphine) and an investigational mu-opioid receptor antagonist to mitigate buprenorphine's abuse liability (samidorphan).
So far, the road to FDA review has been rocky: the FDA initially issued a for the buprenorphine/samidorphan drug based on insufficient evidence of overall effectiveness for the proposed indication. Two weeks later, the and accepted a new drug application.
submitted to the FDA for the drug, including , focused on patients with major depressive disorder who had failed one or two lines of prior therapy. Questions about trial design are likely to surface on Thursday.
Most studies in the drug's development program used sequential parallel comparison design (SPCD), a method that can reduce potentially high placebo response rates in psychiatry trials by filtering out placebo responders from the first stage. SPCD produces data in two stages, with separate randomizations and treatment comparisons in different populations. This marks the first time SPCD studies have been submitted to the Division of Psychiatry Products to provide efficacy evidence. FDA reviewers noted in the that the design made drug safety data hard to analyze.
The endpoint used in the drug's phase III trial also may raise eyebrows. Antidepressant trials typically assess efficacy at a specific time point -- such as after 6 to 12 weeks of treatment -- but here, researchers averaged the values from each patient over several weeks. While this method can decrease the variability in symptoms that fluctuate over time, scores at the final time point carry less weight, and any efficacy loss at the end of the period may be less important in the analysis.
But perhaps the biggest discussions will center around broad concerns about the potential public health consequences of the drug. Samidorphan is designed to negate buprenorphine's mu-opioid properties, but that has not been proven conclusively, the FDA reviewers noted. Although "there are fewer opioid properties for this combination product than there likely would have been from the opioid alone, there remains some evidence of a mild opiate effect (including mild withdrawal effects) from the trials," they wrote.
The risk of opioid overdose if the buprenorphine/samidorphan drug is used with other opioids -- and possible risk reductions strategies that could be implemented -- also will be part of Thursday's discussion.