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Phase 3 data support combination drug targeting opioid system for major depression
Evidence from two phase 3 clinical trials of ALKS 5461, an investigational drug combining buprenorphine with samidorphan that targets the opioid system, supports its safety and effectiveness in decreasing symptoms of major depression when added to standard antidepressant treatment.
This therapy, with its novel opioidergic mechanism of action, may show potential as a new treatment option for patients with MDD, according to the data published in Molecular Psychiatry.
"Because many patients do not respond adequately to standard antidepressant therapies and the next-step options for treatment are very limited," Maurizio Fava, MD, executive director of the Massachusetts General Hospital Clinical Trials Network & Institute, told Healio Psychiatry. "There is a clear need for new therapies for patients with inadequate response to antidepressants."
Researchers reported the efficacy and safety of ALKS 5461 (buprenorphine/samidorphan; Alkermes) as add-on treatment in nearly 800 patients with major depression who had inadequate response to antidepressant therapy in two phase 3, randomized, double-blind, placebo-controlled trials: FORWARD-4 and FORWARD-5.
FORWARD-4 compared two dosage levels of ALKS 5461 — 0.5 mg of each drug or 2 mg of each — with placebo, while FORWARD-5 compared 1-mg and 2-mg doses with placebo, according to the press release. The investigators measured efficacy via the Montgomery–Åsberg Depression Rating Scale (MADRS).
Pooled analysis of the two studies showed consistently greater reduction in depression symptom scores from baseline for buprenorphine/samidorphan 2 mg/2 mg compared with placebo at multiple timepoints, including end of treatment and average change from baseline to week 3 through end of treatment.
In FORWARD-5, buprenorphine/samidorphan 2 mg/2 mg showed superiority over placebo. In FORWARD-4, the differences between the 2-mg dosages and placebo were not statistically significant; however, combining results from both trials produced a significant effect.
Patients receiving the 1-mg doses demonstrated symptom reduction greater than the placebo group, but less than the 2-mg doses, while those receiving the 0.5-mg dose demonstrated results no better than those of the placebo group, according to the press release.
Generally, ALKS 5461was well-tolerated, and most adverse events were mild or moderate in severity. The most common events in the ALKS 5461 2 mg/2 mg treatment group included nausea, constipation, dizziness, vomiting, somnolence, fatigue and sedation. Importantly, there was minimal evidence of abuse, the researchers reported in the full study.
"This combination of two drugs modulating the opioid system consistently produces antidepressants effects which are greater than placebo in patients with inadequate response to antidepressants," Fava said.
In a joint advisory committee meeting taking place on Nov. 1, the FDA will discuss the efficacy, safety and risk-benefit profile of the new drug application for buprenorphine and samidorphan sublingual tablets for adjunctive treatment of major depressive disorder.
"I hope that the committee will embrace the innovations adopted by Alkermes to study ALKS 5461, as the standard, obsolete methods that are typically used in trials have a poor track record in being able to detect therapeutic signals in depression," Fava told Healio Psychiatry. – by Savannah Demko
Disclosures: Fava reports many relevant financial disclosures, some of which included research support for Acadia Pharmaceuticals, Alkermes, Inc., Axsome, BioHaven, Cerecor, Johnson & Johnson, Lundbeck Inc., Marinus Pharmaceuticals, National Institute of Drug Abuse, Neuralstem, NIMH, Otsuka, PCORI, Relmada Therapeutics Inc., Stanley Medical Research Institute (SMRI), Takeda, Taisho and Vistagen. Please see the study for Fava’s and all other authors’ relevant financial disclosures.