FDA Committees Vote on Novel Therapy for Schizophrenia, Bipolar I Disorder

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ALKS 3831 is composed of samidorphan, a mu-opioid receptor antagonist, which is co-formulated with the established antipsychotic agent, olanzapine, in a single bilayer tablet.

The Food and Drug Administration (FDA)’s Psychopharmacologic Drug Advisory Committee and the Drug Safety and Risk Management Advisory Committee jointly voted on ALKS 3831 (olanzapine/samidorphan; Alkermes), a novel atypical antipsychotic therapy, for the treatment of schizophrenia and bipolar I disorder in adults.

ALKS 3831 is composed of samidorphan, a mu-opioid receptor antagonist, which is co-formulated with the established antipsychotic agent, olanzapine, in a single bilayer tablet. The once-daily oral formulation is designed to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain.

The NDA is supported by data from the ENLIGHTEN clinical program, which includes two phase 3 studies. In ENLIGHTEN-1 (N=403), treatment with olanzapine/samidorphan resulted in statistically significant reductions from baseline in Positive and Negative Syndrome Scale scores compared with placebo (P <.001) in patients experiencing an acute exacerbation of schizophrenia; a similar improvement was noted in the olanzapine arm when compared with placebo.

Results from ENLIGHTEN-2 (N=561), which was designed to confirm the favorable weight profile of olanzapine/samidorphan compared with olanzapine, demonstrated both a lower mean percent weight gain from baseline at 6 months with the combination therapy compared with olanzapine (P =.003) and a lower proportion of patients who gained 10% or more of their baseline body weight at 6 months compared with olanzapine (P =.003).

As olanzapine is currently approved for the treatment of bipolar I disorder, the Company also included pharmacokinetic bridging data in the NDA to support treatment with olanzapine/samidorphan for this indication.

With regard to whether samidorphan meaningfully mitigates olanzapine-associated weight gain, the panel members voted 16 to 1 in favor of this outcome. As to whether the safety profile of ALKS 3831 has been adequately characterized, 13 committee members responded favorably while 3 said no, and 1 abstained from the vote. According to meeting documents, the main concern was related to the opioid antagonist effect of samidorphan in real-world settings, specifically “the potential for precipitated withdrawal, inadequate analgesia, and opioid overdose.”

“The epidemiologic data suggest that a substantial subset of the indicated patient population could be at risk for 1 or more of these adverse events,” the FDA panel members noted in the brief.

Regarding the proposed labeling for ALKS 3831, 11 panel members agreed that the labeling was sufficient to mitigate risks related to the opioid antagonist action of samidorphan, while 6 members disagreed. The Company noted that the proposed labeling would include contraindications to use in patients who are opioid-dependent or chronically using opioids, in addition to an education plan for prescribers and pharmacists.

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Although not bound by the committees’ recommendations, the FDA does take them into consideration when making decisions on approval. A Prescription Drug User Fee Act (PDUFA) target action date for the application has been set for November 15, 2020.

For more information visit fda.gov.


  1. FDA Advisory Committee votes in support of ALKS 3831 for the treatment of Schizophrenia and bipolar I disorder. [press release]. Dublin, Ireland; October 11, 2020.
  2. FDA Briefing Document: Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee meeting. US Food and Drug Administration. https://www.fda.gov/media/142784/download. Accessed October 11, 2020.