On Oct 9, 2020: Alkermes announced that FDA Advisory Committee voted in support of ALKS 3831 for the treatment of schizophrenia and bipolar I disorder.
The committee jointly voted that:
- samidorphan mitigated olanzapine-associated weight gain (16 yes, 1 no)
- safety profile of ALKS 3831 has been adequately characterized (13 yes, 3 no, 1 abstention)
ALKS 3831 = Olanzapine (flexible-dose 10 mg or 20 mg) + Samidorphan (fixed dose of 10-mg)
- once-daily dosing
- novel opioid system modulator: μ-opioid receptor antagonist.
- The role behind adding Samidorphan is to mitigate the olanzapine-induced weight gain.
Randomized Double-Blind Phase 2 Study of Olanzapine/Samidorphan in Schizophrenia:
This study (4) found that:
- antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo.
- Olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo.
- Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.
Double-Blind Phase 3 Study of Olanzapine/Samidorphan compared with Olanzapine in Schizophrenia:
This study (5) found that:
- Olanzapine/samidorphan combination treatment was associated with significantly less weight gain and smaller increases in waist circumference than olanzapine.
- This combination was well tolerated.
- The antipsychotic efficacy of the combination treatment was similar to that of olanzapine monotherapy
Can Samidorphan affect Olanzapine’s Pharmacokinetics?
- According to a multicenter, randomized, open-label, Phase I study: combining olanzapine with samidorphan does not affect the pharmacokinetic profile of either drug. (2)
Co-administration of ALKS 3831 with Lithium or Valproate:
- Administration of multiple doses of Olanzapine/Samidorphan did not have a clinically significant effect on the pharmacokinetics of lithium or valproate.
- This combination was well tolerated. (3)
- Alkermes Press Release (Oct 9, 2020)
- Sun L, McDonnell D, von Moltke L. Pharmacokinetics and Short-term Safety of ALKS 3831, a Fixed-dose Combination of Olanzapine and Samidorphan, in Adult Subjects with Schizophrenia. Clin Ther. 2018 Nov;40(11):1845-1854.e2. (pubmed)
- Sun L, Yagoda S, Yao B, Graham C, von Moltke L. Combination of Olanzapine and Samidorphan Has No Clinically Significant Effect on the Pharmacokinetics of Lithium or Valproate. Clin Drug Investig. 2020 Jan;40(1):55-64. (pubmed)
- Martin WF, Correll CU, Weiden PJ, Jiang Y, Pathak S, DiPetrillo L, Silverman BL, Ehrich EW. Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia. Am J Psychiatry. 2019 Jun 1;176(6):457-467. (pubmed)
- Correll CU, Newcomer JW, Silverman B, DiPetrillo L, Graham C, Jiang Y, Du Y, Simmons A, Hopkinson C, McDonnell D, Kahn RS. Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study. Am J Psychiatry. 2020 Aug 14:appiajp202019121279. (pubmed)
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