Phase 3 Study of ALKS 3831 Indicates Schizophrenia Drug Shows Benefit

A phase 3 study of ALKS 3831 demonstrated greater antipsychotic efficacy compared with placebo, as measured by rating scales, according to a poster presented at Psych Congress 2018.

ALKS 3831 is composed of a flexible dose of olanzapine (OLZ) and a fixed dose of 10 mg samidorphan (SAM), an opioid receptor antagonist, formulated as a bilayer tablet. It is being studied for the treatment of schizophrenia to mitigate the weight gain and metabolic effects associated with olanzapine alone.

In a phase 2 study, coadministration of SAM mitigated OLZ-associated weight gain, and the OLZ + SAM combination exhibited antipsychotic efficacy similar to OLZ alone.

Preclinical studies have provided evidence for a role of the opioid system in mediating food reward, feeding behavior and metabolism.

The efficacy of ALKS 3831 and OLZ were similar. However, due to baseline differences between groups with regard to body mass index (BMI), the acute nature of the population, and the short duration of the trial, it was difficult to compare weight gain between groups. Long-term studies to examine the effects on weight and other metabolic measures are continuing.

The study consisted of a 4-week treatment phase of 2 weeks of inpatient treatment (OLZ titration permitted) followed by 2 weeks of inpatient/outpatient treatment (fixed OLZ dose).

Patients were admitted to the trial if they had a primary diagnosis of acute exacerbation of schizophrenia but excluded if they had a primary psychiatric diagnosis other than schizophrenia, or received OLZ within 6 months prior to screening. Antipsychotic efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression—Severity (CGI-S) and CGI–improvement (CGI-I) scales

The primary endpoint, change from baseline in PANSS total score at week 4, was analyzed using a mixed model with repeated measurements (MMRM). The key secondary endpoint, change from baseline in CGI-S score at week 4, was also analyzed by MMRM. The proportions of PANSS responders and CGI-I responders were analyzed by a logistic regression model. PANSS response was defined as ≥30% improvement from baseline in PANSS total score, and CGI-I response was defined as a CGI-I score of ≤2.

In total, 401 patients were randomized and given ALKS 3831, OLZ, or placebo. The mean age was 41 years and 61% of patients were male. Baseline mean BMI was higher in the OLZ group compared with the ALKS 3831 and placebo groups (27.4 kg/m2, 26.4 kg/m2, and 25.9 kg/m2, respectively).

Overall baseline mean ± standard deviation (SD) scores were 101.7 ± 11.9 for PANSS total score and 5.1 ± 0.7 for CGI-S score. The mean OLZ dose was 18.4 mg/day in both active treatment arms. The least squares (LS) mean difference ± standard error (SE) versus placebo from baseline to week 4 in PANSS total score was −6.4 ± 1.8 (P < .001) and −5.3 ± 1.8 (P = .004) for the ALKS 3831 and OLZ groups, respectively.

Change from baseline in PANSS total score by week (MMRM) LS mean difference ± SE versus placebofrom baseline to week 4 in CGI-S score was −0.38 ± 0.12 (P = .002) and −0.44 ± 0.12 (P < .001) for the ALKS 3831 and OLZ groups, respectively

The proportions of PANSS responders at week 4 were statistically significantly greater for ALKS 3831 (59.8%; P < .001) and OLZ (53.8%; P = .015) compared with placebo (38.3%). The proportions of CGI-I responders at week 4 were statistically significantly greater for ALKS 3831 (57.6%; P < .001) and OLZ (50.8%; P = .004) compared with placebo (33.1%).

Common adverse events included weight gain, somnolence, dry mouth, anxiety, headache, and schizophrenia. The most common reason for discontinuation was withdrawal by patient. One patient who was treated with OLZ died of a heroin overdose shortly after completing treatment.

The study was funded by Alkermes.

Reference

Potkin SG, Kunovac J, Silverman BL, et al. A phase 3 study to determine the antipsychotic efficacy and safety of ALKS 3831 in adult patients with acute exacerbation of schizophrenia. Presented at Psych Congress 2018, October 25-28, 2018, Orlando, Florida. Poster 129.