SAN DIEGO -- The safety and efficacy of combination samidorphan and olanzapine (ALKS 3831) for schizophrenia was confirmed during an open-label extension of the ENLIGHTEN-1 trial.
During this 52-week extension, the significant improvement in mean Positive and Negative Syndrome Scale (PANSS) score was maintained in those who continued on samidorphan/olanzapine, dropping an average of 16.2 points from baseline (P<0.001). The improvement in mean Clinical Global Impression-Severity (CGI-S) score was also maintained long-term in these patients, decreasing an average of 0.9 points, reported Sergey Yagoda, PhD, of Alkermes in Waltham, Massachusetts, the agent's developer.
The investigational schizophrenia treatment is a once-daily dose of a fixed combination of 10 mg of the opioid modulator samidorphan with the atypical antipsychotic olanzapine (Zyprexa) in 5-mg, 10-mg, 15-mg, 20-mg doses. The combination treatment is designed to provide symptom improvement while reducing the often associated with antipsychotics.
July 2019, Alkermes expanded its New Drug Application (NDA) to include the treatment of bipolar I disorder and schizophrenia.
The current study builds upon positive 4-week data, and included 281 patients with schizophrenia (ages 18-70) who completed the initial treatment phase of .
Around half of patients experienced at least one adverse event (AE) during follow-up, which were mild to moderate. The most common AEs reported were increased weight gain, somnolence, headache, and nasopharyngitis. Ten serious AEs were reported and all were deemed unrelated to samidorphan/olanzapine.
By the end of the extension study, about 52% of patients were considered to be "PANSS responders," defined as achieving a ≥30% improvement in total score.
Patients who were enrolled in the 4-week randomized trial on olanzapine alone, and then were switched to combination samidorphan/olanzapine for the extension trial, also saw a significant improvement in PANSS total score and CGI-S score from baseline.
However, these individuals who switched to the combination treatment after the initial 4-week trial saw greater weight gain from baseline of the extension through 52-weeks of treatment versus those who remained on samidorphan/olanzapine:
- Placebo to samidorphan/olanzapine: gained 2.91 kg
- Olanzapine alone to samidorphan/olanzapine: gained 1.05 kg
- Remained on samidorphan/olanzapine: gained 1.75 kg
About 27% of participants who completed the 52-week extension saw a clinically significant weight gain of ≥7%, while 15% saw a weight increase of ≥10%. Other laboratory parameters, including HbA1c, fasting glucose, total cholesterol, LDL and HDL cholesterol, and triglycerides did not see a significant change during follow-up.
The investigators noted some study limitations, especially the fact that it was an open-label study with no comparator, so "only limited conclusions can be drawn from efficacy and safety data."
The phase III ENLIGHTEN-2 safety study, also presented here, took another look at weight gain and metabolic outcomes in patients on samidorphan/olanzapine. These outcomes build upon the previously reported phase III efficacy outcomes from ENLIGHTEN-2.
The 24-week open-label safety study included 561 "clinically stable but moderately ill" individuals with schizophrenia, according to Christoph Correll, MD, of Hofstra Northwell School of Medicine in Hempstead, New York, and colleagues. Compared to those on olanzapine alone, patients on the combination treatment saw significantly less weight gain:
- Samidorphan/olanzapine: 4.21% average weight gain
- Olanzapine only: 6.59% average weight gain
Similarly, 30% of patients on olanzapine alone saw a ≥10% weight gain after 24 weeks versus only 18% of combination treatment patients. Significantly fewer patients on the combination saw an increase in waist circumference.
About 74% of participants on the combination experienced any AE during follow-up, while 82% on olanzapine alone experienced any AE, mainly driven by weight gain.
"Although antipsychotic efficacy was not a primary endpoint in this study, improvements in PANSS scores from baseline were similar to those seen with olanzapine and consistent with improvements observed in the ENLIGHTEN-1 study," the researchers noted in July, they also reported plans to seek an indication for bipolar I disorder in addition to schizophrenia.
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Disclosures
The ENLIGHTEN trials were funded by Alkermes. Co-authors are company employees.
Correll disclosed multiple relevant relationships with industry including Alkermes.
Primary Source
Psych Congress
Yagoda S, et al "A phase 3, multi center study to assess the long-term safety, tolerability, and efficacy of olanzapine/samidorphan in patients with schizophrenia" Psych Congress 2019; Poster 317.
Secondary Source
Psych Congress
Correll C, et al "Olanzapine/samidorphan for schizophrenia: weight gain and metabolic outcomes in phase 3 ENLIGHTEN-2 and subsequent long-term, open-label safety study" Psych Congress 2019; Poster 123.