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Long-Term Data On Olanzapine and Samidorphan Highlight Maintained Schizophrenia Symptom Control
Key Takeaways
- OLZ/SAM, approved in 2021, is effective for schizophrenia and bipolar I disorder, offering maintenance and acute treatment options.
- ENLIGHTEN trials confirmed OLZ/SAM's efficacy in symptom control and reduced weight gain compared to olanzapine alone.
The addition of samidorphan can support the antipsychotic efficacy of olanzapine while mitigating associated weight gain.
New, long-term safety, tolerability, and durability data suggest the combination of olanzapine and samidorphan (OLZ/SAM, Lybalvi; Alkermes) maintained symptom control over 4 years for individuals with schizophrenia, schizophreniform disorder, or bipolar I disorder.1
Man with schizophrenia | Image credit: © Anthony Mujica Viera | stock.adobe.com
OLZ/SAM, approved by the FDA in June of 2021, is a once-daily, oral antipsychotic drug indicated as a maintenance monotherapy or for the acute treatment of manic or mixed episodes in adults with schizophrenia or bipolar I disorder, as well as an adjunct to lithium or valproate. Olanzapine is an established antipsychotic agent, whereas samidorphan is a new chemical entity. It is available in fixed dosage strengths of 10 mg samidorphan and 5 mg, 10 mg, 15 mg, or 20 mg of olanzapine.2
It was originally investigated in the ENLIGHTEN clinical development program. ENLIGHTEN-1 (NCT02634346) evaluated the efficacy, safety, and tolerability of the treatment compared with placebo over 4 weeks in patients experiencing an acute exacerbation of schizophrenia. The trial met its prespecified primary end point, demonstrating statistically significant reductions from baseline in Positive and Negative Syndrome Scale (PANSS) scores.2
The ENLIGHTEN-2 (NCT02873208) trial evaluated the weight gain profile of OLZ/SAM compared with olanzapine over 6 months in patients with stable schizophrenia. This study also met its prespecified co-primary end points, demonstrating a lower mean percent weight gain from baseline at 6 months compared with olanzapine alone as well as a lower proportion of patients who gained 10% or more of their baseline body weight at 6 months compared with the olanzapine group.3
Now, results from the phase 3, multicenter, open-label, long-term extension conducted from June 2017 through September 2023 are further reinforcing the efficacy of OLZ/SAM. In the trial, patients completing the ENLIGHTEN clinical program received 2 to 4 years of additional treatment. Of 524 patients enrolled, 523 received 1 or more doses of OLZ/SAM, 88% of whom (n=460) had schizophrenia, 3% (n=15) had schizophreniform disorder, and 9% (n=48) had bipolar I disorder.1
Participants had a mean age of 35.1 years and mean OLZ/SAM exposure was 652.4 days. Of 451 patients eligible for 2 years of treatment, 242 (53.7%) received it; of 335 patients eligible for 4 years, 109 (32.5%) received it.1
The durability of OLZ/SAM was assessed using the change from baseline in the Clinical Global Impression–Severity (CGI-S) scale and the time to study discontinuation. Negative scores on the CGI-S indicate clinical symptom management.1 Safety end points included the incidence and severity of adverse events (AEs) and changes from baseline in body weight and waist circumference, each assessed at monthly visits.1
At 2 years, the mean change from baseline CGI-S score was -0.18, and at 4 years it was -0.24. The median time to study discontinuation was 588 days.1
In total, 314 study participants (60%) reported an AE during the treatment period, most of which were mild or moderate in severity. The most common AEs were weight gain (9.8%), headache (7.1%), anxiety (6.1%), insomnia (5.9%), somnolence (5.9%), nausea (5.7%), and decreased weight (5.7%). In total, 44 (8.4%) patients discontinued due to an AE.1
These new data support the use of OLZ/SAM for patients with schizophrenia, schizophreniform disorder, or bipolar I disorder, increasing the number of options in the armamentarium. Antipsychotic medications are recommended for this patient population because they can reduce acute symptoms and lower the risk of relapse and hospitalization, but weight gain and metabolic changes are frequent concerns.1
This has been a concern with olanzapine monotherapy, limiting its clinical utility. Studies have noted that olanzapine alone can cause adverse cardiometabolic effects such as type 2 diabetes, dyslipidemia, and metabolic syndrome. The addition of samidorphan can support the antipsychotic efficacy of olanzapine while mitigating associated weight gain, with the newest data furthering this use.
REFERENCES
1. Ballon JS, Kahn RS, Arevalo C, Dunbar M, McDonnell D, Correll CU. Long-term safety, tolerability, and durability of treatment effect of olanzapine and samidorphan: results of a 4-year open-label study. J Clin Psychiatry. 2024;86(1):24m15511. doi:10.4088/JCP.24m15511
2. Potkin SG, Kunovac J, Silverman BL, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with an acute exacerbation of schizophrenia: outcomes from the randomized, phase 3 ENLIGHTEN-1 study. J Clin Psychiatry. 2020;81(2):19m12769. doi:10.4088/JCP.19m12769
3. Kahn RS, Silverman BL, DiPetrillo L. A phase 3, multicenter study to assess the 1-year safety and tolerability of a combination of olanzapine and samidorphan in patients with schizophrenia: results from the ENLIGHTEN-2 long-term extension. Schizophr Res. 2021;232:45-53. doi:10.1016/j.schres.2021.04.009
