Schizophrenia
ENLIGHTEN-1
Efficacy & Safety

LYBALVI (olanzapine and samidorphan) demonstrated proven efficacy vs placebo
In ENLIGHTEN-1, LYBALVI demonstrated a statistically significant improvement in the change from baseline in PANSS total score vs placebo at Week 4 in adults with schizophrenia1
STUDY DESIGN1-3
- Antipsychotic efficacy and safety of LYBALVI were evaluated in a 4-week, randomized, double-blind, placebo- and active-controlled, phase 3 study. The study was designed to compare LYBALVI with placebo, not with olanzapine
- Adult patients who met DSM-5 criteria were randomized to LYBALVI, olanzapine, or placebo. Dosing was flexible for the first 2 weeks of the study and fixed thereafter. Patients assigned to LYBALVI could receive either 10 mg/10 mg or 20 mg/10 mg, and patients assigned to olanzapine could receive either 10 mg or 20 mg. Olanzapine was an active control. Patients took one tablet by mouth each day, preferably at bedtime
- Patients were 18 to 70 years of age, with a body mass index (BMI) of 18.0–40.0 kg/m2, Positive and Negative Syndrome Scale (PANSS) total score of ≥80 with a score of ≥4 on at least 3 of the selected Positive Scale items, and Clinical Global Impression-Severity (CGI-S) score of ≥4
- Key exclusion criteria: History of diabetes and previous exposure to olanzapine within 6 months prior to screening. Patients taking opioid agonists (eg, codeine, oxycodone, tramadol, or morphine) within 14 days, or opioid antagonists within 60 days prior to screening were not allowed to participate
The inclusion of samidorphan in LYBALVI did not appear to negatively impact the antipsychotic efficacy of olanzapine.1
PRIMARY ENDPOINT





- The placebo-subtracted difference in change from baseline PANSS total score at Week 4 (95% CI) was -6.4 (-10.0, -2.8) for LYBALVI and -5.3 (-8.9, -1.7) for olanzapine1‡; the LS mean SE was 1.3 for all 3 groups2
‡Difference (drug minus placebo) in least squares mean change from baseline. A negative value for the placebo-subtracted difference represents improvement.1
ENLIGHTEN-1 was not a head-to-head study between LYBALVI and olanzapine, and was not designed to compare the efficacy of LYBALVI to the efficacy of olanzapine. Comparative conclusions of efficacy between LYBALVI and olanzapine cannot be drawn from these data.2
- Early discontinuation rates: 9.0% (n=12) in the LYBALVI group, 10.5% (n=14) in the olanzapine group, and 17.2% (n=23) in the placebo group2
SECONDARY ENDPOINT
Change from baseline in CGI-S at Week 4
- The LS mean difference ± SE versus placebo in change from baseline at Week 4 in CGI-S score was -0.38 ± 0.12 (P=0.002) for the LYBALVI group1,2
Adverse reactions observed in ENLIGHTEN-1
Most Common Adverse Reactions Observed With the Use of LYBALVI (Incidence of ≥5% and ≥2x Placebo)1
10 mg/10 mg and
20 mg/10 mg
(N=134)
(N=134)
- No patient treated with LYBALVI discontinued the study due to these common adverse reactions1
- The reasons for discontinuation for patients taking LYBALVI vs placebo, respectively: patient withdrawal (6% [n=8] vs 6% [n=8]), adverse reaction (1.5% [n=2] vs 5.2% [n=7]), lack of efficacy (0.7% [n=1] vs 6% [n=8]), and loss to follow-up (0.7% [n=1] vs 0% [n=0])2
- Adverse reactions that led to discontinuation in patients treated with LYBALVI included schizophrenia (1%) and abnormal liver function tests (1%)1
- The frequency of reported adverse reactions related to extrapyramidal symptoms, including akathisia, restlessness, muscle spasms, bradykinesia, tremor, extrapyramidal disorder, and parkinsonism was 2% both in patients treated with LYBALVI and placebo-treated patients1
For a complete list of adverse reactions, please refer to the full Prescribing Information for LYBALVI.
ENLIGHTEN-1 safety extension study:
52-week, open-label safety study assessed safety and tolerability
In adult patients with schizophrenia
STUDY DESIGN1,2,4
- Eligible participants in this phase 3, multicenter, open-label safety extension study were adults with schizophrenia who completed the ENLIGHTEN-1 pivotal study. A total of 352 patients completed ENLIGHTEN‑1 and a total of 281 patients enrolled in this safety extension study. Of these, 277 received ≥1 dose of study drug (safety population) and 248 had ≥1 postbaseline PANSS assessment (efficacy population)
- The first study visit occurred within 7 days of the last visit in ENLIGHTEN-1. Study visits occurred weekly for the first 2 weeks, then every other week thereafter to Week 52
- All patients started the safety extension study on LYBALVI 10 mg/10 mg. The LYBALVI dose could be increased to 15 mg/10 mg or 20 mg/10 mg
- Key exclusion criteria from the ENLIGHTEN‑1 pivotal trial were also applied to this study, including patients with diabetes mellitus, or olanzapine use 6 months prior to enrolling in ENLIGHTEN‑1
- Exclusion criteria for the safety extension study included: Findings compromising the safety of patients or affecting their ability to meet study requirements, use of medications contraindicated with olanzapine or that had drug-interaction potential with olanzapine, use of prohibited drugs, and women who were pregnant or nursing
Adverse Events Observed With the Use of LYBALVI (Incidence of ≥2%)4
Based on observed data without imputation.
Numbers rounded to the nearest percentage.
- Adverse events were reported by 49% of patients4
- 3% of patients reported serious adverse events4
- 33.9% (n=94) of patients discontinued before completing the safety extension study4
-
Reasons for discontinuation included patient withdrawal (15.5% [n=43]), patient lost to follow-up (6.9% [n=19]), adverse events (5.4% [n=15]), and lack of efficacy (1.8% [n=5])4
- The only adverse event leading to discontinuation that occurred in more than 1 patient was worsening/exacerbation of schizophrenia (2.2% [n=6])4
In addition to the primary objective of safety and tolerability, durability of treatment effect was evaluated in the 52-week, open-label safety extension study
In adult patients with schizophrenia
The ENLIGHTEN-1 safety extension study was an open-label safety study in which all participants received LYBALVI. The study was not designed to compare efficacy based on prior treatment group from ENLIGHTEN-1, nor was it designed to prospectively assess or evaluate the effect of LYBALVI on PANSS total score or CGI-S. No conclusions of efficacy can be drawn from these data.4
Mean PANSS Total Score for Patients Treated With LYBALVI in Safety Extension Study By Visit, Grouped by ENLIGHTEN-1 Treatment4

- Mean change from baseline for PANSS total score (95% CI) was -16.2 (-18.5 to -14.0) at 52 weeks4
Change From Baseline in CGI-S
- Mean change from baseline for CGI-S (95% CI) was -0.9 (-1.0 to -0.8) at 52 weeks4
Change from baseline in PANSS total score and CGI-S was summarized using last observation carried forward for missing data and was based on observed data without imputation4
The ENLIGHTEN-1 safety extension study was an open-label safety study in which all participants received LYBALVI. The study was not designed to compare efficacy based on prior treatment group from ENLIGHTEN-1, nor was it designed to prospectively assess or evaluate the effect of LYBALVI on PANSS total score or CGI-S. No conclusions of efficacy can be drawn from these data.4
Mean PANSS Total Score for Patients Treated With LYBALVI In Safety Extension Study By Visit, Grouped by ENLIGHTEN-1 Treatment4
- Mean change from baseline for PANSS total score (95% CI) was -16.2 (-18.5 to -14.0) at 52 weeks4
Change From Baseline in CGI-S
- Mean change from baseline for CGI-S (95% CI) was -0.9 (-1.0 to -0.8) at 52 weeks4
Change from baseline in PANSS total score and CGI-S was summarized using last observations carried forward for missing data and was based on observed data without imputation4
PANSS was assessed in all patients who received ≥1 dose of study drug and had ≥1 postbaseline PANSS measurement.4
STUDY LIMITATIONS4
- Open-label study design with loss of randomization, potential differential dropout of patients, and no comparator arm limits interpretation of efficacy and safety
- Missing data may have impacted the findings as approximately one-third of patients discontinued before 52 weeks
- In this study, patients’ baseline characteristics were affected by prior treatment with LYBALVI, olanzapine, or placebo in the antecedent study
References: 1. LYBALVI [prescribing information]. Waltham, MA: Alkermes, Inc.; 2021. 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. 3. Data on file. Alkermes, Inc. 4. Yagoda S, Graham C, Simmons A, Arevalo C, Jiang Y, McDonnell D. Long-term safety and durability of effect with a combination of olanzapine and samidorphan in patients with schizophrenia: results from a 1-year open-label extension study. CNS Spectr. 2020;12:1-31.