Schizophrenia
ENLIGHTEN-2
Efficacy & Safety

LYBALVI (olanzapine and samidorphan) demonstrated less weight gain vs olanzapine1
In adult patients with schizophrenia
STUDY DESIGN1-3
- ENLIGHTEN-2 was a 24-week, randomized, double-blind, active-controlled, phase 3 clinical trial in 561 patients with schizophrenia
- Adult patients who met DSM-5 criteria for schizophrenia were randomized in a 1:1 ratio to LYBALVI or olanzapine for 24 weeks of daily dosing
- Dosing was flexible for the first 4 weeks, and fixed thereafter. Patients were treated with doses of LYBALVI of 10 mg/10 mg or 20 mg/10 mg, or with doses of olanzapine of 10 mg or 20 mg. Patients were instructed to take one tablet by mouth each day, preferably at bedtime
- Eligible patients were 18 to 55 years of age with a BMI of 18 to 30 kg/m2, PANSS total score of 50 to 90, CGI‑S score of ≤4, and symptoms suitable for outpatient treatment
- Exclusion criteria included: diabetes mellitus; use of olanzapine in the 6 months prior to Visit 1; anorexia nervosa, bulimia nervosa, or binge eating disorder; history of weight loss or plan for liposuction during the study; taking part in, or planning to join, a weight management program, during the study period; significant dietary or fitness changes within the past 6 weeks; concomitantly using any weight-loss or hypoglycemic agents; use of an opioid agonist (eg, codeine, oxycodone, tramadol, or morphine) within 14 days of screening, opioid antagonist use within 60 days of screening, or anticipated need for opioid treatment during the study
The inclusion of samidorphan in LYBALVI appeared to result in less weight gain than was seen with olanzapine alone.1,3
Patients on stable, chronic olanzapine therapy were not specifically studied, so the weight effect of switching from olanzapine to LYBALVI is unknown.1
CO-PRIMARY ENDPOINT




- The olanzapine-subtracted difference in percentage change from baseline in body weight with LYBALVI was -2.4% (-3.9, -0.9)1
The rate of discontinuation before the end of the trial was 36% for both groups. Missing weight assessments were imputed by multiple imputation sequentially for each visit, using a regression method.1,3
CO-PRIMARY ENDPOINT




- The risk of gaining ≥10% body weight was lowered by 50% with LYBALVI relative to olanzapine at Week 24, as assessed by odds ratio (OR=0.50; P=0.003)3 Patients taking LYBALVI experienced a lower risk of gaining at least 10% of body weight relative to olanzapine at Week 24, as assessed by odds ratio (OR=0.50; P=0.003)3
- The olanzapine-subtracted risk difference for ≥10% body weight gain with LYBALVI was -13.7% (-22.8, -4.6)1
The rate of discontinuation before the end of the trial was 36% for both groups. Missing weight assessments were imputed by multiple imputation sequentially for each visit, using a regression method.1,3
SECONDARY ENDPOINT
- 28% of patients taking LYBALVI vs 43% taking olanzapine experienced weight gain ≥7% at Week 243
Increased weight was the most common adverse reaction in patients treated with LYBALVI in both pivotal trials for schizophrenia.1
- The 4-week ENLIGHTEN-1 study evaluated antipsychotic efficacy and safety of LYBALVI vs placebo and was not designed to assess or compare the weight effects of LYBALVI vs olanzapine. There, the proportion of patients with ≥7% weight increase was 26% in patients treated with LYBALVI, 20% in patients treated with olanzapine, and 5% in patients treated with placebo
Adverse reactions observed in ENLIGHTEN-2
Most Common Adverse Reactions Observed With the Use of LYBALVI (Incidence ≥5%)1
10 mg/10 mg and
20 mg/10 mg
(N=274)
Numbers rounded to the nearest percentage.
- The incidence of weight increased with olanzapine (10 mg, 20 mg) was 36% (N=276)3
- Adverse reactions that led to study discontinuation in more than one patient treated with LYBALVI included somnolence (2%), weight increased (2%), neutropenia (2%), glycosylated hemoglobin increased (1%), schizophrenia (1%), and liver function test abnormal (1%)1
- Extrapyramidal adverse reactions, including parkinsonism, akathisia, and dyskinesia, had a similar incidence in patients treated with LYBALVI and in those treated with the active control: any extrapyramidal symptom was 8%, akathisia was 3%1
For a complete list of adverse reactions, please refer to the full Prescribing Information for LYBALVI.
ENLIGHTEN-2 safety extension study: 52-week, open-label safety study assessed safety and tolerability
In adult patients with schizophrenia
STUDY DESIGN2,4- Patients who completed the 24-week ENLIGHTEN-2 study were eligible to enroll in this phase 3, multicenter, 52-week, open-label extension study. In total, 266 participants enrolled in the ENLIGHTEN-2 safety extension study. Of these, 265 received ≥1 dose of LYBALVI and were included in the analysis
- The first study visit occurred within 7 days of completion of ENLIGHTEN-2. Study visits occurred every other week through 52 weeks of treatment
- Patients entering the extension received open-label LYBALVI at the equivalent olanzapine dose administered at the end of ENLIGHTEN-2. Dose changes were allowed during study site visits at the discretion of the investigator, but frequent dose changes were discouraged. Over the course of the 52-week study, LYBALVI was administered at daily doses of 10 mg/10 mg, 15 mg/10 mg, or 20 mg/10 mg
- Key exclusion criteria for ENLIGHTEN-2 safety extension study included the use of medications contraindicated with olanzapine or with known drug-interaction potential, use of prohibited drugs identified through a urine drug test, and females who were pregnant or nursing. Exclusion criteria from the ENLIGHTEN-2 pivotal trial, such as exclusion of patients with diabetes mellitus or olanzapine use in the 6 months prior to Visit 1 of the pivotal trial, also affected the population eligible for the 52-week safety extension study
- Overall, 167 patients (63.0%) completed the 52-week treatment period
Adverse Events Observed With the Use of LYBALVI Occurring in ≥2% of Patients in the Safety Extension Study4
(N=265)
*Weight increase was the most common adverse event in the preceding ENLIGHTEN-2 pivotal trial.1
Numbers rounded to the nearest percentage.
- Adverse events were seen in 61% of patients4
- Severe adverse events occurred in 3% of patients4
- Overall 37% (n=98) of patients treated with LYBALVI discontinued treatment4
- Reasons for discontinuation included patient withdrawal (13.6% [n=36]), patient lost to follow-up (8.3% [n=22]), adverse reaction (5.7% [n=15]), nonadherence with study drug (4.5% [n=121), protocol deviation (3% [n=8]), pregnancy (0.8% [n=2]), other (0.8% [n=2]), and lack of efficacy (0.4% [n=1])4
- Glycosylated hemoglobin increase (n=3; 1.1%) and psychotic disorder (n=2; 0.8%) were the only adverse events that led to discontinuation in >1 patients4
As part of the safety and tolerability assessment, change in body weight was evaluated in the 52-week, open-label safety extension study that followed the 24-week pivotal trial
In adult patients with schizophrenia
In the pivotal 24-week ENLIGHTEN-2 study preceding the 52-week open-label safety extension study, participants on average experience weight gain vs baseline.1
The ENLIGHTEN-2 extension study was an open-label study in which all participants received LYBALVI. The study was not designed to prospectively assess nor powered to prospectively evaluate the effect of LYBALVI on change in body weight. No conclusions can be drawn from these data.4
The primary and secondary endpoints of the pivotal ENLIGHTEN-2 study are described here.

In the open-label study3,4
- All patients who received at least 1 dose of LYBALVI were included in the safety analysis
- Safety outcomes were summarized descriptively based on observed data, without imputation for missing values
- The Statistical Analysis Plan planned for the safety data to be presented overall (shown here) and by treatment sequence

In the pivotal 24-week ENLIGHTEN-2 study preceding the 52-week open-label safety extension study, participants on average experience weight gain vs baseline.1 The primary and secondary endpoints of the pivotal ENLIGHTEN-2 study are described here.
The ENLIGHTEN-2 extension study was an open-label study in which all participants received LYBALVI. The study was not designed to prospectively assess nor powered to prospectively evaluate the effect of LYBALVI on change in body weight. No conclusions can be drawn from these data.4

In the open-label study3,4
- All patients who received at least 1 dose of LYBALVI were included in the safety analysis
- Safety outcomes were summarized descriptively based on observed data, without imputation for missing values
- The Statistical Analysis Plan planned for the safety data to be presented overall (shown here) and by treatment sequence
Increased weight was the most common adverse reaction in patients treated with LYBALVI in both pivotal trials for schizophrenia.1
- The 4-week ENLIGHTEN-1 study evaluated antipsychotic efficacy and safety of LYBALVI vs placebo and was not designed to assess or compare the weight effects of LYBALVI vs olanzapine. There, the proportion of patients with ≥7% weight increase was 26% in patients treated with LYBALVI, 20% in patients treated with olanzapine, and 5% in patients treated with placebo
- The 24-week ENLIGHTEN-2 pivotal trial evaluated percentage change in body weight and proportion of patients gaining ≥10% body weight with both LYBALVI and olanzapine. There, the proportion of patients with ≥7% weight increase was 28% in patients treated with LYBALVI and 43% in patients treated with olanzapine
STUDY LIMITATIONS4
- The loss of randomization upon entering the extension study and lack of a comparator in this open-label study limit the conclusions that may be drawn from safety and efficacy data
- In addition, the 37% study discontinuation rate and missing data attributable to the long-term duration of this study may have impacted the results
- Patients in this study were clinically stable at baseline, with an established response to olanzapine in ENLIGHTEN-2; thus, these findings may not be generalizable to patients experiencing acute schizophrenia exacerbations
- The study design of ENLIGHTEN-2, which was conducted prior to this extension, may have been enriched for patients who were relatively resistant to antipsychotic weight gain
- Fasting status was self-reported by patients. Consequently it is possible that not all blood samples were collected from patients in a fasted state
References: 1. LYBALVI [prescribing information]. Waltham, MA: Alkermes, Inc.; 2021. 2. Correll CU, Newcomer JW, Silverman B, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry. 2020. doi.org/10.1176/appi.ajp.2020.19121279. 3. Data on file. Alkermes, Inc. 4. Kahn RS, Silverman BL, DiPetrillo L, et al. 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.