Indications: LYBALVI® is indicated for the treatment of adults with schizophrenia or bipolar I disorder for acute treatment of manic or mixed episodes as monotherapy and as an adjunct to lithium or valproate, or as a maintenance monotherapy treatment.

Schizophrenia

ENLIGHTEN-1
Efficacy & Safety

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Actor portrayal.

LYBALVI (olanzapine and samidorphan) demonstrated proven efficacy vs placebo in adults with schizophrenia1

ENLIGHTEN-1 pivotal study: a 4-week, randomized, double‑blind, placebo- and active-controlled, phase 3 clinical trial1-3

ENLIGHTEN-1 Pivotal Study

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Graphic showing for the ENLIGHTEN-1 Pivotal Study how patients were randomized to LYBALVI, placebo, or olanzapine

*Dosing was flexible for the first 2 weeks and fixed thereafter. Patients were instructed to take one tablet by mouth each day, preferably at bedtime.

Objective

To evaluate the antipsychotic efficacy and safety of LYBALVI compared with placebo in adults with an acute exacerbation of schizophrenia. The study was not designed to compare LYBALVI with olanzapine.

The primary efficacy endpoint was change from baseline in PANSS total score at Week 4.

Inclusion criteria
  • Adult patients with an acute exacerbation of schizophrenia (N=397)
  • Met DSM-5 schizophrenia criteria
  • 18 to 70 years of age
  • BMI 18-40 kg/m2
  • PANSS total score ≥80 with a score ≥4 on at least 3 of the selected positive scale items
  • CGI-S score ≥4
Key exclusion criteria
  • History of diabetes
  • 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

BMI=body mass index; CGI-S=Clinical Global Impressions Scale; DSM=Diagnostic and Statistical Manual of Mental Disorders.

PRIMARY ENDPOINT

Statistically significant improvement in change from baseline in PANSS total score vs placebo at Week 41,2

The inclusion of samidorphan in LYBALVI did not appear to negatively impact the antipsychotic efficacy of olanzapine1

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

Graph showing the change from baseline in PANSS total score (LS mean) for olanzapine, placebo, and LYBALVI

At Week 4:

23.9 point reduction

in PANSS total score from baseline with LYBALVI

  • Baseline mean PANSS total score (SD) was 101.8 (11.6) for LYBALVI, 102.7 (11.9) for placebo, and 100.6 (12.1) for olanzapine1
  • The placebo-subtracted difference in change from baseline in 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 olanzapine; the LS mean SE was 1.3 for all 3 groups1

Difference (drug minus placebo) in least squares mean change from baseline. A negative value for the placebo-subtracted difference represents improvement.1

  • 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

Adverse reactions observed in ENLIGHTEN-1

Most Common Adverse Reactions Observed With the Use of LYBALVI (Incidence of ≥5% and ≥2x Placebo)1

Adverse Reaction LYBALVI
10 mg/10 mg and
20 mg/10 mg
(N=134)
Placebo
(N=134)
Weight increased 19% 3%
Somnolence 9% 2%
Dry mouth 7% 1%
Headache 6% 3%
  • 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: a multicenter, 52-week, phase 3, open-label trial1,2,4

In adult patients with schizophrenia

ENLIGHTEN-1 Safety Extension Study

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Graphic showing how patients were enrolled into the 52-week ENLIGHTEN-1 Safety Extension Study

*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.

Safety population consisted of patients who received ≥1 dose of study drug. Efficacy population consisted of patients who received ≥1 dose of study drug and had ≥1 postbaseline PANSS assessment.

Objective

To assess the long-term safety and tolerability, as well as durability of effect of LYBALVI in adults with schizophrenia.

Eligibility criteria
  • Patients who completed the 4-week ENLIGHTEN-1 study
Exclusion criteria
  • 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
  • Women who were pregnant or nursing

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.

Study limitations
  • 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

Adverse Events Observed With the Use of LYBALVI (Incidence of ≥2%)4

Adverse Event Patients
(N=277)
Increased weight 13%
Somnolence 8%
Headache 4%
Nasopharyngitis 4%
Extra dose administered 3%
Schizophrenia 3%
Anxiety 3%
Dry mouth 3%
Social stay hospitalization 3%
Decreased weight 2%
Increased blood prolactin 2%
Increased blood insulin 2%
Insomnia 2%

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

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Y-axis for the graph showing the mean PANSS total score over time for 52-week ENLIGHTEN-1 Safety Extension Study

In the pivotal, 4-week ENLIGHTEN-1 study preceding the 52-week, open-label safety extension study, participants on LYBALVI had a 23.9 point reduction in PANSS total score; those on placebo had a 17.5 point reduction.1 The primary endpoint of the pivotal ENLIGHTEN-1 study is described here.

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. No conclusions of efficacy can be drawn from these data.4

Mean PANSS total score over time1,3

Graph showing the mean PANSS total score over time for 52-week ENLIGHTEN-1 Safety Extension Study

In the open-label study3,4

  • Mean change from baseline for PANSS total score (95% CI) was -16.2 (-18.5 to -14.0) at 52 weeks
  • Change from baseline in PANSS total score was summarized using last observation carried forward for missing data and was based on observed data without imputation
  • The Statistical Analysis Plan planned for the efficacy data to be presented overall (shown here) and by treatment sequence
References: 1. LYBALVI [prescribing information]. 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. 2021;26(4):383-392.