Small Molecule · LYBALVI
LYBALVI (olanzapine/samidorphan)
Fixed-dose oral combination tablet of olanzapine (an atypical antipsychotic; dopamine D2 / serotonin 5-HT2A antagonist) co-formulated with samidorphan (a novel mu-opioid receptor antagonist), developed by Alkermes and marketed as LYBALVI. The combination is designed to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain via mu-opioid receptor blockade. FDA-approved 28 May 2021 (NDA 213378) for adults with schizophrenia and for bipolar I disorder. This program tracks the PEDIATRIC (adolescent, 13-17) schizophrenia development program, which is in active Phase 3 (ENLIGHTEN-Youth, NCT05303064) and is not yet approved in this age group.
Also known as: LYBALVI, ALKS 3831, OLZ/SAM, olanzapine/samidorphan, olanzapine and samidorphan, olanzapine, 132539-06-1, samidorphan, 852626-89-2, ALKS-33
- Modality
- Small molecule
- Chemical class
- thienobenzodiazepine, morphinan
- DEA schedule
- Unscheduled
- Chemistry
- Single enantiomer
- Mechanism
- D2 antagonist
- Highest phase
- Phase 3
- Lead indication
- Schizophrenia
- Developer
- Alkermes plc (ALKS)
- Trials
- 3 tracked · 1 recruiting · 84 sites
- Next catalyst
- 2H 2026 — Topline data (Schizophrenia)
Mechanism of action
LYBALVI combines two active moieties. Olanzapine is an atypical (second-generation) antipsychotic that acts as an antagonist at dopamine D2 and serotonin 5-HT2A receptors (with additional affinity for D1/D3/D4, 5-HT2C, 5-HT6, H1, muscarinic and alpha-1 adrenergic receptors); D2/5-HT2A antagonism is the basis of its antipsychotic efficacy in schizophrenia. Samidorphan is a 3-carboxamido-4-hydroxy analog of naltrexone that binds with high affinity to human mu-, kappa- and delta-opioid receptors; it is an antagonist at the mu-opioid receptor (MOR/OPRM1) and a partial agonist at kappa and delta. Mu-opioid antagonism by samidorphan is intended to mitigate the weight gain and metabolic effects associated with olanzapine while not altering its antipsychotic activity.
| Target | Action | Affinity |
|---|---|---|
| D2primaryDRD2 | Antagonist | Ki 11 nMⓘ |
| 5-HT2AHTR2A | Antagonist | Ki 4 nMⓘ |
| delta-opioid receptorOPRD1 | Partial agonist | Ki 2.6 nMⓘ |
| kappa-opioid receptorOPRK1 | Partial agonist | Ki 0.23 nMⓘ |
| mu-opioid receptorOPRM1 | Antagonist | Ki 0.05 nMⓘ |
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| LYBALVI oral tabletsfixed-dose combination film-coated tablet (olanzapine + samidorphan L-malate) Film-coated tablets, olanzapine/samidorphan 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, and 20 mg/10 mg; administered orally once daily with or without food as a single tablet. | Oral | Once daily | t½ 43 h · Tmax 6 h |
Development timeline
- UpcomingENLIGHTEN-Youth pediatric Phase 3 (OLZ/SAM vs olanzapine; primary endpoint change in BMI Z-score) — topline anticipated around primary completion (est. Sep 2026).
- ENLIGHTEN-Youth (NCT05303064), the pivotal Phase 3, randomized, double-blind, 52-week study of OLZ/SAM vs olanzapine in pediatric subjects with schizophrenia (13-17) or bipolar I disorder (10-17), began; primary endpoint change in BMI Z-score at week 12. Trial is recruiting.
- ALKS 3831-A311 (NCT04987658), a Phase 1 open-label study of OLZ/SAM safety, tolerability and pharmacokinetics in pediatric subjects (ages 10-12) with bipolar I disorder, initiated; subsequently completed with n=7. Establishes pediatric PK/safety supporting the pediatric program.
LYBALVI (olanzapine/samidorphan) for Schizophrenia
Phase 3RecruitingSchizophrenia indication →
Pediatric (adolescent) schizophrenia development program for LYBALVI (OLZ/SAM). LYBALVI is already FDA-approved (28 May 2021) in ADULTS for schizophrenia and bipolar I disorder; this program extends it to pediatric patients and is in active Phase 3. The lead pediatric trial is ENLIGHTEN-Youth (NCT05303064): a Phase 3, randomized, double-blind, 52-week comparison of OLZ/SAM versus olanzapine evaluating change from baseline in BMI Z-score (primary endpoint at week 12) in pediatric subjects with schizophrenia (ages 13-17) or bipolar I disorder (ages 10-17); start 30 Jun 2022, primary completion estimated Sep 2026, est. enrollment 220, currently RECRUITING. A Phase 1 open-label PK/safety study (NCT04987658, ALKS 3831-A311) in pediatric bipolar I patients (ages 10-12) is completed (n=7), and a Phase 3 long-term safety extension (NCT04987229, ALKS 3831-A313, ages 10-17) is enrolling by invitation from the parent studies. No pediatric efficacy or weight-outcome readout has been reported yet.
Readouts
- 2H 2026AnticipatedTopline dataNCT05303064
ENLIGHTEN-Youth pediatric Phase 3 (OLZ/SAM vs olanzapine; primary endpoint change in BMI Z-score) — topline anticipated around primary completion (est. Sep 2026).
Clinical trials
NCT05303064ENLIGHTEN-Youth / ALKS 3831-A312Phase 3Recruitingn=220
A Phase 3, Randomized, Double-Blind, 52-Week Study of OLZ/SAM vs Olanzapine to Evaluate Weight Gain as Assessed by Change in BMI Z-Score in Pediatric Subjects With Schizophrenia or Bipolar I Disorder (ENLIGHTEN-Youth)
pendingprimaryChange from baseline in body mass index (BMI) Z-score at week 12, OLZ/SAM vs olanzapine
Primary endpoint of the pivotal pediatric Phase 3; no results reported yet (trial recruiting, primary completion estimated Sep 2026). Schizophrenia subjects are ages 13-17, bipolar I subjects 10-17.
NCT04987229ALKS 3831-A313Phase 3Activen=236
Long-term, Safety Extension Study of OLZ/SAM in Pediatric Subjects With Schizophrenia or Bipolar I Disorder
pendingprimaryIncidence of adverse events through 52 weeks (long-term safety of OLZ/SAM)
Long-term (52-week) safety extension enrolling by invitation from the parent pediatric studies (ALKS 3831-A311 and the ENLIGHTEN-Youth A312 study); ages 10-17; est. n=236; primary completion Sep 2027. No results reported. status=active (enrolling by invitation).
NCT04987658ALKS 3831-A311Phase 1Completedn=7
An Open-Label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Combination of Olanzapine and Samidorphan (OLZ/SAM) in Pediatric Subjects With Bipolar I Disorder
pendingprimarySafety, tolerability and pharmacokinetics of OLZ/SAM in pediatric subjects (ages 10-12)
Phase 1 open-label PK/safety study completed (n=7, ages 10-12). Supports pediatric dosing/PK; this is a bipolar I cohort but underpins the broader pediatric OLZ/SAM program including schizophrenia. No detailed posted results.
Conference coverage
LYBALVI appears in 5 CNS Pulse conference abstracts:
- Real-world persistence on olanzapine/samidorphan versus other oral second-generation antipsychotics in patients with schizophrenia
- Olanzapine and samidorphan in adults with schizophrenia or bipolar I disorder: Updated review of clinical data
- Real-world impact of olanzapine and samidorphan on rates of relapse among young adults with schizophrenia or bipolar I disorder
- Real-world comparison of olanzapine/samidorphan vs olanzapine: An assessment of treatment patterns and acute care events among patients with schizophrenia or bipolar I disorder
- ASCP Annual Meeting 2026 — Abstracts
Identifiers
Sources
- ALKS 3831-A311 — Phase 1 PK/safety of OLZ/SAM in pediatric bipolar I (ages 10-12) (NCT04987658) — ClinicalTrials.gov
- ALKS 3831-A313 — Phase 3 long-term safety extension of OLZ/SAM in pediatric subjects (NCT04987229) — ClinicalTrials.gov
- Bymaster et al. — Radioreceptor binding profile of the atypical antipsychotic olanzapine (D2 Ki ~11 nM, 5-HT2A Ki ~4 nM) — Neuropsychopharmacology (1996), PMID 8822531
- ENLIGHTEN-Youth — Phase 3 OLZ/SAM vs olanzapine, BMI Z-score, pediatric schizophrenia/bipolar I (NCT05303064) — ClinicalTrials.gov
- In vivo characterization of the opioid receptor-binding profiles of samidorphan and naltrexone (samidorphan MOR Ki ~0.05 nM antagonist; KOR 0.23 nM, DOR 2.6 nM partial agonist) — Neuropsychiatric Disease and Treatment (2022), PMC9636859
- LYBALVI (olanzapine and samidorphan L-malate) tablet — Prescribing Information — DailyMed / NLM (FDA label, Alkermes)