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-2
Efficacy & Safety

Man wearing a hat looking toward the side of the screen
Actor portrayal.

LYBALVI (olanzapine and samidorphan) demonstrated less weight gain vs olanzapine in adults with schizophrenia1

ENLIGHTEN-2 pivotal study: a 24-week, randomized, double‑blind, active-controlled, phase 3 clinical trial1-3

ENLIGHTEN-2 Pivotal Study

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Graphic showing the ENLIGHTEN-2 Pivotal Study how patients were randomized to LYBALVI or olanzapine

*Dosing was flexible for the first 4 weeks and fixed thereafter. Patients were instructed to take one tablet by mouth each day, preferably at bedtime.

Objective

To evaluate the weight profile of LYBALVI compared with olanzapine in adults with schizophrenia.

Co-primary endpoints were percent change from baseline in body weight and the proportion of patients who gained ≥10% body weight at Week 24.

The key secondary endpoint was proportion of patients with ≥7% weight gain at Week 24.

Inclusion criteria
  • Adult outpatients (N=561)
  • Met DSM-5 schizophrenia criteria
  • 18 to 55 years of age
  • BMI 18-30 kg/m2
  • PANSS total score 50 to 90
  • CGI-S score ≤4
Exclusion criteria
  • 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

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

The inclusion of samidorphan in LYBALVI appeared to result in less weight gain than was seen with olanzapine alone1,3
Co-primary Endpoints
Patients taking LYBALVI experienced a statistically significantly lower mean percent weight gain vs olanzapine at Week 241,3
Graph showing the percent change from baseline in body weight at Week 24 for patients using olanzapine and LYBALVI
  • Baseline mean body weight was 77.0 kg for LYBALVI and 77.5 kg for olanzapine1
  • The olanzapine-subtracted difference in percentage change from baseline in body weight with LYBALVI was -2.4% (-3.9, -0.9)1
Fewer patients taking LYBALVI experienced weight gain ≥10% at Week 241,3
Graph showing the proportion of patients who experienced ≥10% weight gain at Week 24 using olanzapine and LYBALVI
  • The risk of gaining ≥10% body weight was lower by 50% with LYBALVI 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

Secondary Endpoint
  • 28% of patients taking LYBALVI vs 43% taking olanzapine experienced weight gain ≥7% at Week 243

Patients on stable, chronic olanzapine therapy were not specifically studied, so the weight effect of switching from olanzapine to LYBALVI is unknown.1

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. 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

Adverse Reaction LYBALVI
10 mg/10 mg and
20 mg/10 mg
(N=274)
Weight increased 25%
Somnolence 21%
Dry mouth 13%
Increased appetite 11%
Waist circumference increased 6%
Blood creatine phosphokinase increased 5%

Numbers rounded to the nearest percentage.

  • The incidence of weight increase 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: a multicenter, 52-week, phase 3, open-label trial2-4

In adult patients with schizophrenia

ENLIGHTEN-2 Safety Extension Study

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Graphic showing how patients were enrolled into the 52-week ENLIGHTEN-2 Safety Extension Study

*Patients entering the safety extension study 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.

Objective

To further characterize the long-term safety and tolerability of LYBALVI in adults with schizophrenia.

Eligibility criteria
  • Patients who completed the 24-week ENLIGHTEN-2 study (N=266)
Key exclusion criteria
  • Use of medications contraindicated with olanzapine or with known drug-interaction potential
  • Use of prohibited drugs identified through a urine drug test
  • Females who were pregnant or nursing

Exclusion criteria from the ENLIGHTEN-2 pivotal trial, such as 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.2-4

Study limitations
  • 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

Adverse Events Observed With the Use of LYBALVI Occurring in ≥2% of Patients in the Safety Extension Study4

Adverse Event Patients
(N=265)
Weight decreased* 9%
Extra dose administered 8%
Headache 7%
Weight increased 6%
Upper respiratory tract infection 5%
Nasopharyngitis 4%
Back pain 3%
Blood creatine phosphokinase increased 3%
Toothache 3%
Hypertension 2%
Nausea 2%

Numbers rounded to the nearest percentage.

*Weight increased was the most common adverse event in the preceding ENLIGHTEN-2 pivotal trial.1

  • 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=12), 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 patient4

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

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Y-axis for the graph showing the mean body weight over time for the 52-week ENLIGHTEN-2 Safety Extension Study

In the pivotal 24-week ENLIGHTEN-2 study preceding the 52-week, open-label safety extension study, participants on average experienced weight gain vs baseline.1 The primary and secondary endpoints of this 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

Mean body weight over time (kg)2

Graph showing the mean body weight over time for the 52-week ENLIGHTEN-2 Safety Extension Study

In the open-label study2,4

  • 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.1,3

  • 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 placebo1
  • 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.1 There, the proportion of patients with ≥7% weight increase was 28% in patients treated with LYBALVI and 43% in patients treated with olanzapine3
About LYBALVI
References: 1. LYBALVI [prescribing information]. Alkermes, Inc.; 2021. 2. Data on file. Alkermes, Inc. 3. 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;177(12):1168-1178. 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.

Important Safety Information

Contraindications:

LYBALVI is contraindicated in patients who are using opioids or are undergoing acute opioid withdrawal. If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products.

Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis,

including stroke, transient ischemia attack, and fatalities. See Boxed Warning above.

Precipitation of Severe Opioid Withdrawal in Patients who are Physiologically Dependent on Opioids:

LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Prior to initiating LYBALVI, there should be at least a 7-day opioid-free interval from last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. Explain the risks associated with precipitated withdrawal and the importance of giving an accurate account of last opioid use to patients and caregivers.

Vulnerability to Life-Threatening Opioid Overdose:

Attempting to overcome opioid blockade with high or repeated doses of exogenous opioids could lead to life-threatening or fatal opioid intoxication, particularly if LYBALVI therapy is interrupted or discontinued subjecting the patient to high levels of unopposed opioid agonist as the samidorphan blockade wanes. Inform patients of the potential consequences of trying to overcome the opioid blockade and the serious risks of taking opioids concurrently with LYBALVI or while transitioning off LYBALVI. In emergency situations, if a LYBALVI-treated patient requires opioid treatment as part of anesthesia or analgesia, discontinue LYBALVI. Opioids should be administered by properly trained individual(s) and patient should be continuously monitored in a setting equipped and staffed for cardiopulmonary resuscitation. Patients with a history of chronic opioid use prior to treatment with LYBALVI may have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. Advise patients that this decreased tolerance may increase the risk of opioid overdose if opioids are resumed at the previously tolerated dosage.

Neuroleptic Malignant Syndrome,

a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatinine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and close monitoring.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),

a potentially fatal condition reported with exposure to olanzapine, a component of LYBALVI. Symptoms include a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue if DRESS is suspected.

Metabolic Changes,

including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Any patient treated with LYBALVI should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required anti-diabetic treatment despite discontinuation of the suspect drug. Measure weight and assess fasting glucose and lipids when initiating LYBALVI and monitor periodically.

Tardive Dyskinesia (TD):

Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible increases with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after discontinuation. Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. If signs and symptoms of TD appear, drug discontinuation should be considered.

Orthostatic Hypotension and Syncope:

Monitor orthostatic vital signs in patients who are vulnerable to hypotension, patients with known cardiovascular disease, and patients with cerebrovascular disease.

Falls:

LYBALVI may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls, and consequently, fractures or other injuries. Assess patients for risk when using LYBALVI.

Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases):

Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count or history of leukopenia or neutropenia. Discontinue LYBALVI if clinically significant decline in WBC occurs in the absence of other causative factors.

Dysphagia:

Use LYBALVI with caution in patients at risk for aspiration.

Seizures:

Use LYBALVI with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment:

Because LYBALVI may cause somnolence, impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including motor vehicles, until they are certain that LYBALVI does not affect them adversely.

Body Temperature Dysregulation:

Use LYBALVI with caution in patients who may experience conditions that increase core body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Anticholinergic (Antimuscarinic) Effects:

Olanzapine, a component of LYBALVI, was associated with constipation, dry mouth, and tachycardia. Use LYBALVI with caution with other anticholinergic medications and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications.

Hyperprolactinemia:

LYBALVI elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Risks Associated with Combination Treatment with Lithium or Valproate:

If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for a description of the risks for these products.

Most common adverse reactions observed in clinical trials were:

  • Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache
  • Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor
  • Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium or Valproate (olanzapine): dry mouth, dyspepsia, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia

Concomitant Medication:

LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Concomitant use of LYBALVI is not recommended with strong CYP3A4 inducers, levodopa and dopamine agonists. Reduce dosage of LYBALVI when using with strong CYP1A2 inhibitors. Increase dosage of LYBALVI with CYP1A2 inducers. Use caution with diazepam, alcohol, other CNS acting drugs, or in patients receiving anticholinergic (antimuscarinic) medications. Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling.

Pregnancy:

May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy.

Renal Impairment:

LYBALVI is not recommended for patients with end-stage renal disease (eGFR of <15 mL/minute/1.73 m2).

To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indications

LYBALVI is indicated for the treatment of:

  • Schizophrenia in adults
  • Bipolar I disorder in adults
    • Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate
    • Maintenance monotherapy treatment

Please see full Prescribing Information, including Boxed Warning, for LYBALVI.

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