ENLIGHTEN-1 PIVOTAL
Pose of bird in flight

Power to reduce symptoms vs placebo in adults with schizophrenia

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

a 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

Prior antipsychotic medications

  • 89% of patients had taken at least one antipsychotic prior to study entry, including risperidone, haloperidol, quetiapine, and aripiprazole

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 (eg, naltrexone) within 60 days prior to screening

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

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

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 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 olanzapinec; the LS mean SE was 1.3 for all 3 groups1,2

cDifference (drug minus placebo) in least squares mean change from baseline. A negative value for the placebo-subtracted difference represents improvement1

  • 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

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

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.

Long-term safety and tolerability

ENLIGHTEN-1 open-label safety extension study: a multicenter, 52-week, phase 3 trial2,4

ENLIGHTEN-1 Safety Extension Study

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

aAll 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.4
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 >1 patient was worsening/exacerbation of schizophrenia (2.2% [n=6])4

ENLIGHTEN-1 open-label safety extension study also evaluated 52-week durability of treatment effect4

In adult patients with schizophrenia

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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

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

Graph showing the mean PANSS total score over time for the ENLIGHTEN-1 4-week pivotal study and 52-week Safety Extension Study Graph showing the mean PANSS total score over time for the ENLIGHTEN-1 4-week pivotal study and 52-week 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

Patients to consider for LYBALVI

Alyssa, 22

Previously diagnosed and treated adult living with
symptoms of schizophrenia

Schizophrenia symptoms include

  • Delusions

  • Grandiosity

  • Excitement

  • Poor rapport

  • Active social avoidance

Actor portrayal of a patient Actor portrayal of a patient
Isaiah, 34

Previously diagnosed and treated adult living with
symptoms of schizophrenia

Schizophrenia symptoms include

  • Auditory hallucinations

  • Suspiciousness

  • Hostility

  • Anxiety

  • Emotional withdrawal

Actor portrayal of a patient Actor portrayal of a patient

Note: These symptoms are a nonexhaustive list that patients may exhibit. LYBALVI has not been demonstrated to improve any of these symptoms individually.

Superiority of LYBALVI to other agents has not been established. Use clinical judgment when selecting appropriate patients. Results from treatment with LYBALVI will vary by patient.

Patient candidate profiles are for illustrative purposes only. Individuals depicted are not actual patients.

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ENLIGHTEN-2 Efficacy & Safety
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References: 1. LYBALVI [prescribing information]. Alkermes, Inc. 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.

Important Safety Information

Boxed Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. LYBALVI is not approved for the treatment of patients with dementia-related psychosis.

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.

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 creatine 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, and may 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.

Interference with Laboratory Tests for Opioid Detection:

LYBALVI may cause false positive results with urinary immunoassay methods for detecting opioids. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results.

Most Common Adverse Reactions observed in clinical trials were:

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:

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

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