Lybalvi, a combination of olanzapine and samidorphan, is a medication approved for the treatment of adults with schizophrenia and bipolar I disorder. While olanzapine is known for its efficacy, it is also associated with weight gain and metabolic side effects. Samidorphan is included in Lybalvi to mitigate these effects. This article examines the clinical data on Lybalvi, focusing on its impact on weight, efficacy, safety, and long-term treatment outcomes.
Understanding Lybalvi: Composition and Mechanism
Lybalvi is a single bilayer tablet composed of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist. It is available in fixed dosage strengths of 5mg, 10mg, 15mg, or 20mg of olanzapine combined with 10mg of samidorphan. The body’s endogenous opioid system is involved in the regulation of weight and metabolism. Samidorphan works by binding to and blocking opioid receptors. While the exact mechanism by which samidorphan mitigates olanzapine-associated weight gain is unknown, the endogenous opioid receptor system is involved in the regulation of weight gain and metabolism. Opioid receptors exist in both the central nervous system and in the periphery (e.g., the pancreas, muscle, and liver), making the opioid system a potential therapeutic target for addressing antipsychotic-associated weight gain.
Clinical Trials: Evaluating Efficacy and Weight Effects
The clinical development program of OLZ/SAM includes 18 studies: 10 Phase 1, two Phase 2, three randomized, double-blind Phase 3, and three open-label, long-term, phase 3 safety extension studies. The pharmacokinetics of oral olanzapine and samidorphan have been extensively characterized alone and in combination. Samidorphan has an oral bioavailability of 69% and a half-life of approximately 7 to 10 hours, making it suitable for once-daily dosing in combination with olanzapine.
Antipsychotic Efficacy
The antipsychotic efficacy of OLZ/SAM was primarily evaluated in a pivotal phase 3 study in patients with an acute exacerbation of schizophrenia, while weight efficacy was primarily evaluated in a pivotal phase 3 study of stable outpatients with schizophrenia. Additional studies support the antipsychotic and weight mitigation efficacy of OLZ/SAM.
In an acute exacerbation of schizophrenia, OLZ/SAM and olanzapine provided similar symptom improvements versus placebo at week 4. Treatment with OLZ/SAM resulted in significant improvements in symptoms compared with placebo at week 4, as measured by changes in Positive and Negative Syndrome Scale (PANSS) total scores from baseline. Improvement in PANSS scores with OLZ/SAM relative to placebo was similar to that observed with olanzapine. Antipsychotic efficacy of OLZ/SAM relative to placebo was also supported by improvements in Clinical Global Impression-Severity (CGI-S) scores.
Read also: Weight Loss Guide Andalusia, AL
The efficacy of OLZ/SAM in controlling symptoms of schizophrenia was further supported by findings from a pivotal study assessing weight gain as the primary endpoint. In that study, 24 weeks of treatment with either OLZ/SAM or olanzapine resulted in similar improvements in PANSS total and CGI-S scores.
Weight Mitigation Efficacy
In stable outpatients with schizophrenia, OLZ/SAM treatment resulted in significantly less weight gain, reducing the risk for clinically significant weight gain and waist circumference increases of ≥5 cm by half, compared with olanzapine at week 24.
In a 24-week study, the least squares (LS) mean percent weight change from baseline to the end of treatment was 4.2% with OLZ/SAM versus 6.6% with olanzapine, yielding an LS mean difference of -2.4%. In a phase 2 study, the LS mean percent change from baseline in weight at week 12 was 2.6% with OLZ/SAM versus 4.1% with olanzapine, yielding an LS mean difference between groups of -1.5%. In both studies, patients treated with olanzapine and OLZ/SAM had similar weight gain for the first 4 to 6 weeks.
The risk of gaining 10% or more of body weight from baseline was reduced by 50% with OLZ/SAM compared with olanzapine. The odds of gaining 7% body weight or more from baseline at week 24 was also reduced by 50% for OLZ/SAM compared with olanzapine. Based on a number needed to treat (NNT) analysis of the proportion of patients with clinically significant weight gain at week 24, the NNT for OLZ/SAM versus olanzapine was 7 and 8 for the ≥7% and ≥10% weight gain thresholds, respectively.
OLZ/SAM was also associated with smaller increases in waist circumference compared with olanzapine, which occurred as early as week 1. The risk of experiencing a 5-cm increase in waist circumference was 50% lower for patients treated with OLZ/SAM versus olanzapine.
Read also: Beef jerky: A high-protein option for shedding pounds?
Changes in metabolic laboratory parameters in patients treated with olanzapine or OLZ/SAM were generally small and were similar between groups. In addition, there were little differences between the two treatment groups in metabolic parameter changes considered to be of potential clinical significance, based on commonly used thresholds.
Long-Term Treatment Effects
Based on open-label extension studies, OLZ/SAM is safe and well tolerated for up to 3.5 years of treatment, while maintaining schizophrenia symptom control and stabilizing weight. Long-term treatment with LYBALVI was associated with minimal changes in body weight (mean change from baseline of +1.47 kg) and waist circumference (observed mean change from baseline of +0.61 cm) with up to four years of treatment. Similarly, there were generally minimal changes in lipid and glycemic parameters, including HDL cholesterol, LDL cholesterol, triglycerides, fasting glucose and HbA1c over the measured time period.
OLZ/SAM was effective in controlling symptoms of schizophrenia over 52 weeks of treatment, as evidenced by sustained improvements in PANSS and CGI-S scores over time.
Safety and Tolerability
Overall, safety and tolerability findings from clinical studies with OLZ/SAM indicate a similar safety profile to that of olanzapine, with the exception of less weight gain. The AE profile of OLZ/SAM was consistent with the known AE profile of olanzapine. Long-term tolerability was evidenced by low rates of AEs that led to treatment discontinuation: in both extension studies, the rate of discontinuation due to an AE was ≤6%. Additionally, neither extension study reported any clinically meaningful changes over time in hematology, biochemistry, vital signs, or electrocardiogram parameters.
However, it's important to note the following safety considerations:
Read also: Inspiring Health Transformation
- Weight Gain: Yes, weight gain is a possible side effect of Lybalvi. In a 4-week clinical trial, 19% of people taking Lybalvi reported weight gain, compared to 3% of those on a placebo. Not everyone will gain weight from taking Lybalvi.
- Opioid Withdrawal: As OLZ/SAM contains the opioid antagonist samidorphan, it is contraindicated in patients using opioids and in those undergoing acute opioid withdrawal. One of the medicines in LYBALVI (samidorphan) can cause opioid withdrawal that may be severe and cause hospitalization in people who are physically dependent on opioids. You should not start taking opioids for at least 5 days after you stop treatment with LYBALVI. LYBALVI blocks the effects of opioids, such as heroin, methadone, or opioid pain medicines. You should not take large amounts of opioids to try to overcome the opioid-blocking effects of LYBALVI. After you take LYBALVI, its blocking effect slowly decreases and completely goes away over time. You may be more sensitive to the effects of opioids.
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): One of the medicines in LYBALVI (olanzapine) can cause DRESS, which can cause death.
- Increased Blood Sugar: Increases in blood sugar can happen in some people who take LYBALVI. Extremely high blood sugar can lead to coma or death.
- Tardive Dyskinesia (TD): LYBALVI may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking LYBALVI.
- Other Precautions: Do not drive a car, operate machinery, or do other dangerous activities until you know how LYBALVI affects you. Stay out of the sun. If you are pregnant or plan to become pregnant, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. LYBALVI passes into your breast milk. Your healthcare provider can tell you if it is safe to take LYBALVI with your other medicines. Tell your healthcare provider if you take a urine drug screening test because LYBALVI may affect your test results.
Lybalvi vs. Olanzapine: A Comparative Look
Olanzapine plus samidorphan (Lybalvi) vs. olanzapine alone is associated with less weight gain while achieving similar clinical outcomes in patients with recent-onset severe mental illness, new research suggests. In the ENLIGHTEN-Early trial, researchers examined weight-gain profiles of more than 400 patients with early schizophrenia, schizophreniform disorder, or bipolar I disorder. Results showed those given combination treatment gained just over half the amount of weight as those given monotherapy.
In a 12-week study, results showed a significant difference in percent change in body weight from baseline between the two treatment groups, with a gain of 4.91% for the olanzapine plus samidorphan group vs. 6.77% for the olanzapine-alone group (between-group difference, 1.87%; P = .012). This equates to an average weight gain of 2.8 kg (6.2 pounds) with olanzapine plus samidorphan and a gain of about 5 kg (11pounds) with olanzapine. The proportion of patients who gained 10% or more of their body weight by week 12 was 21.9% for those receiving olanzapine plus samidorphan vs. 30.4% for those receiving just olanzapine (odds ratio, 0.64; P = .075).
Considerations and Contraindications
As OLZ/SAM contains the opioid antagonist samidorphan, it is contraindicated in patients using opioids and in those 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.
Alternative Weight Management Strategies
While Lybalvi aims to mitigate weight gain associated with olanzapine, other strategies may be considered. These include:
- Lifestyle Modifications: Following a reduced calorie diet and exercise program.
- Medications: Other medications, such as metformin, have been used to manage weight gain associated with antipsychotics.
- GLP-1 Receptor Agonists: Medications like Ozempic, Mounjaro and Zepbound can lead to weight loss. It takes time, about 8 to 12 weeks to see a 6% to 8% weight loss in adults using Mounjaro. The most common Ozempic side effects with Ozempic include stomach problems, like nausea, vomiting, diarrhea, stomach pain and constipation. These tend to be mild-to-moderate and usually clear up in a few weeks in most people. Low blood sugar (hypoglycemia) is also a common side effect (when used with certain other diabetes treatments) and it can be serious.