Lybalvi (olanzapine + samidorphan) is a new medication indicated for the therapy of adult patients with schizophrenia or bipolar I disorder. In the latter, Lybalvi can be used equally for the management of acute manic or mixed episodes, either monotherapeutically or as an adjunct to lithium or valproate, or as part of maintenance monotherapy.
Regulatory approval for Lybalvi, developed by Alkermes (Ireland), is granted by the U.S. Food and Drug Administration (FDA) in June 2021.
Lybalvi, built around the widely used antipsychotic olanzapine, added samidorphan to suppress olanzapine-induced weight gain.
Lybalvi: Mechanism of Action
Oral Lybalvi (ALKS 3831) is a combination of the atypical antipsychotic olanzapine and the opioid antagonist samidorphan.
The mechanism of action of olanzapine is uncertain. It is believed that its neuroleptic properties are mediated by the antagonism of dopamine and serotonin receptors. Olanzapine, in comparison to other common atypical antipsychotics, has a low risk of extrapyramidal side effects, including tardive dyskinesia, due to its increased affinity for the 5-HT2A serotonin receptor relative to the D2 dopamine receptor.
A common adverse event with all atypical neuroleptics, and with olanzapine in particular, is metabolic dysregulation expressed as significant weight gain with a concomitant increase in the risk of hyperglycemia and type 2 diabetes mellitus. The weight gain is thought to be due to antagonism of the H1 histamine receptor, causing sedation, and antagonism of 5-HT2C and D2, leading to appetite stimulation. In addition, olanzapine exhibits strong antagonism of the M3 muscarinic receptor, which may explain its diabetogenic effect.
Samidorphan works mainly as an μ-opioid receptor antagonist, with partial agonism against κ- and δ-opioid receptors.    Opioid receptor antagonism, according to in vivo studies in mice, helps to mitigate drug-induced weight gain and/or metabolic disorders.   
Lybalvi: Clinical Effectiveness in Treatment of Schizophrenia and Bipolar I Disorder
Because the primary drug component of Lybalvi is olanzapine, which has long been successfully used in the treatment of schizophrenia and bipolar I disorder, regulatory approval of the new drug by Alkermes required confirmation that Lybalvi’s clinical effectiveness is equal to that of olanzapine.
The ENLIGHTEN-1 (NCT02634346) phase 3 clinical trial (randomized, double-blind, placebo-controlled, active-control, multicenter, international) enrolled adult patients (n=352) with schizophrenia; Positive And Negative Syndrome Scale (PANSS) total score ≥80 (at least 3 subscales of the positive scale had to be ≥4) and a score ≥4 according to the Clinical Global Impression–Severity (CGI-S).
The primary endpoint was established by a change in the PANSS total score after 4 weeks of treatment, during which participants received daily oral Lybalvi, olanzapine, or placebo.
The Lybalvi group showed a mean change in PANSS total score relative to placebo of −6.4 (95% CI: −10.0 — −2.8) [p<0.001], the olanzapine group of −5.3 (95% CI: −8.9 — −1.7) [p=0.004]. Thus, the therapeutic efficacy of Lybalvi was no worse than that of olanzapine.
The ENLIGHTEN-2 (NCT02694328) phase 3 clinical trial (randomized, double-blind, active-control, multicenter) set out to compare weight change in adult patients with schizophrenia (PANSS total score 50–90, CGI-S score ≤4) treated with Lybalvi or olanzapine.
After 24 weeks of treatment, Lybalvi group averaged a weight gain of 4.2% of baseline — versus 6.6% in the olanzapine group (p=0.003). At the same time, 17.8% of subjects in the experimental treatment group experienced a weight gain of ≥10% — vs. 29.8% in the control group: odds ratio (OR) 0.50 (95% CI: 0.31–0.80).
The ENLIGHTEN-2-EXT (NCT02873208) phase 3 clinical trial (non-randomized, open-label, multicenter) evaluated the long-term effects of Lybalvi among adult patients with schizophrenia who completed ENLIGHTEN-2.
After 52 weeks of therapy, it was shown that long-term use of Lybalvi was reflected in the actual stabilization of weight gain. Thus, after completing ENLIGHTEN-2, the average weight gain was 5.6% (from baseline, hereafter), then after 12 weeks of ENLIGHTEN-2-EXT therapy the weight gain was 6.4%, after 28 weeks it was 5.4%, and finally, after 52 weeks, it was 4.5%.
According to Alkermes, this is particularly noteworthy given the fact that long-term use of olanzapine is in some cases accompanied by a permanent increase in body weight.
The therapeutic efficacy of Lybalvi in the therapy of bipolar I disorder has not been separately tested because there is extensive data from appropriate clinical trials of olanzapine.
Lybalvi: Market Perspective
Two meta-analyses found that olanzapine is one of the most effective antipsychotics for the acute and maintenance treatment of schizophrenia. However, it is olanzapine use that has the strongest effect of all other antipsychotics on significant weight gain.  
Olanzapine is also suitable for therapy of manic or mixed episodes associated with bipolar I disorder.   But again, its prescription is linked to an increased risk of significant weight gain and metabolic disorders, including the development of type 2 diabetes mellitus and dyslipidemia.     
Because of these characteristics, there has been a decrease in physician and patient interest in olanzapine.
A meta-analysis of clinical trials testing 15 different pharmacological interventions to inhibit atypical antipsychotics-induced weight gain found that metformin, fenfluramine, sibutramine, topiramate, and reboxetine do provide this beneficial effect, but in a very modest range that does not allow them to be recommended for use in psychiatric treatment.
The addition of samidorphan to olanzapine restrains weight gain, but not on such a large scale that Lybalvi could easily displace olanzapine. Especially since the latter is widely available in the form of inexpensive generic copies. Patients will be prescribed Lybalvi, most likely after several courses of other antipsychotics, when patients are already “tired” of being overweight.
- For reference: among oral antipsychotics, olanzapine accounts for 21% of the treatment of schizophrenia and 12% of bipolar I disorder.
In addition, there are some concerns about the safety of Lybalvi. The fact is that samidorphan, being an opioid antagonist, can cause withdrawal syndrome in patients physically dependent on opioids (opioid abuse is relatively high in the population of psychiatric patients) or lead to opioid overdose among those who try to overcome the opioid-blocking effect of samidorphan. This is why Lybalvi’s prescribing information includes appropriate warnings.
Evaluate Pharma predicts that Lybalvi sales will reach the $380 million mark by 2026.
It is appropriate to recall that olanzapine, which debuted as Zyprexa in 1996, generated a slew of lawsuits against the originator, Eli Lilly, which made billions of dollars from it: in 2005, olanzapine sales were $4.2 billion, or a third of the company’s total revenue. According to the plaintiffs, olanzapine was responsible for the development of diabetes and other diseases, and therefore the pharmaceutical company should be punished. And so it did: in 2006–2007, Eli Lilly paid more than $1.2 billion in settlements of about 28,500 legal claims.
Later, internal Eli Lilly documents came to light showing that the pharma company intentionally and knowingly downplayed the significance of the negative side effects of olanzapine and considered patient weight gain a major threat to Zyprexa sales.
In 2009, Eli Lilly was found guilty of marketing olanzapine inappropriately: Zyprexa was illegally promoted (especially among the elderly) as a drug against agitation, aggression, hostility, depression, generalized sleep disorder, and dementia, including that caused by Alzheimer’s disease. The penalty amounted to $1.415 billion.
Lybalvi (olanzapine + samidorphan). Prescribing information. U.S. [PDF]
Lybalvi. Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management Advisory Committee (DSaRM) meeting. FDA briefing document. October 9, 2020. [PDF]
Lybalvi. Alkermes pre-recorded presentation slides for the FDA briefing. [PDF]
Lybalvi. Alkermes pre-recorded presentation slides for the FDA briefing. Summary presentation. [PDF]
Alkermes Investor Day. March 25, 2021. [PDF]
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 Mar 3;81(2):19m12769. [source]
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 May 17;232:45-53. [source]