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. However, least one expert says the weight difference between the two drugs is of “questionable clinical benefit.”
Last year, the US Food and Drug Administration (FDA) approved the drug for the treatment of adults with schizophrenia or bipolar I disorder, as a maintenance monotherapy or as either monotherapy or an adjunct to lithium or valproate for acute manic or mixed episodes.
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. They were also 36% less likely to gain at least 10% of their body weight during the 12-week treatment period.
These findings add to those from the earlier ENGLIGHTEN-2 trial, which included patients with a more established disorder, said lead investigator René S. Kahn, MD, PhD, Icahn School of Medicine at Mount Sinai, New York City.
They indicate that the weight-mitigating effects shown with olanzapine plus samidorphan are “consistent, regardless of the stage of illness,” Kahn added.
He presented the findings at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
“Early intervention with antipsychotic treatment is critical in shaping the course of treatment and the disease trajectory,” co-investigator Christine Graham, with Alkermes, Inc, which manufactures the drug, told Medscape Medical News.
Olanzapine is a “highly effective antipsychotic, but it’s really avoided a lot in this population,” Graham said. Therefore, patients “could really stand to benefit” from a combination that delivers the same amount of antipsychotic effect, but “reduces the profit” for clinically significant weight gain, she added.
Kahn noted in his meeting presentation that antipsychotics are the “cornerstone” of the treatment of serious mental illness, but that “many are associated with concerning weight and cardiometabolic effects.”
While olanzapine is an effective medication, it has “one of the highest weight gain” profiles of the available antipsychotics and patients early on in their illness are “especially vulnerable,” Kahn said.
Previous studies have shown the combination of olanzapine plus samidorphan is similarly effective as olanzapine, but is associated with less weight gain.
To determine its impact in recent-onset illness, the current researchers screened patients with schizophrenia, schizophreniform disorder, or bipolar I disorder aged 16-39 years who had an initial onset of active phase symptoms less than 4 years previously. They also had less than 24 weeks’ cumulative lifetime exposure to antipsychotics.
Participants were randomly assigned to receive olanzapine plus samidorphan or olanzapine alone for 12 weeks, and then followed up for safety assessment for a further 4 weeks.
A total of 426 patients were recruited and 76.5% completed the study. The mean age was 25.8 years, 66.2% were men, 66.4% were White, and 28.2% were Black.
The mean body mass index at baseline was 23.69 kg/m2. The most common diagnosis among the participants was schizophrenia (62.9%) followed by bipolar I disorder (21.6%).
Less Weight Gain
Results of the 12-week study 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).
Kahn noted this equates to an average weight gain of 2.8 kg (6.2 lb) with olanzapine plus samidorphan and a gain of about 5 kg (11 lb) with olanzapine.
“It’s not a huge difference, but it’s certainly a significant one,” he said. “I also think it’s clinically important and significant.”
The reduction in weight gain compared with olanzapine was even maintained in patients assigned to olanzapine plus samidorphan who dropped out and did not complete the study, Kahn reported. “No one really had a weight gain,” he said.
In contrast, patients in the olanzapine groups who dropped out of the study had weight gain larger than their counterparts who stayed in it.
Further analysis showed 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).
As expected, the improvement in Clinical Global Impression–Severity scale scores was almost identical between the olanzapine + samidorphan and olanzapine-only groups.
For safety, Kahn said the adverse event rates were “very, very similar” between the two treatment arms, which was a pattern that was repeated for serious AEs. This led him to note that “nothing out of the ordinary” was observed.
Clinical Impact “Questionable”
Commenting for Medscape Medical News, Laura LaChance, MD, a psychiatrist at St. Mary’s Mary’s Hospital Centre, McGill University, Montreal, Canada, said the actual amount of weight loss shown in the study “is of questionable clinical significance.”
She added that she has “experience with the naltrexone/bupropion combination for weight loss and find it to have a very modest, if any, clinically effect.”
On the other hand, LaChance said she has achieved “better results with metformin, which has a great safety profile and is cheap and widely available.”
“Cost is always a concern in patients with psychotic disorders,” she concluded.
The study was funded by Alkermes, Inc. Kahn reported having relationships with Alkermes, Angellini, Janssen, Sunovion, Otsuka, Merck, Minerva Neuroscience, Roche, and Teva. Graham is an employee of Alkermes, Inc.
Congress of the Schizophrenia International Research Society (SIRS) 2022: Abstract T165. Presented April 7, 2022.
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