Alkermes' Novel Schizophrenia Drug Shows Less Weight Gain, Addressing Top Patient Complaint

Alkermes’ combination therapy for schizophrenia—olanzapine and samidorphan—produces the same antipsychotic effects as olanzapine alone but with far less weight gain, addressing a top complaint that researchers say causes some patients to stop taking medication.

That’s the sum of 4 separate studies presented in a pair of posters Monday and Tuesday at the 175th Annual Meeting of the American Psychiatric Association in San Francisco, California. Presentations included results from ENLIGHTEN-2, the phase 3 study unveiled last month at the Congress of the Schizophrenia International Research Society in Orlando, Florida. Alkermes had announced topline results in November 2018.

Officials with Alkermes told The American Journal of Managed Care^® (AJMC^®) that the manufacturer will file a new drug application for the investigational drug, known as ALKS 3831, later in 2019.

Weight gain is the most common complaint among patients taking antipsychotics for schizophrenia; a February 2019 patient survey by Achytes et al found it was most worrisome side effect as well as the top reason patients with schizophrenia would be unwilling to try a new medication. A 2017 review by Dayabandara et al found that the risk of weight gain is highest with olanzapine and clozapine, and that most weight gain occurs in the first 6 months, but weight gain continues more slowly after that point. Weight gain is also the second highest concern of caregivers, after a drug’s sedative effects.

As Christoph U. Correll, MD, professor of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New York, explained during Tuesday’s poster presentation, weight gain can have a snowball effect, as it can lead to poor adherence, which it affects outcomes—and can lead to hospitalizations that drive up costs.

“if you look at patients and also family member accounts of which side effects drop quality of life the most, it’s weight gain and sedation,” Correll said in an interview with AJMC^®. “If you have improvement in symptoms, but your quality of life drops because of the medication, how likely are you to continue?”

He said a sample of 900 patients produced data that showed patients who gained the most weight were more likely to have poor adherence, and in turn, these patients were the ones who ended up in the emergency department and were admitted to the hospital. “Side effects are not the only cause for stopping medication, but they are certainly a cause,” Correll said.

ENLIGHTEN-2

Correll presented results for ENLIGHTEN-2, a randomized, double-blind, 24-week study of 561 patients. Of these, 538 of 550 patients had at least 1 post baseline weight assessment and 352 completed treatment. Reasons for discontinuation were adverse events (10.9%), withdrawal by patient (9.1%) and lost to follow-up (8.7%).

Doses began at 10/10 mg of olanzapine/samidorphan or olanzapine alone, and olanzapine doses were increased to 20 mg for both groups after week 1. Olanzapine doses could be reduced back to 10 mg based on tolerability or the clinician’s discretion.

Less average weight gain. Patients taking olanzapine alone (n = 272) had a 6.59% mean change from their baseline body weight at 24 weeks, compared with 4.21% for those taking the study drug (n = 266), for a 57% higher mean percent weight gain at 24 weeks (difference = —2.38 [0.765]%; P = .003).

Lower risk of 10% weight gain. Patients taking antipsychotics anticipate gaining some weight, but the Achtyes survey found that patients’ unwillingness to try a new medication rises above 70% if they anticipate gaining more than 5 kg. Patients taking olanzapine alone had twice the risk of gaining 10% or more of their baseline weight at 24 weeks.

Correll pointed out how ALKS 3831 not only caused less weight gain, but the patterns are different from what is typically seen with antipsychotics. “What’s very exciting is that after about 6 weeks, there’s a total leveling off” of weight gain, he said. “It’s unusual to have only about 5 kilograms of weight gain over 6 months—we would expect much more than that.”

The share of patients who gained 10% or more of their baseline weight was 29.8% for olanzapine alone, compared with 17.8% for the study drug (P = .003). Similarly, patients in the olanzapine-only group had twice the risk of gaining 7% or more of their baseline weight; the share was 42.7% for the olanzapine group compared with 27.5% for the study drug (P = .001). Weight gain of 7% of baseline is considered clinically significant, meaning it is the point at which a person would expect changes in health outcomes.

No metabolic benefits. A surprising finding of ENLIGHTEN-2 (as well as a study included in Monday’s poster presentation) is that ALKS 3831 did not yield any immediate metabolic benefits compared with placebo, despite the fact that patients gained less weight. Correll noted that at least for ENLIGHTEN-2, the average body mass index for both arms was slightly more than 25, just past overweight; these participants may be relatively healthy.

Interim results: patients keeping weight off. Tuesday’s poster presentation included interim data on 265 dosed patients in ENLIGHTEN-2-EXT, a long-term open label study. At 52 weeks, patients taking ALKS 3831 had kept their weight stable; Correll said is significant, because typically patients continue to gain weight slowly as they take antipsychotics over time. “If you look at the 1-year study, it seals the deal,” he said.

Effective for Different Populations

Adam Simmons, Alkermes’ director of Clinical Program Management, was the lead author on an abstract presented Monday that consolidated data from 3 separate studies that showed ALKS 3831 worked as well as olanzapine alone in distinct populations.

• A phase 2 study of patients without recent exacerbation of schizophrenia found that after 12 weeks, the least square mean (LSM) change change in Positive and Negative Syndrome Scale (PANSS) were similar for groups taking ALKS 3831 and olanzapine only: —2.2 (95% CI: –3.2, –1.3) for ALKS 3831 versus –2.9 (95% CI: –4.5, –1.3) for olanzapine. The LSM difference between the 2 arms was 0.6 (95% CI: –1.2 to 2.5).
• A second phase 2 study compared the effectiveness of ALKS 3831 and olanzapine in reducing heavy drinking days among people with both schizophrenia and alcohol use disorder. While the study found that patients taking the study drug did not reduce their drinking as much as those taking olanzapine, both groups drank less; those taking ALKS 3831 outperformed the olanzapine group on PANSS and Clinical Global Impression scores.
• A 4-week phase 3 study among patients experiencing an acute exacerbation of schizophrenia found the LSM (95% CI) of change from baseline was —17.5 (95% CI: –20.1, –14.9) for placebo, –23.9 (95% CI: –26.5, –21.4) for ALKS 3831, and –22.8 (95% CI: –25.3, –20.2) for olanzapine. The LSMD of ALKS 3831 compared with olanzapine was –1.2 (95% CI: 4.7, 2.4 P = 0.517).

Adding samidorphan to olanzapine did not decrease the antipsychotic efficacy compared to olanzapine alone in adults with schizophrenia, the abstract reports.

References

1. Correll CU, Kahn R, Silverman B, et al. A combination of olanzapine and samidorphan mitigates weight gain observed with olanzapine: results from the phase 3 ENLIGHTEN-2 schizophrenia study. Presented at: 175th Annual Meeting of the American Psychiatric Association, San Francisco, California; May 18-22, 2019; P7-63.
2. Simmons A, Weiden P, McDonnell D, Jiang Y, DiPetrillo, Silverman B. Antipsychotic efficacy of a combination of olanzapine and samidorphan across three olanzapine-controlled clinical studies. Presented at: 175th Annual Meeting of the American Psychiatric Association, San Francisco, California; May 18-22, 2019; P6-90.