Jacob Ballon, MD, MPH: Discusses Takeaways from Studying Long-Term Olanzapine and Samidorphan

A recent phase 3, open-label extension study evaluated the long-term safety, tolerability, and durability of olanzapine and samidorphan (LYBALVI) in adults with schizophrenia, schizophreniform disorder, and bipolar I disorder. The study produced positive topline results, suggesting the drug was well-tolerated for up to 4 years of treatment.

The study included 523 participants who received ≥ 1 dose of LYBALVI, equaling 5 – 20 mg of olanzapine and 10 mg of samidorphan. The cohort was 61.6% male, 72.7% White, and had a mean age of 35.1 years old. Participants came from either the ENLIGHTEN 1 safety extension study, the ENLIGHTEN 2 safety extension study, or the 12-week ENLIGHTEN randomized controlled trial comparing LYBALVI to olanzapine.

In total, 35.9% of participants completed the 4-year treatment with minimal changes in body weight, waist circumference, and lipid and glycemic parameters such as HDL, cholesterol, LDL cholesterol, triglycerides, fasting glucose, and HbA1C. Adverse events occurred in 60% of participants but were mild to moderate in severity, with common events being weight gain, headache, anxiety, insomnia, somnolence, nausea, and weight decrease.

In an interview with HCPLive, Jacob Ballon, MD, MPH, clinical professor of Psychiatry and Behavioral Sciences at Stanford University, discussed takeaways and challenges from the pivotal trial.

HCPLive: What would you want the main takeaway from these results among clinicians?

Ballon: [The] biggest takeaway that I get from this study is how well tolerated and clinically impactful LYBALVI was for the patients who stayed in the study to the very end. This extension study lasted for 4 years, and nearly half of the patients remained in the study for that entire time. That is an astounding number of completers for a trial of this duration, particularly in this population. Many of these patients came from the earlier trial in the first episode, a population that is notoriously fickle when it comes to clinical trials.

Of the people who made it to the end of the trial, the rate for hospitalization over 4 years was vanishingly rare, and these patients overall maintained their metabolic parameters at a very encouraging level. We already knew that olanzapine was a highly effective antipsychotic and one that we would use, absent the concerns about metabolic side effects, in many more patients than we do currently.

These data help support the use of LYBALVI in people who might otherwise not want to take a chance on giving olanzapine because we know that for the patients who do well on this drug, they do really well, and that level of clinical stability may be difficult to achieve with many other medications.

HCPLive: Can you provide context for the significance of this data?

Ballon: It is rare that we get to see data of this type of duration. Seeing how many patients were able to tolerate this medication, and stay in a study for this long, gives real credibility to the results shown. It isn’t that these data can necessarily tell us that LYBALVI is the medication for every patient, no medication can claim that, but it definitely lets us know that for those for whom LYBALVI is well tolerated, we can expect that they will also achieve be robust outcome psychiatrically.

HCPLive: How does this add to our understanding of the safety profile for olanzapine and samidorphan?

Ballon: Earlier studies of shorter duration initially showed that the risk for weight gain with LYBALVI and olanzapine was the same for the first six weeks and then leveled off for the LYBALVI group while the olanzapine continued to show increased weight gain. These data show that over a longer term the LYBALVI group settles into a safer metabolic profile than we might have otherwise expected.

Further, initial trials showed that metabolic parameters other than weight were roughly the same for the LYBALVI and olanzapine, but these data show that over the long term the metabolic parameters we also concerned about, including glucose and cholesterol/triglycerides stayed at a safer level for the people who completed the study than we might have otherwise expected.

HCPLive: Were there any specific challenges or limitations you would want to highlight?

Ballon: Like all studies that take place around the world, it can be difficult to fully standardize treatment. However, one of the advantages of this study is that with weight gain and metabolic parameters as the main outcome measures, those are relatively consistent and easier to measure internationally.

Another challenge with this study is that it blended groups of patients from all the prior studies of LYBALVI. That means that it included both people in the early courses of illness as well as people who had a longer time having already taken antipsychotics. This blending of groups might have diminished the impact, especially in the people who had longer exposure to antipsychotics before starting in this trial.

^References

^{Derman, C. Olanzapine, Samidorphan Effective for Long-Term Schizophrenia, Bipolar Disorder Treatment. January 6, 2024. https://www.hcplive.com/view/olanzapine-samidorphan-effective-long-term-schizophrenia-bipolar-disorder-treatment. Accessed January 17, 2024.}