An FDA decision is looming for Alkermes’ ALKS 3831, a treatment for schizophrenia and bipolar I disorder that adds an opioid antagonist to a well-known antipsychotic to negate the weight gain and metabolic issues that come with the latter. An FDA panel will meet Friday to help the agency decide the treatment’s fate—and their major focus will be how the opioid antagonist will affect patients also taking opioids like morphine or oxycodone.
In briefing documents (PDF) published Wednesday, the FDA flagged several risks of combining olanzapine, an antipsychotic Eli Lilly markets as Zyprexa, with samidorphan, an opioid antagonist designed to counteract extreme weight gain and other side effects. Those risks include a reduced painkilling effect in patients taking opioids, withdrawal symptoms in patients dependent on opioids and opioid overdose if patients try to overcome either of these issues by taking more opioids than normal.
In the clinical trials for the drug, there were no reports of such incidences, but that wasn’t surprising; Alkermes designed the studies to exclude patients who used opioids, so the potential risks of withdrawal or reduced painkilling effects “could not be quantitatively measured,” Alkermes wrote in its own briefing document (PDF).
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Alkermes plans to address these risks in the labeling for ALKS 3831, which will be consistent with that of approved drugs that contain opioid antagonists like samidorphan. It will also include identical labeling to Zyprexa to highlight the risks of the drug’s other component, olanzapine.
In addition to labeling, Alkermes will put together a communication plan that will make sure healthcare professionals and patients know of the drug’s risks, including that of withdrawal in patients who have not disclosed their opioid use to their doctors, according to the company's briefing documents.
Still, Jefferies analyst Biren Amin expects the subject to feature prominently in the advisory committee meeting, he wrote in a note to clients on Wednesday.
“The agency cited data suggesting pts with opioid use disorder and use opioids non-medically are 1.5-1.9X at risk for a new bipolar disorder diagnosis, suggesting that there are some safety related concerns for a subset of the indicated pt population for '3831,” he said. “We believe this will be a focus of the panel discussion, as two voting questions relate to adequate characterization of '3831's safety profile and sufficient labeling to mitigate the risks related to the opioid antagonist action.”
The third voting question will focus on whether samidorphan “adequately mitigates” weight gain linked to olanzapine.
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The Alkermes candidate hit the mark in a six-month phase 3 study (ALK3831-A303), with patients taking ALKS 3831 gaining less weight on average than patients taking olanzapine alone. But there was “no appreciable difference between the ALKS 3831 group and the olanzapine-only group” in various metabolic measures, including levels of hemoglobin A1c, insulin, fasting blood sugar, triglycerides and both “good” and “bad” cholesterol,” FDA staff wrote. If patients lost weight without showing improvement in these measures, “this may argue against approval” of ALKS 3831, the agency wrote.
"We think this issue may be discussed at the AdCom, and could endanger the possibility of a full approval,” Amin wrote.
After the FDA’s Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee convenes Friday to review ALKS 3831, the FDA expects to make a decision by Nov. 15.