FDA Panel Vote Weighs in Favor of Alkermes Psych Drug, With Caveats

FDA Panel Vote Weighs in Favor of Alkermes Psych Drug, With Caveats

An Alkermes antipsychotic treatment designed to offer the benefits of a commonly prescribed medicine, but without the weight gain side effect, won the backing of an FDA advisory committee on Friday. But even some of the panel members who supported the drug qualified their votes, expressing concern about what the drug could mean for patients taking opioid painkillers.

The vote of the independent panel isn’t binding, but the FDA will consider the body’s votes and comments as it evaluates the drug developed by Dublin, Ireland-based Alkermes (NASDAQ: ALKS), which also maintains operations in Waltham, MA. The agency is expected to make a regulatory decision by Nov. 15.

The Alkermes drug, ALKS 3831, is a once-daily pill that combines olanzapine (Zyprexa) and samidorphan to treat schizophrenia and bipolar 1 disorder. Olanzapine is an Eli Lilly (NYSE: LLY) antipsychotic that was first approved in 1996 and is now generic. While that drug is effective and remains widely prescribed, as is the case with many psychiatric medications, weight gain is a noted side effect. Alkermes aims to mitigate that problem by combining the drug with samidorphan, a new molecule. Samidorphan blocks opioid receptors, an approach that Alkermes hypothesizes modulates the body’s food-reward circuitry and insulin sensitivity, according to briefing documents the company submitted to the FDA.

In Phase 3 testing, the Alkermes drug’s antipsychotic results were comparable to those of patients treated with olanzapine. Results also showed that the weight change in patients given the olanzapine/samidorphan combination was “significantly lower” compared to the group of patients given olanzapine alone. Side effects reported in patients given the Alkermes drug included an increase in weight, sleepiness, dry mouth, and upper respiratory tract infections. But the rates of these side effects were similar to those reported in the patient group given olanzapine.

Panel members were asked to vote on three questions. On the first—whether Alkermes provided enough evidence to show that samidorphan “meaningfully mitigates” olanzapine-associated weight gain—panelists voted 16 to 1 in favor. On the question of whether Alkermes adequately characterized the safety of its drug, the advisory body voted 13 to 3 with 1 abstention.

The third question asked panelists to vote whether labeling is sufficient to mitigate the risks related to samidorphan’s mechanism of blocking opioid receptors. Panelists voted 11 to 6 in support. But many panel members who backed the drug on this question also voiced agreement with those who voted “no.”

Samidorphan’s blocking of opioid receptors may lead patients who are dependent on opioids to experience withdrawal symptoms, FDA staff noted in briefing documents. The drug could also render opioid painkillers ineffective when they are medically necessary, or they could drug block the high sought by those who abuse opioids. In these latter two scenarios, there is a risk of an overdose as a patient takes more of an opioid to overcome the opioid-blocking effects of samidorphan, FDA staff wrote.

Some panelists said that instructions on the drug label might be insufficient because the clinicians who prescribe painkillers—emergency room physicians, oral surgeons, anesthesiologists—are not the same as those who prescribe antipsychotic medications and they likely won’t be aware of the dangers of taking the two drugs together. Steven Meisel, system director of medication safety at M Health Fairview in Minneapolis, said that labeling will to “absolutely nothing” to mitigate the safety risks. “The notion that there’s going to be a negative interaction or a problem with the prescribing of the opioid is going to fly right by them,” Meisel said.

Felipe Jain, director of the healthy aging studies depression clinical and research program at Massachusetts General Hospital agreed with Meisel, saying that it would be far too easy for non-psychiatrists to be unaware what medication a patient is taking and what the consequences are of prescribing a drug that could interact with the ALKS 3831. He added that clinicians will need to explain to patients that the Alkermes drug is an opioid antagonist and what that means if they are also take an opioid drug. But that explanation might get lost in the midst of psychosis.

“It’s also well validated that people who are manic or psychotic don’t remember what happened prior to being started on the medication,” Jain said.

Karim Calis of the National Institutes of Health described his vote as a “qualified yes” based on the narrow wording of the question. But he added that he agreed with the comments of Meisel and Jain. He also said it’s important for Alkermes to convey that its medication is not a weight loss drug and that the marketing materials do not exaggerate weight gain  mitigation, which he viewed as modest. Another “yes” voter, Jessica Jeffrey, a clinical professor of psychiatry at UCLA, said she believes the potential risks could be mitigated with proper labeling and education. The challenge is making that education cross specialities ranging from psychiatry, to emergency medicine, to primary care.

“The devil is in the details in the labeling and the post-marketing plan,” Jeffrey said.

Some committee members said that even the weight gain benefits of the drug must be qualified. Erin Krebs, chief of general internal medicine at the Minneapolis VA Health Care System, said that she doesn’t see enough evidence that switching from olanzapine to the Alkermes drug will have enough effect on weight to justify the change. People could be switched for little to no benefit but much more cost, she said. Jess Fiedorowicz, head and chief of the department of mental health at the Ottawa Hospital, said that he noticed a running theme in the public comments featuring many patients who said they had been on a cycle of going off and on their medication in an attempt to balance the weight problems they experienced. Their statements suggested that the believe the Alkermes drug might prevent weight gain, when in fact, in his view, the weight mitigation is modest.

This isn’t the first time that the FDA has been asked to review an Alkermes behavioral drug that includes samidorphan as a component. The drug developer previously sought regulatory approval for ALKS 5461, a combination of buprenorphine and samidorphan, as a treatment for major depressive disorder. In that drug combination, samidorphan was meant to counteract the addictive properties of buprenorphine, an opioid receptor stimulator. Last year, the FDA rejected the drug and asked the company to provide more clinical data. That rejection followed a no confidence vote from an FDA advisory panel.

In a research note earlier this week, SVB Leerink analyst Marc Goodman wrote that his firm expects that ALKS 3831 will win FDA approval, but given that the olanzapine component of the combination drug is generic and physicians now have alternative therapies that don’t come with the same weight gain side effects, payers will likely make it difficult for patients to get access to the Alkermes drug. SVB Leerink expects ALKS 3831 will be priced in line with other antipsychotics, such as Intra-Cellular Therapies (NASDAQ: ITCI) drug lumateperone (Caplyta) and cariprazine (Vraylar), which came to AbbVie (NYSE: ABBV) via its acquisition of Allergan. The investment bank projects the Alkermes drug could reach $300 million in peak US sales.

Image: iStock/libre de droit


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