Opioid-related hazards with Alkermes plc’s combo drug ALKS-3831 – specifically, with the samidorphan element – and the significance of weight-gain reduction brought about by the tablet, which also includes olanzapine, became key topics in the joint meeting of the FDA’s Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management (DSaRM) Advisory Committee.

Meant to treat schizophrenia and bipolar I disorder, ALKS-3831 consists of the new molecular entity samidorphan, an opioid antagonist, formulated in a two-layer oral dose with olanzapine, an established antipsychotic agent. Dublin-based Alkermes invented the paired-drug candidate in order to provide olanzapine’s efficacy while mitigating weight gain known to accompany the approved drug. The FDA cleared olanzapine as Zyprexa/Zyprexa Zydis in 1996, and it’s marketed in the U.S. by Eli Lilly and Co., of Indianapolis.

Olanzapine is indicated for schizophrenia, acute mixed or manic episodes associated with bipolar I disorder (as monotherapy or in combination with lithium or valproate), and for maintenance monotherapy of bipolar patients. Samidorphan, also known as 3-carboxamido-4-hydroxynaltrexone, preferentially acts as an antagonist of the μ-opioid receptor. Alkermes has proposed Lybalvi as the brand name for its product to treat adult schizophrenia and adult bipolar I as an acute treatment of manic and mixed episodes, as maintenance treatment, and as an adjunct to valproate or lithium in manic or mixed episodes.

Trading in Alkermes shares (NASDAQ:ALKS) was halted as the committees balanced the relevance of reducing weight gain – which can head off worse metabolic problems due to extra pounds – with concerns about would-be harm to patients on opioids. The session ended with three voting questions. On the first, “Has the applicant presented adequate evidence that samidorphan meaningfully mitigates olanzapine-associated weight gain?,” panelists voted 16 yes, one no. On the question, “Has the applicant adequately characterized the safety profile of ALKS-3831?,” the vote was 13 yes, three no, and one abstention. On the third question, “Is labeling sufficient to mitigate the risks related to the opioid antagonist action of samidorphan?,” panelists balloted 11 yes, six no.

In August, results from the phase III trial called Enlighten-2 were published in the American Journal of Psychiatry. The six-month study evaluated the weight-gain profile of ALKS-3831 compared to olanzapine in 561 patients with stable schizophrenia. Positive top-line data from the experiment were first reported in November 2018.

‘Unique vulnerability’ cited

Ahead of the meeting, Wainwright analyst Douglas Tsao pointed out that, in briefing documents, the FDA did not question the combo drug’s ability to mitigate the olanzapine weight gain but wanted the committees to measure, if possible, the value of the upside with regard to weight against other factors. Psychiatric patients bear a greater risk of opioid dependence. “Given the FDA’s caution regarding opioids, considerable time could be spent on the third question,” Tsao predicted in a report, and that’s what happened. DSaRM panelist Steve Meisel, system director of medication safety with M Health Fairview in Minneapolis, voted a strong no. “I think labeling will do absolutely nothing to mitigate the risks related to the opioid antagonist qualities of this drug,” he said, because the prescribers of opioids and the those of Alkermes’ drug likely will not be the same people. “The notion that there’s going to be a negative interaction or a problem with prescribing the opioids is going to fly right by them. They’re not going to go back and read the label of this drug when they’re prescribing an opioid in an emergency room or dentist’s office. The conundrum here is that the labeling [of Alkermes’ drug would be] designed for prescribers, but the risks are not when the prescriber uses it because they’re not prescribing the opioids, in general. It’s going to be with the people who are caring for patients in non-psychiatric situations.”

Amy Bohnert investigator with the VA Center for Clinical Management Research, and associate professor of anesthesiology and psychiatry at the University of Michigan in Ann Arbor, voted yes, saying she “share[d] the concerns” of dissenters “but I felt like, on balance, the labeling would be sufficient for patients to make an informed choice.” Felipe Jain, assistant professor of psychiatry at Harvard Medical School and director of healthy aging studies in the depression research program at Massachusetts General Hospital, agreed “100%” with Meisel’s no vote. “It will be far too easy for non-psychiatrists to not realize what medication the patient is taking and what its properties are,” she said. “Although labeling has been sufficient for opioid antagonists when used for other purposes,” Alkermes’ combo prospect is different. “Particularly, this [drug] could be started when a person is manic or psychotic or suffers from cognitive disorganization, which often accompanies those states. They may not realize what they have been placed on, and the implications of it being an opioid antagonist. It’s well validated that people who are manic, and sometimes those who are psychotic, do not remember everything,” due to their “unique vulnerability in the time period when it is likely they will be started on the medication.”

Jefferies’ Biren Amin touched on the matter, saying in a report that, “while Alkermes listed chronic use of opioids and opioid dependence as contraindications for ALKS-3831, the agency notes situations where a prescriber may be unaware of a patient’s opioid use, and the risks associated with samidorphan in such settings. Examples included precipitating withdrawal in patients that are opioid dependent, risk of overdose in [patients] with pain conditions requiring opioid analgesics, and risk of overdose due to loss of opioid tolerance as a result of ALKS-3831 in former opioid users.”

Alkermes stock (NASDAQ:ALKS) was halted for the day, closing on Oct. 8 at $16.86, a midpoint of its 52-week range.

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