麻豆传媒

Cutting one type of risk associated with a popular drug by adding another drug with a very different set of risks -- as drugmaker Alkermes seeks to do with the antipsychotic olanzapine -- presents an FDA advisory panel with an unusual quandary when it meets on Friday.

The Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee will review ALKS 3831, a once-daily oral treatment that combines with the opioid antagonist samidorphan.

With a proposed trade name of Lybalvi, Alkermes is seeking indications for adult schizophrenia, as well as adult bipolar I disorder as acute treatment of manic or mixed episodes as monotherapy and maintenance monotherapy treatment or as adjunctive therapy to lithium or valproate for manic or mixed episodes. It would come as fixed-dose combination pills in a variety of strengths.

Olanzapine is a highly effective "atypical" antipsychotic drug, but most patients gain substantial weight while taking it. The addition of samidorphan erases much of that risk, but at the cost of potential interactions with licit and/or illicit opioids.

"Weight gain thus presents a long-term safety risk to patients and is a significant factor to consider when deciding whether to prescribe [olanzapine]," read submitted by Alkermes. "As such there is an unmet medical need for a medicine that retains the established efficacy of [olanzapine] while mitigating [olanzapine]-associated weight gain and thereby producing a more favorable benefit-risk profile."

In long-term studies of olanzapine monotherapy -- treatment lasting at least 48 weeks -- 64% of patients gained at least 7% of their body weight and 32% gained at least 15% of their body weight. And in addition to weight gain, olanzapine monotherapy is also linked to an increased prevalence for a slew of other metabolic conditions including diabetes, hypertension, and dyslipidemia.

But by adding samidorphan to the mix, a novel mu-opioid antagonist not currently approved, weight gain associated with olanzapine is substantially mitigated, although not completely eliminated.

"Opioid antagonists have been shown to play a role in regulating weight and metabolism, potentially through mechanisms involving food reward circuitry as well as modulation of insulin sensitivity," Alkermes explained.

However, the company emphasized that it's not seeking an indication of weight gain mitigation with the combination.

Clinical trials of olanzapine/samidorphan demonstrated significant improvement and maintenance in mean Positive and Negative Syndrome Scale (PANSS) score comparable to treatment with olanzapine alone. This was likewise paired with a 50% reduced chance of gaining a clinically significant amount of weight -- more the 7% of body weight -- versus olanzapine alone.

One likely point of contention to arise during the FDA Advisory Committee meeting will surround the risks associated with an opioid agent. These include the potential for opioid overdose, reduced opioid analgesia, and the potential for acute opioid withdrawal in already opioid-dependent patients.

The drug's fate could hinge on safety concerns with samidorphan, as points out that "epidemiologic data suggest that a substantial subset of the indicated patient population could be at risk for one or more of these adverse events."

Addressing such concerns in its application, Alkermes proposed that its label contain a contraindication for patients with opioid dependency, along with warnings and precautions regarding vulnerability to opioid overdose.

Alkermes also outlined a provider and patients education plan in briefing documents, including a discussion guide for healthcare providers to speak to patients about these risks and a proposal for a patient support call-center.

This isn't the first time Alkermes sought approval for a combination treatment involving samidorphan. Last November, its investigational treatment ALKS 5461 -- a combination of buprenorphine and samidorphan seeking an indication as adjunctive therapy to antidepressants -- was turned down for recommendation by an advisory committee in a 21-2 vote citing uncertainty over the risk-benefit profile.

Comment