ICER highlights short-term gains amid long-term uncertainties of Karuna schizophrenia drug

2024-01-26

临床结果

An experimental schizophrenia treatment that Bristol Myers Squibb picked up in a $14-billion deal for Karuna Therapeutics late last month, has a unique mechanism of action that raises uncertainties about its long-term efficacy and safety, according to a US drug pricing watchdog.

In an updated evidence report, the Institute for Clinical and Economic Review (ICER) said KarXT, which is currently under review at the FDA, could be cost-effective if priced between $16,000 and $20,000 per year. An FDA decision deadline has been set for September 26.

The twice-daily oral therapy consists of xanomeline, which targets both the M1 and M4 muscarinic receptors, plus trospium, which reduces the peripheral side effects of muscarinic receptor activation. ICER chief medical officer David Rind says its short-term advantages are promising, particularly with respect to lower weight gain compared to existing treatments, but "current evidence on benefits and harms is limited."

The FDA filing is based on the EMERGENT-1, -2 and -3 trials, in which KarXT significantly improved the total Positive and Negative Syndrome Scale (PANSS) score, as well as the proportion of patients with ≥30% improvement in the PANSS score over five weeks in those hospitalised for acute worsening of their schizophrenia.

The ICER report notes that KarXT was also associated with significantly lower weight gain, potentially leading to fewer cases of metabolic syndrome, diabetes and cardiovascular complications over the longer run.

Looking beyond five weeks

"Treatment with second-generation antipsychotics can result in serious long-term adverse effects including metabolic syndrome and tardive dyskinesia. A safer antipsychotic may be preferable to use initially even if it has lower efficacy," the ICER report says, but "the major source of uncertainty is the lack of data…for longer than five weeks."

Still, while the initial data suggest weight gain may not be an important side effect of KarXT, ICER said this needs to be confirmed over a longer period of time. "Similarly, we have no data on the incidence of tardive dyskinesia and other long-term movement disorder side effects…[or] on the prevention of relapse, return to work and school, or improvements in relationships with friends and family."

Assuming KarXT does not increase the risk of metabolic syndrome and associated consequences, ICER said Karuna's drug "results in less time with diabetes and in greater QALYs (quality-adjusted life years)." If it does, the cost-effectiveness range would be lower. On the other hand, ICER's analysis assumed that there was no reduction in the risk of tardive dyskinesia with KarXT compared to other second-generation antipsychotics; if this turns out to be true with longer testing, then the proposed price range would be higher.

Back into neuro

Speaking at the recent JP Morgan healthcare conference earlier this month, Bristol Myers Squibb's chief commercialisation officer Adam Lenkowsky stated that the company is eyeing a Q4 launch of KarXT. He highlighted the drug's "unsurpassed" efficacy without the "significant baggage" of side effects associated with existing antipsychotics. "We've been out of neuroscience since we launched Abilify," the executive said, but "we think [KarXT] is going to drive significant growth in the back-end of the decade and well beyond, and also get us…back into neuro."

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