European Regulators Investigating CV Safety of Weight-Loss Drug Mysimba

The European Medicines Agency (EMA) has started a review of the weight-loss therapy naltrexone/bupropion (Mysimba; Orexigen Therapeutics) given outstanding questions over its long-term cardiovascular safety.

As part of that review, the Committee for Medicinal Products for Human Use (CHMP) sent a long list of questions to the manufacturer that it wants addressed, including the estimated patient exposure to naltrexone/bupropion globally and all available data from clinical and nonclinical studies on the cardiovascular safety of treatment in its approved indication.

“This should include previously submitted data and any new data that were not submitted yet,” according to the EMA, adding that this should all ongoing clinical studies whether they were sponsored by Orexigen or not. “A comprehensive summary and critical discussion of these data should be provided, with a special focus on long-term cardiovascular safety.”

The drug is currently approved for weight loss in Europe as an adjunct to diet and exercise in overweight or obese adults. At the time of approval in 2015, there were issues raised in phase III testing regarding transient increases in blood pressure and heart rate with treatment, as well as a numerically higher risk of MI, compared with placebo. To satisfy the marketing authorization, the company was required to conduct a large-scale, cardiovascular outcomes trial to reassure on safety.    

The controversial LIGHT trial, sponsored by Takeda Pharmaceuticals, who partnered with Orexigen to distribute the drug, was set to evaluate the cardiovascular safety of naltrexone/bupropion but was terminated early following Orexigen’s public leak of interim data that compromised the study. A second cardiovascular outcomes study, known as CONVENE, was also stopped early after Takeda sold the rights of the weight-loss drug back to Orexigen. At the time, Orexigen said they wanted to redesign the trial to meet their global marketing authorization requirements, including those from the EMA.  

Since then, Orexigen has proposed several alternative studies, including a retrospective cohort study using electronic health records as the data source and a pragmatic phase IV trial, that the CHMP shot down as insufficient to address the long-term safety of naltrexone/bupropion. In view of the ongoing uncertainty and “lack of adequate study plan to address the uncertainty about this risk,” CHMP told the EMA that a review of all available should be conducted.

Orexigen has until October 23, 2023, to submit their responses to the CHMP’s list of questions, with the CHMP expected to issue an opinion by the end of the year. The EMA will then decide whether the marketing authorization for naltrexone/bupropion should be maintained, changed, suspended, or revoked.

In the US, naltrexone/bupropion is approved by the Food and Drug Administration and is marketed as Contrave (Currax Pharmaceuticals). Like the EMA, the agency approved the weight-loss drug contingent on the still-missing outcomes study showing treatment didn’t increase the risk of cardiovascular events.