麻豆传媒

In a further sign of the chaos surrounding weight-loss drug naltrexone/bupropion (Contrave), drugmaker Orexigen has again terminated an FDA-mandated cardiovascular outcomes trial with the drug.

Following a year of controversy (more details in the links below), Orexigen last month assumed sole control of Contrave from former partner Takeda. The company has now terminated enrollment in and has notified sites participating in the trial. The company says it has also notified the FDA of the changes.

By way of background, Contrave was approved by the FDA in 2014 and was the first obesity drug to be approved on the basis of a novel FDA program in which obesity and diabetes drugs could gain approval before final results were available from a cardiovascular outcomes trial (CVOT). For Contrave, approval was dependent on a prespecified interim analysis of , a CVOT which was designed to rule out a significant increase in cardiovascular risk.

Problems emerged when LIGHT's data and monitoring committee performed its first interim analysis after the 9,000-patient trial had reached 25% of its primary endpoint events (major adverse cardiovascular events). The results were supposed to be held in strict confidence, but Orexigen shared them with over 100 people both within and outside the company. When the FDA found out about the leak they said that the trial should continue but that a second additional cardiovascular outcomes trial -- CONVENE -- would have to be performed.

But then the situation went from bad to worse. In March 2015, Orexigen provoked a firestorm by making the results of the interim analysis public in a patent application. The negative reaction to the premature disclosure of the data was overwhelming. In May the executive committee of LIGHT said the trial had been impossibly compromised and announced that the trial would be prematurely terminated.

As part of the fallout over these events, Takeda dropped out of its partnership with Orexigen. Takeda had earlier assumed control of CONVENE. But with Takeda out of the picture, Orexigen was in charge and decided to start over. Here is a statement sent to me by Orexigen:

"As a result of the recent transfer of the Contrave NDA [new drug application] and IND [investigational new drug] from Takeda to Orexigen, Orexigen is responsible for executing the postmarketing development programs for Contrave in the U.S. and also for Mysimba in Europe. The company expects to make certain changes to optimize the Contrave/Mysimba post-marketing requirement studies for the company's global needs.

"Transfer of the recently initiated multi-year CONVENE trial to Orexigen involves substantial complexity due to the scope, size and nature of the study. In order for this trial to have continued under Orexigen sponsorship, a significant number of operational details would require re-initiation. Based on the amount of time that it will take to effectuate these changes, and the very limited number of subjects enrolled in the CONVENE study, Orexigen is terminating the study. The company will finalize a revised protocol and initiate startup activities under new contracts.

"Orexigen has notified the FDA of these changes and specifically reaffirmed its commitment to meeting the post-marketing requirements.

"'Orexigen plans to conduct a new cardiovascular outcomes trial to satisfy the FDA's post-marketing requirement for Contrave,' said Mike Narachi, CEO of Orexigen."

A key question now is whether the FDA will allow Contrave to remain on the market, since its approval was contingent upon an ongoing cardiovascular outcomes trial. I have asked the FDA and other experts for comments.

Update:

, of the Cleveland Clinic and principal investigator of LIGHT and CONVENE, sent the following comment:

"The termination of the CONVENE trial will result in a significant delay in assessing the cardiovascular safety of naltrexone/bupropion. In the wake of the premature termination of the LIGHT trial, discontinuing a second trial is extremely disappointing and highly irregular. It now remains in the hands of the FDA to determine what actions are warranted to protect patients and ensure that prior commitments are honored."

of Cedars-Sinai Heart Institute in Los Angeles, sent the following comment:

"This will be a litmus test of FDA’s regulatory policy of allowing conditional approvals of therapies which require confirmation post approval. I will be curious to see how the FDA will respond. Remove the conditional approval?"

Additional Update:

Representatives from both the FDA and Orexigen have sent statements explaining that when the FDA approved Contrave it required the completion of a cardiovascular outcomes trial by July 2021.

Here is the FDA statement:

“With respect to the post-marketing requirement to conduct a cardiovascular outcomes trial to evaluate the cardiovascular safety of Contrave, the approval letter states that the trial is to be completed by July 2021 and a final report submitted to FDA by January 2022. FDA has not modified these expectations since approval.”

Here is the Orexigen statement:

“The company has notified FDA of changes to the postmarketing requirement programs and specifically reaffirmed the commitment to meeting the post-marketing requirements including completing a CVOT. The upshot there is that this change shouldn’t prompt any decisions about whether the product remains on the market.”

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