Most FDA Advisors Say Likely Benefits of Contrave Diet Drug Outweigh Its Cardiovascular Risks
A majority of members of the US Food and Drug Administration (FDA)’s Endocrinologic and Metabolic Drugs Advisory Committee believe the likely benefits of a new diet drug would outweigh its risks. The vote makes Contrave, a combination of naltrexone 4 mg and bupropion HCL 8 mg (Orexigen Therapeutics), the first agent for weight loss and weight-loss maintenance to get a majority “yes” vote from FDA advisors this year. If approved, it would be the first new diet drug on the US market in the past decade.
In all, 13 panel members voted “yes” to the question of whether the potential benefits of naltrexone/bupropion outweigh its potential risks if used long term, while seven voted “no.” In their statements, several experts who voted “yes” said that approvability would have to depend on assurances that a cardiovascular-outcomes study would go forward promptly.
Indeed, that was the first question the panel was asked to vote on, and the differences in the tally here speak to the panel’s misgivings about the lack of outcomes data: eight voted to recommend that a cardiovascular-outcomes study be conducted prior to drug approval, while 11 voted that such a study could happen postapproval. One panel member abstained.
Earlier in the day, an Orexigen spokesperson said it was in discussions with the FDA about what a large outcomes trial would look like. The drug, a 90-mg extended-release tablet, combines two already-approved agents with known side-effect profiles: naltrexone is approved for opioid and alcohol addiction and bupropion for depression, smoking cessation, and seasonal affective disorder. Obesity researchers have told heartwire that they believe the way forward in treating obesity is likely going to be with combination drugs that target both appetite centers and reward centers simultaneously–the promise of the naltrexone/bupropion combination.
Contrave was the third proposed new diet drug to go before the committee this year–the other two, lorcaserin (Arena Pharmaceuticals) and phentermine/controlled-release topiramate (proposed name: Qnexa, Vivus) were not recommended for approval by the committee, and the FDA subsequently rejected their marketing applications, asking for more data. Yet another diet drug, sibutramine (Meridia, Abbott Laboratories), was yanked from the market this year due to concerns about its cardiovascular safety.
The sponsor is seeking FDA approval of naltrexone/bupropion for the treatment of obesity and weight management, including weight loss and maintenance of weight loss, in patients with an initial body-mass index >30 kg/m2 or >27 kg/m2 with one or more risk factors (eg, diabetes, dyslipidemia, or hypertension).
Weight-Loss Indication
Evidence in support of the application comes from a total of four placebo-controlled trials, enrolling, in all, some 3200 subjects to the study drug and roughly 1500 subjects to placebo, over one year. As FDA briefing documents noted, study completion hovered at just over 50% in the 56-week studies, with 20% of subjects taking the lower dose of the study drug and 24% of those taking the higher-dose drug withdrawing from the studies due to adverse events (there was a 12% withdrawal rate in the placebo arm).
The mean weight-loss difference between the drug and placebo groups in the combined trials was 4.2%. Of note, this difference does not meet the criterion set out by the FDA in 2007 stipulating that new drugs seeking FDA approval should demonstrate a statistically significant difference in mean weight loss of at least 5% at one year. However, in three of the four studies, the proportion of subjects taking naltrexone/bupropion who lost at least 5% of their initial weight was 35% or more, double that seen in the placebo-treated group–meeting the FDA’s second criterion for efficacy.
Discussing these data during today’s meeting, panel members pointed out that the FDA in fact only required applicants to meet one of the criteria for efficacy to be demonstrated. But the bigger issue, for panel members, was the fact that blood-pressure and heart-rate changes went in the wrong direction–something debated at length by the panel.
Panel members were particularly uncomfortable with the finding that the only patients in the studies whose blood pressure improved were those who managed to lose at least 10% of their original weight–a minority of patients in the trials–and even then the blood-pressure improvements were nominal. Several panel members also repeatedly invoked the specter of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the cardiovascular-outcomes study that ultimately sank sibutramine, saying that they were concerned a lack of clear benefit on cardiovascular-risk parameters might portend cardiovascular problems if the drug were widely used. SCOUT was a postapproval study that did not get under way for several years after approval was first granted to sibutramine: no such delay could be tolerated for a CV-outcomes study of naltrexone/bupropion, panel members said.
Dr Sanjay Kaul (Cedars Sinai, Los Angeles, CA), who believed the benefits did not outweigh the risks, observed, “The more I look into it, the more I conclude that this drug resembles sibutramine both in terms of efficacy and cardiometabolic profile, blood pressure, and heart-rate signals. There is an opportunity to learn from history, or we are likely to repeat it.”
Regardless of whether they voted for or against Contrave–that is, whether they felt its benefits exceeded its risks–panel members were remarkably similar in their comments: almost everyone was concerned about the blood-pressure effects, everyone stressed the need for hard outcome studies, and most lamented the lack of a profound effect on weight loss.
Dr Ed J Hendricks (Center for Weight Management, Roseville and Sacramento, CA), who voted in favor of the drug’s benefit/risk profile, summed up the views of many on the panel, saying that while he was “disappointed” with the efficacy data, he nevertheless felt it would be a “useful” drug.
Source: December 8th, 2010 at http://www.medscape.com/viewarticle/733831?sssdmh=dm1.653101&src=nldne&uac=146330HN
