FDA advisory committee recommends approval of combination weight-loss drug

The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 13-7 for approval of the novel combination of bupropion plus naltrexone for the treatment of obesity and weight management.

Decisions were based on results of four phase 3 trials suggesting that the drug is associated with statistically significant and clinically meaningful weight loss, as compared with placebo. Safety data also indicate that, during the trials, adverse events occurred early in treatment, and were generally mild or moderate in severity and self-limited, according to briefing documents supplied by Orexigen. Researchers also noted that the treatment’s safety profile was similar to those of bupropion (Wellbutrin, GlaxoSmithKline) and naltrexone (Embeda, King Pharmaceuticals; Revia, Duramed; Vivitrol, Alkermes) alone.

While panel members commended Orexigen for providing quality evidence and adhering to the guidelines set forth by the FDA, some expressed concerns during the vote about the study results supporting the efficacy of bupropion plus naltrexone (Contrave, Orexigen) as well as a lack of long-term data. Further, they remained apprehensive because of data that link the treatment to increased risk for blood pressure.

“Despite the fact that the company has done an excellent job putting data together, I’m just not convinced that the benefits of this drug outweigh the cardiovascular risks,” Vera A. Bittner, MD, MSPH, professor of medicine and section head of preventive cardiology at the University of Alabama at Birmingham, said during the meeting.

Other members also pointed out that the withdrawal of sibutramine (Meridia, Abbott Laboratories) from the market made them wary of approving another drug that would eventually be pulled after more data become available.

Some panel members, however, noted that the decision to approve combination naltrexone plus bupropion was difficult but they felt the treatment is sorely needed.

“It’s not going to be a perfect drug for everyone, but it will give us one more treatment option,” patient representative Melanie Coffin, said.

More research needed

In a separate decision, the panel voted 11-8 to include a controlled clinical trial designed to thoroughly examine the effects of combination bupropion and naltrexone on major CV events as a post-approval requirement.

Members who voted for the post-approval requirement said the sponsor met the FDA’s criteria for efficacy, and although safety concerns regarding CV events persist, the risks did not appear overwhelmingly alarming. Additionally, they felt that adding a post-approval requirement may expedite initiation of controlled clinical trial and would perhaps help acquire more long-term data in larger cohorts.

“It would most likely be difficult to enroll the large scale populations needed for these studies if they were conducted pre-approval,” Coffin said.

Panel member Jacqueline S. Gardner, PhD, MPH, professor in the department of pharmacy at the University of Washington, also explained that the extensive research on the individual components, which have been available for the past 20 years, influenced her decision regarding safety.

“These compounds have been in wide use, and in fact have been evaluated repeatedly for different indications in recent years,” Gardner said.

Sanjay Kaul, MD, director of the fellowship training program in cardiovascular diseases at Cedars-Sinai Heart Institute, disagreed.

“I could have voted for a post-market approval study if the weight loss was more impressive,” he said. “Also, it is not exactly clear whether weight loss or modest weight loss may enhance life expectancy or exert impact on CV mortality or morbidity. Data on hand are insufficient, but there are sufficient clues [related to BP risks] to be concerned.”

Public, patient concerns

In light of the hearing, the Obesity Society and the Obesity Action Coalition asked the FDA to bear in mind the need for more tools to address the obesity epidemic when considering approval of combination bupropion and naltrexone.

“We are deeply concerned about the effect that the FDA’s recent decisions will have for ongoing and future research into desperately needed new obesity treatments,” Jennifer Lovejoy, PhD, president of the Obesity Society, said in a press release. “As the FDA’s advisors consider the application before them, we hope that the agency will assure a balanced process, taking into account the urgent medical need.”

President and CEO of the Obesity Action Coalition Joe Nadglowski agreed. “The number of those affected by obesity is growing at an incredibly rapid rate and the millions of Americans already affected by the disease are lacking the necessary medically approved treatment and long-term options so desperately needed.”

Bruce Wolfe, MD, president of the American Society for Metabolic and Bariatric Surgery, also weighed in, highlighting how the advisory panel's decision may represent yet another step toward finding a solution to the obesity epidemic.

"The federal government and medical experts agree that obesity is the single biggest threat to America for the coming century, and the FDA can be part of the solution," Wolfe said. "We support [the agency's recent] decision on expanded indications for gastric banding, and we call on the FDA to adopt a comprehensive approach and define a clear path for innovation in all forms of treatment of this disease."

Reactions

The committee's decision inspired hope and reassured Lovejoy, Nadglowski and members of other obesity organizations.

"The OAC is encouraged because this is the first indication in some time that a new treatment can receive a favorable hearing from the FDA," Nadglowski said. "Treating obesity is a complex problem requiring many tools in the toolbox."

Lovejoy also praised the agency and its advisory panel's process.

"The FDA carefully weighed the evidence in reaching this decision and laid out future research needs," Lovejoy said. "Today was a good example of how the FDA can balance risks and benefits in reviewing new treatments."

Nadglowski also expressed optimism about the future.

"We greatly hope that the FDA will continue working with the pharmaceutical industry and utilize a fair and balanced approach moving forward weighing the well-documented benefits of treating obesity against the risks associated with any medication developed for the treatment of obesity," he said. "We are at a crucial crossroad where the time to develop safe and effective treatment options for those affected by the disease of obesity is now."

While the FDA is not required to follow the recommendations of the advisory committee, it usually does. – by Melissa Foster

The FDA advisory committee's recommendation to approve Orexigen's Contrave as a new drug is a hopeful step forward in the treatment of overweight and obesity in the United States. During 2010, we have seen the FDA vote to reject applications for two new drugs (Qnexa and Lorcaserin) and withdraw another (Meridia), leaving both practitioners and patients with fewer and fewer options. The recommendation this week for both a new drug and the expanded use of a medical device (Lap-Band), is very encouraging.

We are currently facing a health epidemic in our nation, with nearly 100 million adults affected by obesity - and we need more tools in the toolbox to help those involved in this struggle. Some people may look at the study results of a drug like Contrave and wonder if it's effective enough. It's important to understand that 5% weight loss may sound small, but many people cannot achieve or sustain it thought diet and exercise alone, and it can have a huge impact on health and well being. In many individuals, while this may still not get them to their ideal body weight, it will substantially improve conditions like hypertension, metabolic syndrome, polycystic ovary syndrome, and overall quality of life.

While some safety concerns were raised with Contrave, this must be measured against the risk of non-treatment or ineffective treatment. Obesity has devastating, long-term heath effects, substantial known co-morbidities, and simply increases all-cause mortality. Under the supervision of experienced physicians, potential side effects can be monitored and - ideally - mitigated It was already known that elevated blood pressure could result from the use of bupropion (one half of Contrave), so doctors can monitor this.

Because the recommendation of the FDA advisory panel is not an approval, we will still have to wait for the final ruling in early next year. I think the whole obesity community is feeling very encouraged at the moment, however. Hopefully, we will enter 2011 with an expanded list of treatment options, and this is great news indeed.

– Jacqueline Jacques, ND
Chief Science Officer, Bariatric Advantage, A Division of Metagenics, Inc.
Obesity Action Coalition Board Member

From a clinician's standpoint, the panel's decision to recommend approval of Contrave is great news. Currently, there are no real treatment options, other than surgery, for the millions of individuals suffering from the disease of obesity. The last medication approved for weight loss and weight loss management became available in 1999, so approval of this treatment would certainly add another tool to our toolbox. However, it's clearly no magic bullet. If people think that they're going to take the pill and lose massive amounts of weight, it's not for them. The medication definitely needs to be used in conjunction with diet, exercise and behavior modification. Nevertheless, recommendation for approval represents a huge step forward for those not only suffering from obesity but also for those with comorbid conditions, such as diabetes, sleep apnea and fatty liver disease.

This is the third medication up for review in the last 6 months. In the past, the FDA may have been a little gun-shy, especially in light of sibutramine's withdrawal from the market. However, this may also be because the agency might hold obesity medications to a higher standard. Even so, I think they evaluated the data and considered the severity of the obesity epidemic and determined that Contrave is a good potential treatment option for the millions of Americans affected by the disease.

– Christopher D. Still, DO
Director, Center for Weight Management and Nutrition
Associate, Department of Gastroenterology & Nutrition
Geisinger Health System
Danville, PA

There are a lot of physicians who, given the advisory committee's two prior decisions regarding the Vivus combination and Arena's Lorcaserin, are very pleased to see that it is actually possible to get an obesity drug past the panel. Many of us were somewhat pessimistic about Contrave's risk/benefit profile being fully evaluated in a way that would allow a recommendation for approval.

This is a very important milestone for the field as a whole, but it is also very important for patients who have issues with body weight regulation and comorbidities, such as diabetes. Further, practitioners will appreciate that the toolkit is expanding. They will have more in the clinic than just advising patients to eat less and exercise more.

Having a second vote was actually very interesting. The advisory panel's meetings for the previous two medications were not specifically asked about pre- or post-approval studies specifically. It may be a response by the FDA to additional concerns regarding CV safety broadly across obesity therapies after sibutramine's withdrawal from the market. I also think it provides some insight into the future. Currently, we have clear guidance for the development of diabetes drugs, but that guidance does not specifically exist for obesity medications. This goes one step further in at least revealing that CV assessments can occur post-market as opposed to being pre-market, which is more in line with guidance for diabetes drug development.

– Steven R. Smith, MD
Scientific Director, Translational Research Institute of Florida Hospital
Professor, Sanford Burnham Medical Research Institute

Following the diappointment after the previous FDA Advisory Panels that examined potential new treatments for obesity, I was pleased to see the positive vote in favor of Contrave. This means that the FDA has been advised to approve this combination therapy, opening the way to marketing this combination of drugs for treatment of obesity.

– George A. Bray, MD
Endocrine Today Editorial Board Member

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