July 13, 2010
The investigational obesity drug Qnexa -- a combination of phentermine and topiramate -- could become the first new prescription drug for paring pounds approved in several years, based on review documents released today by the FDA.
The agency's review appears favorable, acknowledging that the drug met standards for approval, including a reduction in body weight of 5% or greater compared with placebo -- although FDA does caution about the cardiovascular, psychiatric, and cognitive side effects.
If approved, Qnexa will be limited to use in obese patients with a body mass index (BMI) of 30 or higher, or in overweight patients (those with a BMI of 27 or higher) who also have weight-related comorbidities such as hypertension, diabetes, dyslipidemia, or central adiposity. It is indicated as an adjunct to diet and exercise.
The FDA advisory committee meeting on Qnexa will take place Thursday July 15.
In its review, the FDA found that two randomized, double-blind, placebo-controlled 56-week trials -- conducted by drugmaker Vivus and presented at medical meetings, but not yet published in peer-reviewed journals -- showed significant weight reduction associated with all three doses of the drug.
Mean reductions ranged from about 3% of body weight on the lower dose of Qnexa to 11% in the highest dose. The studies also showed improvements in blood pressure, lipids, and glycemia.
Yet the FDA report highlights five areas of potential safety concerns: cardiovascular, psychiatric, cognitive, teratogenic, and metabolic acidosis.
Overall side effect rates were low, but the agency's report notes that approximately four to seven times as many patients in studies of Qnexa discontinued the drug due to anxiety, sleep, and depression-related adverse events.
Patients also had more cognitive-related adverse effects on attention, memory, and language, and more of them had increases in heart rate relative to the placebo group.
In documents provided to the FDA by Vivus, the most common adverse events were paresthesia, dry mouth, dysgeusia, and insomnia. But the company said that it will conduct a large cardiovascular outcomes trial if the drug is approved.
Cardiovascular safety is a key concern largely because one half of the combination is phentermine, a component of Fen-Phen (fenfluramine/phentermine), a popular obesity drug pulled from the market about six months after its approval in 1997 because of an increased risk of valvulopathy.
However, FDA reviewers wrote that "current evidence indicates that the valvulopathy was attributable to fenfluramine" -- not phentermine.
Several of the other diet drugs have had their share of harmful side effects. Along with fenfluramine, dexfenfluramine (Redux) was also withdrawn from the market in 1997 for similar concerns.
Ten years later, drugmaker sanofi-aventis withdrew its new drug application for rimonabant (Zimulti) -- marketed in Europe as Accomplia -- after associated reports of depression and suicide.
And the two drugs currently approved for long-term weight loss have also raised concerns about their side effects. Some research suggests that sibutramine (Meridia) may be linked to increased blood pressure, heart rate, and heart attacks, and orlistat (Xenical, Alli) was recently slapped with a label change to reflect an increased risk of liver injury.
On the over-the-counter, weight-loss aids containing phenylpropanolamine, such as Dexatrim, were pulled from drugstore shelves in 2000 due to concern about an increased risk for hemorrhagic stroke. The FDA also banned ephedra in 2004, following the death of Baltimore Orioles pitcher Steve Bechler, and a review that found the supplement raises blood pressure and stresses the circulatory system.
Donny Wong, PhD, an analyst with Design Resources, said 2010 is one of "the most exciting years we've had" in terms of obesity medications.
"The market is ripe ... for something in double-digit weight loss," Wong told MedPage Today in an interview.
Two other weight-loss drugs are also up for FDA hearings later in the year -- a combination of bupropion and naltrexone (Contrave) and a combination of benzazepine and hydrochloride (Lorcaserin).
Researchers say Qnexa appears to be the most efficacious of the three.
The drug appears to work by decreasing hunger -- via phentermine's anorectic effects of releasing norepinephrine in the hypothalamus -- while increasing satiety -- through topiramate's variety of mechanisms of action, including GABA inhibition and effects on glutamate receptors in the brain.
Qnexa has been given once-daily in three doses: low (3.75 mg phentermine/23 mg topiramate), middle (7.5 mg/46 mg) and high (15 mg/92 mg).
Wong says the "big question for FDA" in terms of approval is whether the drug is safe.
"Just because these compounds don't have the same chemical mix as Fen-Phen doesn't mean they don't have a chemical mix that can cause long-term harm," Joanne P. Ikeda, RD, of the University of California Berkeley, said in an e-mail to MedPage Today.
"I think we should demand long-term safety studies for these drugs," she added. "Obesity isn't killing off that many people that we need to rush these drugs to market."
Melina B. Jampolis, MD, who has a private practice in San Francisco and Los Angeles, told MedPage Today that she isn't sure whether the drugs raise the bar in terms of safety, but "I think they are going to have to as we begin to understand that we need to approach obesity as a chronic condition that requires long-term therapy."
Other researchers are more skeptical about the need for obesity medications.
"If you need to lose weight, start now and go slow but steady," Keith Ayoob, EdD, RD, of Albert Einstein College of Medicine, said in an e-mail to MedPage Today. "Don't wait for approval of any drug. Make gradual changes and be consistent. Consistency will beat out any drug."
David L. Katz, MD, MPH, of Yale University, agreed. "Pharmacotherapy will, at best," he told MedPage Today, "be a very small part of the solution for epidemic obesity."
This article was developed in collaboration with ABC News.
Return to In the News