The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted overwhelmingly (20 to 2) in favor of approving the obesity drug Qnexa (Vivus, Inc.), a combination of phentermine and controlled-release topiramate. Qnexa could be the first prescription drug for obesity to reach the market since 1999.…
The panel voted 20 to 2 in favor of approving Qnexa, stating that the risk/benefit ratio is appropriate in patients with a body-mass index (BMI) of >30 kg/m2 or >27 kg/m2 in patients with weight-related comorbidities. Despite some concerns over increases in heart rate, as well as concerns about potential birth defects in babies born to women taking the drug, particularly risks of cleft lip with or without palate, the panel felt the risks of untreated obesity outweighed these concerns.
“Obesity is in epidemic proportions in the US, with serious morbidity and mortality consequences, and there is an urgent need for better pharmacological options for individual patients,” advisory committee panelist Dr. Elaine Morrato (University of Colorado, Aurora), who voted yes for the approval, said in explaining her affirmative vote. “I believe that Qnexa demonstrated a meaningful efficacy benefit and that there are consequences to not treating obesity.”
Despite the dramatic vote in favor of approval, the panel strongly recommended the initiation and completion of a large morbidity and mortality study to address any potential cardiovascular risks, as well as the use of a risk evaluation and mitigation strategy (REMS) to accompany approval. One of the questions the panel grappled with was whether or not a cardiovascular-outcomes study would be required prior to approving the Qnexa. On the whole, most committee members did not believe the clinical trial was needed to approve the drug, stating that a postapproval study would be sufficient.
Dr. Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA), who also voted yes on approval, said the sponsor demonstrated sufficient efficacy with Qnexa, “but now they need to step up to the plate and do the cardiovascular-outcomes trial and do it fast.” He urged the FDA to hold the sponsor’s “feet to the fire” and use its legislative authority to ensure that the study is done in a timely manner.
In contrast, Dr. Michael Lauer (National Heart, Lung, and Blood Institute, Bethesda, MD), one of two voices against approval, said he was concerned about approving Qnexa on the basis of surrogate outcomes only, saying the approval would be a mistake based on hope and suppositions.
“We’ve seen many cases in the history of medicine where we thought we understood the physiology or pathophysiology of disease and made policy decisions on the basis of that, and it turned out to be wrong once we actually looked,” said Lauer. “As a result, we caused an enormous amount of harm. In an epidemic as serious as obesity, we really need to do this right. We should have no trouble getting a trial put together and finding high-risk patients to answer this question [about cardiovascular risk].”
He cited torcetrapib, the HDL-raising medication that moved surrogate end points in all the right directions but still increased the risk of mortality. Based on the data, Lauer said there is good reason to believe that Qnexa has the potential to do enormous good, but this won’t be known for a long time.
“There is a real possibility that this agent, with the data we have available to us, may help people lose weight, may make the chemistry test look better, but it may end up causing heart attacks, stroke, or higher death rates. It would be a terrible, terrible shame if that were to happen and we didn’t take the appropriate precautions.”
Dr. Jenny Cragan (University of Pennsylvania School of Medicine, Philadelphia) said the Qnexa recommendation was a more difficult decision than the 20 to 2 vote suggests. Like others, she urged the completion of the cardiovascular-outcomes study, the implementation of the REMS, and further evaluation of data to fully assess and characterize the risk of birth defects. Dr. Lamont Weide (University of Missouri, Kansas City) also voted yes, saying that Qnexa is the most efficacious drug that has come to market. Still, he expressed concerns similar to Lauer’s and the rest of the panel’s.
Although it is not clear when the clinical trial will be started or even if it will be a condition of approval, Vivus did provide some details of a study that would address the panel’s concerns. The outcomes trial would include approximately 11,000 patients at high risk for cardiovascular disease or patients with cardiovascular disease. The company also hinted at the possibility of including intermediate-risk patients, such as those with diabetes mellitus, hypertension, or dyslipidemia, in the hopes of enrolling patients faster. The primary end point of the study would likely be a composite of death/MI/stroke.
This isn’t the first time Qnexa has come before the advisory committee. In July 2010, the panel voted against the approval of the drug because of concerns about its safety, and this led the FDA to reject it. At the time, most panelists, many of whom served again on yesterday’s panel), agreed the drug was effective at promoting weight loss but were disconcerted by the number of adverse events linked to the drug, including cognitive disorders, metabolic acidosis, increased heart rate, and birth defects.
Again, the efficacy was never in doubt for yesterday’s committee. One-year data showed that low-, mid-, and high-dose Qnexa was associated with a large percentage of patients losing more than 5% of their body weight, while two-year data, which was requested by the FDA, showed that patients treated with mid- and high-dose Qnexa lost 9.3% and 10.5% of their body weight from baseline. There was an increase in weight, however, observed in the second year of treatment. Surrogate markers also moved in the right direction, too, with Qnexa-treated patients having reductions in blood pressure, HbA1c levels, and improvements in lipid parameters, including HDL cholesterol.
The two concerns the advisory committee had with Qnexa were related to the increases in heart rate and the increased risk of cleft lip with or without cleft palate. The drug appears to increase heart rate 1 to 2 beats per minute and, based on FDA analyses, increases the risk of cleft lip two- to fivefold among children born to women taking topiramate.
As part of the proposed REMS, the sponsor stressed the importance of adequate birth control in women taking Qnexa and recommended pregnancy testing before and during drug treatment and stopping the drug immediately if a pregnancy occurs. As part of the REMS, they also proposed controlled distribution and provider training and the use of communication tools to inform patients, physicians, and pharmacists about the risk of congenital malformations with the antiobesity agent.
The inclusion of the REMS as part of approval appeared to satisfy panel members enough to vote yes, including some who reversed their 2010 vote.
Morrato noted that the active ingredients in Qnexa have been marketed for years including the use of topiramate for the treatment of epilepsy and migraine headaches and that these drugs individually carry side effects. She added that the population-attributable risk with Qnexa could be quite large given the large numbers of patients, possibly tens of millions, who are likely to be treated with the weight-loss drug. She voted no to approval in 2010 because of the lack of an adequate risk-management plan and an inadequate focus on ensuring that only patients with an appropriate risk profile would be treated.
With the REMS, and the proposed morbidity and mortality trial with Qnexa, “I believe the sponsor and the FDA are striving to find the right balance to provide access to effective antiobesity medications and mitigating the risks,” said Morrato.
If the FDA ends up following the advice of its advisors, Qnexa could be the first prescription drug for obesity to reach the market since 1999. Experts called to present data and perspectives on behalf of Vivus argued that there is an unmet clinical need in the management of obesity. In particular, they said Qnexa could fill a need between the use of lifestyle changes and surgery to achieve weight loss. While bariatric surgery cuts weight by 20% to 30%, there is a need for a treatment that can reduce body weight in the range of 5% to 20%, which is more than lifestyle changes alone can achieve, they said.
Food and Drug Administration clinical briefing document. Endocrinologic and metabolic drugs advisory committee meeting, February 22, 2012. Available here.