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Good Lancet Article on Qnexa


Metabolic Markets commented a few months about about the structure of the risk mitigation approach from both a label and distribution control standpoint for Qnexa and what approach would would give the FDA confidence (code for: "political cover") to approve.   An article in the LANCET recently dove into the advisory panel vote.  In particular, it was interesting to note the comments of the Qnexa panel chair, ""This risk mitigation strategy probably is what was most important in terms of swaying the vote", says Abraham Thomas, endocrinologist at Henry Ford Hospital, Detroit, MI, USA, and chairman of the advisory panel."

We still have about 5 weeks until the FDA is scheduled to render a decision on Qnexa.  While Wall Street seems to be convinced of an approval, we are not as bullish, but two powerful forces, time and bureaucracy, will soon tell.

Two other  important dates upcoming for industry are the panel FDA public discussion on obesity / cardiovascular safety trial design and a report to the Senate on how the  FDA is taking steps toward obesity agent development.

Below is the full Lancet text

Panel meeting prompts excitement for antiobesity drug

Asher Mullard

pg. 882 Vol. 379 No. 9819 ISSN: 0140-6736


An FDA advisory panel has recommended approving Vivus's weight-loss drug, potentially paving the way for the first new obesity drug in the USA in 13 years. Asher Mullard reports.

In a highly anticipated US Food and Drug Administration (FDA) panel meeting about Vivus's antiobesity therapy Qnexa at the end of last month, independent advisers voted 20-2 in favour of approving the therapy. The final decision now lies with the FDA, who are due to either approve or reject the drug by mid-April, but the vote nevertheless raised hopes that new antiobesity agents are on the horizon.

"I think it will now be approved, but probably with a label that restricts use and advises patients to discontinue treatment early if they aren't losing weight", says Arne Astrup, anobesity expert at the University of Copenhagen, who has acted as a consultant for drug developers including Vivus.

Vivus's Qnexa is a combination of the appetite suppressant phentermine and the antiepileptic topiramate. In clinical trials it induced average placebo-adjusted weight-loss of up to 9·3% of bodyweight, leading to a first filing with the FDA in 2009. At a panel meeting held at the time, experts voted 10-6 against the drug, noting that it increased pulse rate, carried a risk of cleft palette in babies conceived by mothers on the drug, could potentially cause memory problems and depression, and induced a teratogenicity signal in rats, leading the agency to reject the drug.The therapy was refiled last year, however, leading to a second advisory meeting in February, 2012.

Although many of the same key concerns remain-including lingering uncertainty over Qnexa's cardiovascular profile and birth defects-Vivus presented some new data that shed new light on the risks. The company also proposed a strategy to minimise adverse events by educating patients and physicians, limiting drug dispensing to specified mail-order pharmacies, and recommending monthly pregnancy tests. "This risk mitigation strategy probably is what was most important in terms of swaying the vote", says Abraham Thomas, endocrinologist at Henry Ford Hospital, Detroit, MI, USA, and chairman of the advisory panel.

Vivus also said it is possible to identify non-responders early on, which could further minimise risks. And it plans to run an 11 000 patient trial to resolve the heart safety uncertainty issues. Panellists agreed that such a trial will be necessary, and most felt that given thedrug's clear efficacy signal it could be started after approval.

Although the final positive tally of the vote suggests that the combination therapy should now be a shoe in for approval, the numbers belie the complexity of the debate. "I was surprised that the vote was so overwhelmingly positive", said Thomas. The final decision, consequently, remains far from certain. The agency rejected another antiobesity agent, Orexigen's Contrave, in 2011, despite a positive advisory panel vote.

Because just over a third of the US adult population is considered to be obese, and because an approved drug could be misused, regulators have historically held antiobesity agents to particularly high standards. Even the few products that have run the gauntlet have struggled to gain a foothold. GlaxoSmithKline and Roche's lipase inhibitor orlistat, as well as generic phentermine as a monotherapy, have had limited uptake due to their side-effects. Abbott's serotonin-norepinephrine reuptake inhibitor sibutramine was withdrawn by regulators in 2010 after it was linked to heart attacks and stroke. And Sanofi's cannabinoid receptor rimonabant was pulled off the market in the European Union in 2008 after it was linked to severe depression and suicidal thoughts (the drug never got the green light in the USA).

Some hope that an approval for Qnexa might represent a shift in the regulatory stance to antiobesity drugs, although each drug is of course reviewed on its own benefit:risk merits. Arena is pushing for approval of its serotonin receptor agonist lorcaserin. The drug, which has the lowest efficacy of the potential newcomers, was first filed in 2009 as well, but was rejected due to carcinogenicity and efficacy concerns. Lorcaserin was resubmitted with the FDA last year, and a decision is now expected by the end of June. Orexigen, meanwhile, will run a 10 000 patient study to address the cardiovascular safety of Contrave, a combination of opioid receptor antagonist naltrexone and antidepressant bupropion, potentially paving the way for a 2014 approval. Other upcoming events may also help broadly define the future for antiobesity agents. At the end of March, the FDA will hold a 2-day public panel meeting with its independent advisers to discuss the cardiovascular safety requirements for weight-loss drugs, potentially defining the safety benchmarks for experimental agents. The agency is also due to report to the Senate Appropriations Committee on the steps it is taking to support the development of antiobesitydrugs by March 30, reflecting the growing governmental pressure to address the obesity endemic.