After a second FDA Advisory Committee meeting, Qnexa received a landslide 20-2 vote in favor of approval. Opinion seems to have turned in Qnexa's favor following reassurance that the proposed REMS will prevent the use of Qnexa in pregnant women and will serve to monitor the emergence of adverse effects. This vote does not guarantee approval; the final decision will come from the FDA in April 17, but the agency will be under pressure to approve Qnexa following such a positive result.
Vivus knows its way around an Ad Com meeting. Last time, in 2010 the Advisory Committee panel voted 10-6 against approval and a complete response letter followed from the FDA. Advisors and regulators concluded that Qnexa met weight loss efficacy standards but approval was declined due to two major uncertainties of Qnexa's safety. Firstly, topiramate has a known, although poorly defined birth defect risk. Secondly the agency wanted reassurance that a mean heart rate increase of 1.6bpm does not increase the risk of cardiovascular events. Vivus was also asked to submit data from the OB-305 (or SEQUEL) trial that was incomplete at the first NDA submission.
Since the 2010 rejection, Vivus has conducted the Fetal Outcome Retrospective Topiramate Exposure Study (FORTRESS) and performed a review of studies linking topiramate to potential birth defects. Vivus also performed a retrospective analysis of MACE events that occurred in its clinical trial program. FORTRESS was statistically limited by low events, and SEQUEL data were positive but compromised by a selection bias. There was never any hope of providing reassurance of CV event risk without a randomized, outcomes-driven trial. Where Vivus has really managed to win the panel over is with its risk evaluation and mitigation strategy (REMS). Vivus's plans are to limit the supply of Qnexa to a network of pharmacies for which specific training will be required. Additionally, prescriptions will be accompanied with obligatory patient education materials and the drug will be subject to periodic REMS assessments. With a category X pregnancy label, obese female patients of child bearing potential will be free to use Qnexa without the requirement of monthly pregnancy tests. The REMS is subject to change prior to approval, but if the final version grants access to Qnexa to all women of child bearing potential, it will be a huge win for Vivus. Vivus appears to have persuaded the Advisory Committee that Phase IV trials and careful monitoring in a post approval setting is the most appropriate way forward for Qnexa. Pressure to approve new therapies for a growing unmet need and the risk associated with preventing the approval of Qnexa also seem to have factored heavily into the voting decisions.
Another hot topic of debate was regarding the most appropriate point to conduct a cardiovascular outcomes trial (CVOT): pre- or post-approval? Vivus has had already outlined an 11,000 patient, event-driven trial that would take over 4 years to be conducted after approval. Panel members expressed considerable concern that this timeframe is too long given the degree of patient exposure likely to occur in the period immediately after approval. Although the Advisory Committee reluctantly agreed that a post-approval trial would be sufficient, Qnexa is not home and dry yet. Another important Advisory Committee meeting: the role of cardiovascular assessment in the preapproval and post approval settings for obesity drugs, is scheduled for March 28 and 29. This meeting could define what the FDA considers acceptable cardiovascular risk in obesity, and how one goes about proving it. This would have implications on the endpoint design, enrollment and potentially the initiation timeframe of the CVOT Vivus is planning for Qnexa. Without a marketing partnership, Vivus and potential partners will be watching the March meeting closely to see what kind of investment will be required to keep obesity drugs on the market going forward.
The huge voting swing from 10 - 6 against in 2010, to 22 - 2 in favor in 2012, may just indicate the regulatory environment for obesity drugs is softening, especially given that the additional data generated between the two meetings was unimpressive. When justifying their voting, most panel members expressed how difficult the decision was. Whilst safety uncertainties surround Qnexa, the growing feeling that failing to introduce new obesity therapies carries its own risk to the U.S public, seemed to factor quite highly into the panel's decision. Our position on Qnexa remains unchanged; we forecast a U.S launch in 2012 and for it to approach blockbuster peak sales.