FDA has concluded that a long-term cardiovascular outcome study is necessary to determine the CV safety of Vivus Inc.’s weight-loss drug Qnexa (phentermine/topiramate) – and the agency is asking the Endocrinologic and Metabolic Drugs Advisory Committee Feb. 22 for input on whether the study should be conducted pre- or post-approval.

Studies of the drug to date have involved mostly overweight and obese patients with low-to-moderate baseline cardiovascular risk, the agency explains in briefing documents for the meeting. As a result, the agency concludes, “it is unknown what the clinical significance of Phen/TPM’s cardiovascular effects and metabolic effects will be in a higher risk cardiovascular population with chronic treatment.”

Because of that, the agency concludes that “only a long-term, cardiovascular outcome trial can define the effect of Phen/TPM treatment on risk for major adverse cardiovascular events in an obese at-risk population.”

When such a trial should be conducted is a discussion question for the panel.

Uncertainty about the CV safety of Qnexa contributed to a 10-6 vote against approval of the drug when it last went before the advisory committee in 2010 Also see "Qnexa May Get Staged Launch After No Vote From Advisory Panel" - Pink Sheet, 19 July, 2010..

Twelve of the 16 voting members from that panel will consider Qnexa this time around as well, according to the draft roster for the meeting. Six of the returnees voted in favor of approval in 2010 and six voted no. They will be joined by 10 new voting members.

Contrave CV Study Could Be A Clue

Even if the panel indicates that a post-approval CV study would be acceptable, that does not guarantee FDA will go along.

The agency directed Orexigen Therapeutics Inc. to study CV risk in Contrave, a combination of naltrexone and bupropion, in a pre-approval trial although an advisory panel voted 13-7 in favor of approving the drug; the committee voted 11-8, with one abstention, that a post-market CV trial would be acceptable Also see "Panel Continues To Push For Obesity CV Guidance As It Backs Contrave Approval" - Pink Sheet, 13 December, 2010..

After first announcing it would discontinue development of Contrave, Orexigen reached an agreement with the agency to move forward with an outcomes trial, under a special protocol assessment Also see "Orexigen Agreement On Contrave CV Trial Hints At FDA’s Thinking On Obesity" - Pink Sheet, 26 September, 2011..

The study, as outlined by Orexigen, provides a glimpse into FDA thinking on what it currently is willing to accept in terms of CV safety in weight-loss drugs. The Contrave trial is to enroll 10,000 patients overall, with an estimated background rate of 1% to 1.5% annual risk of major cardiovascular events. An interim analysis can be conducted when 87 major adverse CV events occur and serve as the basis for re-filing the Contrave NDA. The company expects that to come within two years and after an enrollment of 7,000.

As for the acceptable risk threshold, the agreement on the Contrave trial is that the upper bound of the 95% confidence interval should exclude those with a risk of 2.0 at the interim and 1.4 at the final analysis. Any patient who does not achieve a pre-defined weight-loss goal after 16 weeks of treatment will discontinue Contrave therapy Also see "With SPA Finalized, Orexigen To Begin CV Outcomes Study For Contrave In Second Quarter" - Pink Sheet, 6 February, 2012..

Guidance for diabetes drugs calls on sponsors to exclude an 80% or higher increased risk of CV events preapproval. Post-approval CV outcomes trials may be necessary if the risk ratio from a meta-analysis of Phase II and Phase III studies is between 1.3 and 1.8, but may not be required if the risk ratio is below 1.3.

Some members of the panel that reviewed Abbott Laboratories Inc.’s Meridia (sibutramine) in 2010 suggested that sponsors be required to rule out an unacceptable level of CV risk for investigational weight-loss drugs similar to that for the diabetes treatments Also see "FDA Pressed At Meridia Committee Review To Finalize Obesity Drug Guidance" - Pink Sheet, 20 September, 2010..

Advisory committee members pushed for obesity CV guidance throughout their 2010 reviews of four weight-loss drugs, which also included Arena Pharmaceuticals Inc.’s Lorqess (lorcaserin).

A March 28-29 advisory committee on CV risk in obesity drugs will give panel members an opportunity to weigh in on an acceptable risk and should give an indication of whether FDA leans toward the risk level set out in the Contrave trial protocol or in the diabetes guidance Also see "Advisory Committee Set To Review Cardiovascular Risk Assessment For Obesity Drugs" - Pink Sheet, 7 February, 2012..

One of the factors that prompted Orexigen to proceed with its study was FDA’s agreement that any changes in its expectations with regard to CV safety for weight-loss drugs would not affect how the agency will assess results from the Contrave study.

REMS For Teratogenicity Up For Debate

The potential teratogenicity of the topiramate component of Contrave was another factor in the “complete response” letter for the drug, but it seems more resolved than the cardiovascular safety issue. The company initially resubmitted for an indication excluding women of child-bearing potential, but FDA said a contraindication against women who are pregnant is sufficient Also see "Regulatory Update For Qnexa Could Signal A Change In The Obesity Landscape" - Pink Sheet, 10 January, 2012..

Teratogenicity will be discussed at the committee review. The briefing materials note that preliminary results from three studies conducted since the previous advisory committee meeting “were consistent in demonstrating a lack of association between topiramate exposure and risk of major congenital malformations.”

However, the agency points out that “depending on the analysis, topiramate monotherapy exposure in pregnancy is likely to be associated with a two to five-fold increased prevalence of oral clefts.”

FDA is asking the committee to consider the risk of oral clefts in babies born to women taking topiramate and a proposed Qnexa Risk Evaluation and Mitigation Strategy.

FDA has proposed and the company has agreed to a REMS that includes certification of pharmacies that dispense the drug and voluntary training of health care providers to support their risk/benefit discussions with women of child-bearing potential.

Certified pharmacies would be required to remind women of child-bearing potential to use contraception and to test for pregnancy. The drug could be shipped directly to the patients or to a nearby pharmacy for pick-up.

FDA’s Division of Risk Management suggested that restricted distribution of Qnexa with mandatory pregnancy testing would have limited impact because the same restrictions are not required when topiramate is used for seizures or migraine prophylaxis. Doctors also could bypass the REMS by prescribing the topiramate and phentermine individually, the division notes.

The impact on other topiramate prescriptions was a factor for the agency. To impose the same restrictions on topiramate used for epilepsy and migraine would impose an undue burden for patients with those conditions, the division said.

FDA Says Qnexa Needs CV Outcome Trial, Asks Cmte. To Consider Pre- Or Post-Approval Timeframe

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