FDA appears to be testing weight loss agents against an easier-to-meet threshold for cardiovascular risk compared to diabetes drugs, based on Orexigen Therapeutics Inc.’s announcement of an agreement with the agency on a cardiovascular outcomes trial for its obesity agent Contrave (naltrexone/bupropion).

After the markets closed on Sept. 20, Orexigen announced that it has revived the Contrave development program after reaching an agreement with FDA on a cardiovascular risk trial design. While the company was not happy about conducting a pre-market study in the first place, it has settled on doing a less stringent study than the agency had originally proposed (Also see "Orexigen Resurrects Contrave With New Trial Agreement With FDA" - Pink Sheet, 20 September, 2011.).

“Of course, we would have preferred that such a trial … would be required as a post-marketing requirement, but we are pleased that a feasible path to approval has now been very clearly identified and that we have an opportunity to bring this important product to market,” CEO Michael Narachi said during a conference call to discuss the agreement.

Narachi added that he believes FDA’s decision to offer more lenient trial criteria for the drug was an amalgamation of political pressure, outspoken advocacy groups, and “inspiring input” from the academic and scientific community – which was disappointed with FDA’s decision to withhold approval on all three obesity agents reviewed last year.

The CV study requirements for Contrave are similar to those put in place for type 2 diabetes agents in 2008, although the safety bar for diabetes drugs has been set higher.

Prior to approval, diabetes drug developers must rule out an 80% or higher increased risk of major adverse cardiovascular events, meaning that the upper bound of the 95% confidence interval for the estimated risk ratio must be below 1.8. If the upper bound is between 1.3 and 1.8 and the overall risk-benefit analysis supports approval, a post-marketing study generally will be required to definitively show that the increased cardiovascular risk does not exceed 30%. A post-marketing study generally may not be required if the upper bound of the 95% confidence interval falls below 1.3.

For the Contrave trial – which will enroll patients that are obese or overweight with at least one co-morbidity, with an estimated background rate of 1% to 1.5% annual risk of CV events – the upper bound of the 95% confidence interval should exclude a hazard ratio of 2.0 and 1.4 at the interim and final analyses, respectively.

Orexigen Chief Medical Officer Preston Klaussen notes that patients who fit these criteria are more at risk for certain co-morbidities like diabetes and dyslipidemia than people in the general population, but they are not the highest risk patients or the sickest patients.

Klaussen believes the company will be able to enroll its trial faster than a typical diabetes CV safety trial because it will not have the restrictions of finding patients with elevated Hb1Ac levels. The company could not provide a specific time frame for enrollment because it still has modeling to do to determine exactly the types of patients that it will need to participate. Orexigen expects to announce further details regarding trial design after finalizing the criteria with FDA.

The Requirements

According to a letter sent by FDA, the study will be based on an intent-to-treat analysis, meaning it will take into account all the patients that start the trial, regardless of whether they complete treatment. Yet, patients will only continue to take the drug if they show signs of weight loss during the first few months of the trial.

“It’s important that at the end of the day we have results that are generalizable to the population that would receive treatment in the real world,” Narachi said in an interview.

The trial data will be assessed after 87 CV events have occurred in the entire population. The company believes that it will take about 10,000 patients and two years to reach that point, with a cost of about $10,000 to $12,000 per patient.

According to FDA recommendations, if fewer than twice as many heart attacks have occurred in the drug group than the placebo group, the company will be able to resubmit the Contrave NDA for approval – potentially in 2014.

A Changing Mindset?

The new testing recommendations were put in place for diabetes drugs after CV risks began to appear with GlaxoSmithKline Plc’s Avandia (rosiglitazone), spurring a wave of concern about the long-term effects of other diabetes products.

Similar concerns have been expressed about obesity drugs. During four advisory committee meetings held last year, outside experts expressed worries that cardiovascular problems could become a wider problem should any of the current slate of obesity drugs reach the mass market, where patients who were not included in the label may take the drug.

The controversy over obesity drug development prompted FDA to look more closely at the matter. The agency will convene another advisory panel in the first quarter of 2012 that focuses on the safety issues surrounding weight loss medications, particularly cardiovascular effects (Also see "Obesity Drugs Go Back To The Drawing Board; FDA To Hold Advisory Cmte On CV Risk" - Pink Sheet, 3 June, 2011.). Orexigen said that it has a written agreement with FDA that the current agreement on trial design will not be affected by the outcome of the panel.

“We believe this demonstration of collaboration by the FDA is not only a strong signal of progress for Orexigen and the obesity development landscape, but more broadly for the pharmaceutical and biotech industries, increasing confidence in the agency’s willingness and ability to work to a common goal of approving novel, effective therapies while maintaining a responsibility to safety,” wrote JMP Securities analyst Charles Duncan in a note to investors.

Further evidence that FDA is working toward a common goal was its recent compromise with another obesity drug maker.

In mid-September, Vivus Inc., announced plans to resubmit its obesity drug Qnexa (topiramate/phentermine) by the end of October, earlier than had previously been anticipated. Vivus has opted to narrow the patient population, no longer seeking to treat women of child-bearing age. By eliminating patients who could become pregnant, it sidesteps the concerns about teratogenicity raised in FDA's "complete response" letter rejecting initial approval (Also see "Vivus Will Cut Population In Qnexa Resubmission" - Pink Sheet, 15 September, 2011.).

Vivus will continue studies to rule out any issues with use during pregnancy and will re-file for the full patient population once that work is complete.

Now that Orexigen has a path forward for Contrave, the company plans to reopen discussions with partners. The company already has partnered the North American rights with Takeda, but may find additional funding by partnering the ex-North American rights.

Orexigen had $70 million in the bank at the end of the second quarter and has been “in conservation mode” since getting the action letter in January. Narachi said that Orexigen’s current cash stores should be able to fund a significant portion of the trial, but the company will need more cash to get to the interim analysis. He sees partnering as the most “shareholder-friendly” means of acquiring the necessary cash and indicated that the company is looking into expanding its agreement with Takeda to include worldwide rights. But Narachi said the company will investigate other forms of non-equity and equity financing if necessary.

“From our view, the probability that this will make it to market is high enough and the business case is strong enough that Contrave should go forward and development should be re-initiated,” said Narachi. “But the passion behind that is that we really believe in this product and that it can help a lot of people. We are really excited about that end goal and that’s what motivates us to get it across the finish line.”

By Lisa LaMotta

Orexigen Agreement On Contrave CV Trial Hints At FDA’s Thinking On Obesity

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