The Food and Drug Administration and Orexigen Therapeutics are in the early stages of discussing a cardiovascular risk study for the firm’s obesity drug Contrave, and it could be up to an FDA advisory committee as to whether that trial is conducted before approval or as a postmarketing requirement.
Only a "dedicated study in an appropriate population of overweight and/obese individuals" can provide the rigorous assessment needed to determine the risk profile of the naltrexone/bupropion combination, the FDA said in briefing documents for a Dec. 7 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.
One of the questions for the committee discussion is whether the study needs to be conducted before approval is granted.
The agency is concerned that during clinical trials, the combination of naltrexone and bupropion failed to provide the improved blood pressure and pulse levels typically associated with weight loss. In addition, FDA briefing documents note there were too few major adverse cardiac events to make reliable inferences about the drug’s effect on CV risk.
Cardiovascular risk has been a recurring issue for obesity drugs, most recently prompting the market withdrawal of Abbott’s Meridia (sibutramine) after the FDA decided there was no benefit to offset even a low attributable risk for CV events.
The agency cited the potential for heart-rate elevation to lead to CV risk in its "complete response" letter for Vivus’ pending obesity agent Qnexa, but did not request new studies.
How to study CV risk and judge the results has been a source of consternation for sponsors and advisory panels alike, as the FDA continues to revise draft guidance for developing weight-loss drugs.
During a September advisory committee on Meridia, several members pushed for the agency to create a requirement for CV risk assessment and set a limit on the amount of risk that is allowed for obesity drugs, as is the case with diabetes therapies.
Dr. Eric Colman, deputy director of the Division of Metabolism and Endocrinology Products, said during the advisory committee’s July 16 review of Vivus’ Qnexa that the agency was still considering how to handle the issue.
In the case of Contrave, FDA briefing documents note that patients receiving the dose proposed for approval – 32 mg naltrexone/360 mg bupropion – had small, but statistically significant, mean increases in systolic and diastolic blood pressure and pulse rate relative to placebo. Bupropion is an inhibitor of neuronal reuptake of norepinephrine and dopamine and has the capacity to increase blood pressure and pulse. Placebo responders had the most favorable changes overall in blood pressure and pulse, the agency said.
FDA Cautious on Suicidality
While CV risk will be the center of attention, the FDA also is seeking committee members’ input on whether there has been an adequate assessment and characterization of Contrave’s potential to prompt suicide and psychiatric-related adverse events, cause seizures, and increase serum creatinine.
There were no reports of completed or attempted suicide in the Contrave phase III trials, but all bupropion products carry a boxed warning for serious neuropsychiatric events, including suicidal ideation, suicide attempt, and completed suicide, when the drug is taken for smoking cessation.
Neuropsychiatric events have been an issue for obesity drugs in the past. Sanofi withdrew a new drug application for rimonabant in 2007 after an advisory community unanimously recommended against approval because of concerns about suicide risk.
The next year, the company took the drug off the European market following a report from the European Medicines Agency committee that postmarketing experience and clinical trials found psychiatric disorders to be more common than anticipated from earlier trials.
Seizure risk is also a known issue with bupropion. Two patients in the Contrave arm of the pivotal trial experienced seizures, compared with none in the placebo group. But bupropion labeling carries a contraindication for people with a history of seizures, and that was an exclusion criterion in the clinical trials.
Along with the possible safety issues, Contrave offers only mixed efficacy results. Statistically significant weight loss occurred in obese patients in four phase III trials, but the results failed to meet one of two criteria in the FDA’s draft obesity drug guidance – that there is at least 5% difference in mean weight loss between the active product and placebo-treated patients, at 1 year, with a difference that is statistically significant.
The drug did achieve the second criterion – that the greater proportion of patients in the active treatment group who lose at least 5% of baseline weight compared with the placebo group is at least 35%, is approximately double the proportion in the placebo group, and the difference between the two is statistically significant.