The Food and Drug Administration is asking its Endocrinologic and Metabolic Drugs Advisory Committee whether bolstered label warnings for Abbott’s Meridia about the need to monitor patients’ blood pressure, pulse, and weight can save the obesity agent from market withdrawal.
During a Sept. 15 meeting on Meridia’s cardiovascular safety and the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), the FDA will ask the panel to vote on one of four regulatory options, according to briefing documents released on Sept. 13. The options are:
• continued marketing with no label changes;
• continued marketing with addition of a boxed warning on the increased risk for major adverse cardiac events and the need to closely monitor patients’ blood pressure, pulse, and body weight;
• continued marketing, boxed warning, and restricted distribution, such as through specially trained physicians; or
• market withdrawal.
First Up: Assessing the Level of Risk
Ahead of the question on regulatory options, however, the FDA will ask the committee to comment on the design and results of SCOUT and whether, as Abbott argues, the CV risks seen in that study can be mitigated with additional warnings on monitoring and discontinuation of therapy based on blood pressure, pulse, and weight-loss parameters.
The committee’s discussion of SCOUT is expected to focus on the meaningfulness of the study’s findings given that it enrolled a high CV risk population – which is largely contraindicated under the current Meridia label – and treated patients for an extended period of time regardless of weight loss.
SCOUT is believed to be the first clinical trial intended to document the impact of modest weight loss on CV events and mortality.
The FDA has been working to finalize a 2007 draft guidance on obesity drug development, and it remains to be seen whether the agency will require sponsors to exclude a threshold level of CV risk, as is now mandated for diabetes agents.
In July, the Endocrine and Metabolic Drugs Advisory Committee opposed approval of the Vivus obesity drug Qnexa (phentermine/topiramate), citing the desire for more information about its CV risks and a proposed risk management strategy aimed at avoiding use during pregnancy.
After the Meridia meeting, the advisory committee will have two more opportunities this year to opine on the CV risk profile and risk management strategies for obesity drugs. A panel review for Arena’s lorcaserin is set for Sept. 16, the day after the Meridia meeting, while a review of Orexigen’s Contrave (bupropion/naltrexone) is scheduled for Dec. 9.
Study Population Was High-Risk
Conducted at the request of the European Medicines Agency, SCOUT was a randomized, double-blind, placebo-controlled study of approximately 10,000 overweight or obese individuals at risk for CV events. The primary efficacy endpoint was major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, CV death, and resuscitated cardiac arrest.
In the primary efficacy analysis, 11.4% of sibutramine subjects and 10% of placebo subjects experienced a MACE, resulting in a significant 16% increased risk with Abbott’s drug. These results were driven by a 28% increased risk of non-fatal myocardial infarction and a 36% increased risk of non-fatal stroke with sibutramine.
Release of the preliminary SCOUT data in November 2009 prompted the FDA to issue an “early communication” about an ongoing safety review. This was followed by a petition from Public Citizen’s Health Research Group, renewing its initial request, denied by the FDA in 2005, to ban Meridia for safety reasons. The FDA has not yet acted on the second petition.
In January, Abbott announced it was withdrawing sibutramine in Europe at the request of regulators there. The FDA chose another path, however, requesting that Abbott strengthen labeling to contraindicate use in patients with a history of CV disease, including heart attack, stroke, heart arrhythmias, and uncontrolled hypertension. Labeling previously included warnings against use in patients with CV disease.
A “changes being effected” supplement reflecting the new contraindications was approved by FDA in August; at that time, the agency also signed off on the addition of a Risk Evaluation and Mitigation Strategy that included a medication guide.
Assessing Risk by Subgroup
There were three CV risk subgroups in SCOUT: patients with type 2 diabetes; a history of CV disease; or a history of CV disease and diabetes.
In its January announcement, the FDA said the SCOUT data suggested the increased risk was seen only in patients with a history of CV disease. Abbott also argues this point in its briefing documents for the advisory committee meeting, asserting there was no increased risk for a primary outcome event in the diabetes-only group without a history of known CV disease. This finding is important to Abbott’s position that the SCOUT results show no increased CV risk when used according to the U.S. label and when patients are managed according to standard clinical practice.