An FDA advisory committee review could lead to a narrowed indication for Abbott's dyslipidemia drug Trilipix (fenofibric acid) given the absence of an overall cardiovascular benefit, and an increased risk of CV harm among females, in a study of type 2 diabetics.

The Endocrinologic and Metabolic Drugs Advisory Committee could recommend limits on use and warnings about concomitant therapy with statins among diabetics. The meeting also could revive debate about the approval of drugs for use in diabetics based on surrogate endpoints - in this case, lipid level improvements - absent CV outcomes data.

The committee will meet on May 19 to discuss findings from the Action To Control Cardiovascular Risk In Diabetes-Lipid (ACCORD Lipid) trial as they relate to Trilipix's efficacy and safety.

Trilipix, a follow-on to Abbott's TriCor (fenofibrate), was approved in December 2008 as the only fibrate indicated for combination use with a statin (Also see "Abbott Gets TriLipix Approval, Ensuring Lipid Lowering Franchise Beyond TriCor" - Pink Sheet, 15 December, 2008.). The approval gave Abbott an opportunity to shift fenofibrate users to the second-generation product ahead of generic competition for TriCor, which could begin as early as this year.

Trilipix is approved for combination use with a statin to reduce triglycerides and increase HDL-cholesterol in patients with mixed dyslipidemia and coronary heart disease or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-cholesterol goals. It is also approved as monotherapy for patients with severe hypertriglyceridemia, primary hyperlipidemia or mixed dyslipidemia.

Labeling states that the drug has not been shown to provide an incremental benefit on CV morbidity and mortality beyond that demonstrated for statin monotherapy. Furthermore, labeling notes that fenofibrate at a dose equivalent to 135 mg of Trilipix was not shown to reduce CHD morbidity and mortality in a large, randomized controlled trial of type 2 diabetic patients, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, published in 2005.

ACCORD Studied Tricor/Zocor Combination Use

The recent ACCORD data appear to support the findings in FIELD.

The National Institutes of Health-funded trial evaluated the occurrence of major CV events (nonfatal heart attack, nonfatal stroke and CV death) in type 2 diabetics receiving TriCor in combination with simvastatin (Merck & Co.' s Zocor and generics) compared with simvastatin alone. Patients were followed on average for 4.7 years.

The results, released in March 2010, showed no difference in CV outcomes between the two treatment groups (HR= 0.92, 95% CI: 0.79-1.08, p = 0.32). Study investigators concluded the results did not support routine use of fenofibrate/statin combination therapy to reduce CV disease risk in the majority of type 2 diabetics at high risk for CV events.

However, Abbott said the ACCORD results were unsurprising given that two-thirds of patients in the trial would not have qualified for fibrate treatment under current guidelines (Also see "Abbott's Fibrate Franchise Will Likely Remain Limited To High-Risk Patients After ACCORD" - Pink Sheet, 14 March, 2010.).

At the time the results were announced, FDA said it would review the primary data from ACCORD but made no new conclusions or recommendations about combination use of fenofibrate with statins." Part of FDA's review of the ACCORD trial will be to determine how the study's findings relate to the approved indication and labeling for Trilipix," the agency said.

CV Impact On Women Is A Concern

In the Federal Register notice announcing the meeting, FDA draws attention to several safety concerns with combination use. "In a pre-specified subgroup analysis from the ACCORD Lipid Trial, there was an increase in the proportion of female trial subjects treated with simvastatin plus placebo who experienced a major adverse cardiac event," the agency says. "The clinical significance of this finding is unclear."

The agency also highlights an additional and well-recognized safety concern - muscle toxicity - associated with the combination use of fenofibrate and statins.

Trilipix' labeling includes a warning about reports of myopathy and rhabdomyolysis in patients taking fenofibrate. This risk is increased with concomitant administration of statins, particularly in elderly patients and those with diabetes, renal failure or hypothyroidism, labeling states.

In its approval of Trilipix, FDA required Abbott to conduct a post-marketing observational study to estimate the incidence and risk factors for hospitalized rhabdomyolysis in patients treated with a fibrate in combination with a statin, versus statin or fibrate monotherapy. The study's final report was due in January 2010.

Abbott said it completed the required study and submitted the results to FDA. It stands to reason that the advisory committee will be asked to consider the observational study data.

Revisiting The Avandia Debate On Surrogate Endpoints?

While the advisory committee's deliberations could result in a narrowed indication for combination use of Trilipix with statins, it also could renew concerns about approving drugs for use in diabetics, a population at heightened risk for CV events, in the absence of CV outcomes data.

Debate over the use of surrogate endpoints reached a crescendo with Avandia (rosiglitazone). GlaxoSmithKline's thiazolidinedione was approved on the basis of hemoglobin A1C reduction, but post-marketing epidemiological data and meta-analyses have suggested an increased risk of CV events.

Concerns about Avandia's CV safety led to an FDA guidance requiring that sponsors of type 2 diabetes drugs in development exclude an 80% or higher excess CV risk before approval. For those products that meet this regulatory filing threshold but have not excluded an increased risk of 30% or more, a post-marketing CV outcomes trial will generally be required (Also see "FDA’s Diabetes Guidance On CV Risk Will Get First Test With Pending NDAs" - Pink Sheet, 22 December, 2008.).

-Sue Sutter (s.sutter@elsevier.com)

Trilipix Use In Diabetics Might Be Restricted After FDA Panel Review Of ACCORD Data

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