Trilipix CV Outcomes Study To Focus On Patients With High Triglycerides, Low HDL-Cholesterol
This article was originally published in The Pink Sheet Daily
Executive Summary
FDA follows its advisory committee’s recommendation and requires a post-marketing study of Abbott’s fibrate to determine whether combination use with a statin provides a cardiovascular benefit over statin monotherapy in high-risk patients.
FDA’s requirement for a new cardiovascular outcomes study of Abbott Laboratories Inc.’s Trilipix (fenofibric acid) provides an opportunity to confirm benefit in one patient subgroup in the ACCORD-Lipid trial that showed positive results.
Abbott will conduct a randomized, double-blind, placebo-controlled trial evaluating the effect of Trilipix on the incidence of major CV events in high-risk men and women. These patients must have reached their goal for LDL-cholesterol on statin therapy but still have residually high triglycerides and low HDL-cholesterol levels.
The National Institutes of Health-funded ACCORD trial suggested that patients with high triglycerides and low HDL-C may experience a CV benefit with combination use of Trilipix and simvastatin compared to simvastatin monotherapy.
The agency notified Abbott in July that it was exercising its authority under the FDA Amendment Act’s drug safety provisions to require the new post-market clinical trial.
Plans for the study are referenced in a Sept. 30 sNDA approval letter, which also included revisions to the Trilipix label reflecting the ACCORD results. FDA announced the labeling changes in a drug safety communication issued on Nov. 9.
ACCORD Leaves Questions On Combo’s Use In Subgroups
Trilipix is approved for combination use with a statin to reduce triglycerides and increase HDL-C in patients with mixed dyslipidemia and coronary heart disease or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-C goal.
The ACCORD-Lipid (Action to Control Cardiovascular Risk In Diabetes-Lipid) study evaluated whether adding Trilipix to simvastatin therapy in patients with Type 2 diabetes reduced the rate of CV events in high-risk patients compared to simvastatin alone. The results, announced in March 2010, showed no significant difference in CV outcomes (Also see "Abbott's Fibrate Franchise Will Likely Remain Limited To High-Risk Patients After ACCORD" - Pink Sheet, 14 Mar, 2010.).
Compared to simvastatin alone, the combination was associated with an 8% reduced risk of a composite endpoint of CV events, but this finding did not reach the level of statistical significance. A gender subgroup analysis suggested an increased risk of major CV events in women compared to men treated with the fibrate/statin combination versus statin monotherapy.
FDA convened its Endocrinologic and Metabolic Drugs Advisory Committee in May 2011 to discuss the ACCORD-Lipid data and implications for Trilipix’s indication for combination use with a statin (Also see "Trilipix Use In Diabetics Might Be Restricted After FDA Panel Review Of ACCORD Data" - Pink Sheet, 25 Apr, 2011.).
At the meeting, Abbott suggested Trilipix labeling could be revised to reflect that co-administration with a statin can help patients with high triglycerides and low HDL-C. A pre-specified subgroup analysis in ACCORD suggested benefit for these patients, with 12.4% in the combination therapy group experiencing a major adverse cardiovascular event compared with 17.3% on simvastatin monotherapy.
However, the panel unanimously concluded that ACCORD did not provide sufficient evidence to make a determination on Trilipix’s use with a statin in any subgroup. The committee said another CV outcomes study should be conducted in high-risk patients (Also see "Could ACCORD Results Mean Another Trial For Trilipix?" - Pink Sheet, 19 May, 2011.).
FDA followed the committee’s advice in requiring a new study.
However, whether the trial confirms a benefit in the targeted population (high triglycerides/low HDL-C) is a question that will not be answered quickly. According to FDA’s approval letter, the study is scheduled for completion in January 2020, with a final report due in January 2021.
If FDA is waiting on final results from this new trial before taking further action to restrict or eliminate Trilipix’s approval for combination use with a statin, Abbott’s as-yet-unnamed successor pharmaceutical company (under a recently announced plan to split the medical products firm into two publicly traded companies) will have at least another 10 years to market the indication. The drug has patent protection until 2025, according to FDA’s “Orange Book.”
FDAAA Safety-Related Labeling Change
At the advisory committee meeting, six of the 13 panelists favored revising the Trilipix labeling to incorporate the ACCORD data, four committee members voted to withdraw the indication for concomitant use with a statin and three favored no labeling changes (Also see "Trilipix Advisory Committee Call For Outcomes Trial Could Be Damaged By Niaspan Failure" - Pink Sheet, 30 May, 2011.).
The agency followed the views of the committee plurality and ordered a safety-related labeling change under FDAAA.
The label’s Warnings and Precautions section now includes a paragraph reflecting the overall results in ACCORD as well as the gender-based subgroup analysis. “The clinical significance of this subgroup finding is unclear,” it notes.