Heart of the Matter

To FDA: Wait for clinical outcomes data



The recent endorsements by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee of the new genetically manufactured, subcutaneously administered cholesterol-lowering agents alirocumab (Sanofi-Regeneron) and evolocumab (Pfizer) have sent a jolt through the world of cholesterol therapy. Proposed for the treatment of patients with high-risk cardiovascular disease and homozygous familial hypercholesterolemia (HoFH), the decisions suggest that the committee has developed a severe case of scientific amnesia.

A case can be made for the approval for the very-high-risk and untreatable patients with HoFH, but the decision to treat millions of Americans based on the paucity of clinical data available would be disturbing, if not irresponsible.

It is clear that these proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide a powerful therapy for reducing LDL cholesterol, with a reported decrease of about 60% after only 12 or 52 weeks of treatment. Based on four small studies lasting 10-12 weeks and without any clinical outcome data, the committee recommended approving evolocumab for lifetime therapy without anything to support its clinical effectiveness or safety.

Dr. Robert J. Smith, who chaired the advisory committee meeting, faced with approving the drug or delaying a decision until a randomized clinical trial can be completed said, “I am unwilling to subject patients to the wait.” A publication of the American College of Cardiology suggested that these two monoclonal antibody drugs could replace generic statins in 70 million Americans at an estimated cost of $7,000-$12,000 a year. Talk about breaking the bank.

Only recently, we decided that the appropriate statin therapy for cholesterol control should use the dosing from the original clinical trials rather than chasing LDL levels to the lowest level possible. We now have a class of drugs that clearly can lower the cholesterol to a level never seen before, and we are about to discard that therapeutic advice.

We have experience in chasing blood levels with uncertain outcomes. Reducing blood sugar to a very low hemoglobin A1c level led to adverse clinical events and increased mortality in type 2 diabetes. Raising HDL with the cholesterol ester transfer protein (CETP) inhibitor torcetrapib in a study of 15,000 patients in an outcome trial carried out over a number of years led to increased blood pressure and mortality by 58%, which was associated with a 25% decrease in LDL cholesterol and a 72% increase in HDL, both effects presumed to be remarkably beneficial (N. Engl. J. Med. 2007;357:2109-22).

It is quite possible that these new agents can further decrease coronary vascular mortality. A healthy controversy has raged for some time in regard to the “LDL hypothesis,” compared with therapy based upon the clinical trial outcome. The recent IMPROVE-IT report (N. Engl. J. Med. 2015;372:2387-97) provides some data to support the LDL hypothesis. In that study, the addition of 10 mg of ezetimibe to 40 mg of simvastatin in 18,144 patients followed for up to 6 years resulted in a 2% decrease in mortality associated with a 15.8-mg decrease in serum LDL.

Would it not be prudent to have similar data with the new drug on the street? If it is as potent as it appears to be, a trial of much shorter duration might demonstrate its potency and safety before it is offered to 70 million Americans. The FDA has been reluctant to use surrogate endpoints for approving drugs, but its position has not always been consistent. For some time the FDA has, on occasion, approved drugs that can lower cholesterol with limited outcome data as it did with ezetimibe. However, the decision in regard to the PCSK9 inhibitors will have a much larger impact on care than an add-on drug like ezetimibe. Let’s hope that the FDA shows better judgment than its advisory committee.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

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