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Panel Recommends Two Cholesterol-lowering Drugs for FDA Approval

Jun 19, 2015

The two new injectable drugs, alirocumab and evolocumub, have been recommended for FDA approval by the agency’s Endocrinologic and Metabolic Advisory Committee.

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The drugs are monoclonal antibodies that inhibit the proprotein convertase subtilisin kexin 9 gene (PCSK9). PCSK9 is involved in the metabolism of LDL in the liver. By blocking this gene, the monoclonal antibodies make LDL receptors more available in the liver; thereby increase the clearance of LDL from the bloodstream.

The discovery of these drugs was based on evidences that people with mutated PCSK9 gene have astonishingly low LDL and seemed to be protected from cardiovascular diseases with no other complications. This may indicate that it is safe to block this gene in patients with fully functioning PCSK9 gene. In addition, safety studies found no difference in side effects between the drugs and the placebo, but larger trials are needed to obtain more substantial data.

Despite a significant LDL reduction of PCSK9 inhibitors, many experts are still hesitant in the decision due to lack of definitive evidence that these drugs reduce heart attacks and deaths from large clinical trials. Furthermore, the cost of these drugs raise another concern. Given that these drugs are monoclonal antibodies produced from living cells, the estimated annual cost will be from $7,000-$12,000. Therefore, it is suggested that these drugs should only approved for groups of people with genetic condition such as heterozygous familial hypercholesterolemia, or people at very high risk for heart attack, or people with diabetes and cannot lower LDL level enough with statins, or people that cannot tolerate statin.

While many physicians are excited about the coming of PCSK9 inhibitors, some are still concerned about the clinical outcomes of these new drugs. A couple of promising drugs in the past improved surrogate end points but failed to prevent MI, stroke and cardiovascular deaths. Two studies (FOURIER and ODYSSEY) are still in the process of testing PCSK9 inhibitors against statin therapy for the reduction of the primary composite endpoint of cardiovascular death, MI, hospitalization for unstable angina, stroke, or coronary revascularization. Full results are expected to be available in 2017 and 2018. Until then, it is suggested that the FDA issues a limited approval of PCSK9 inhibitors to be used restrictively in certain group of patients.

Practice Pearls:

  • PCSK9 inhibitors are monoclonal antibodies drugs that reduce LDL by mimic the loss-of-function polymorphism known to protect people from cardiovascular disease.
  • It is suggested that PCSK9 inhibitors should only be approved for use in those with primary hypercholesterolemia, or people who cannot lower LDL level enough with statin, or statin intolerance
  • The FDA should warrant limited approval of PCSK9 so that it can be used in certain groups of patients while waiting for data from larger clinical studies.

Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1500-1509.