The U.S. Food and Drug Administration has granted approval to Merck for Lipfendra, marking the first time an oral PCSK9 inhibitor has received regulatory clearance. The drug is indicated for adults with hypercholesterolemia, including those with heterozygous familial hypercholesterolemia, to reduce low-density lipoprotein cholesterol levels as an adjunct to diet and exercise. The approved dosage consists of a 20 mg tablet taken once daily.
The approval relies on data from two Phase III clinical trials within the CORALreef program. The CORALreef Lipids study involved 2,904 patients with hypercholesterolemia and a history of or elevated risk for major cardiovascular events. At week 24, participants taking Lipfendra experienced a 56% reduction in LDL-C compared to those receiving a placebo.
A post-hoc reanalysis that excluded biologically impossible baseline LDL-C values showed a 60% decrease in LDL-C versus a 3% increase in the placebo group. Secondary endpoints in this trial also demonstrated reductions of 54% in non-HDL-C and 50% in apolipoprotein B.
The second trial, CORALreef HeFH, enrolled 303 patients with heterozygous familial hypercholesterolemia. Results showed a 59% decline in LDL-C compared to placebo at week 24. Non-HDL-C and ApoB levels fell by 52% and 48%, respectively.
The most frequent adverse reactions reported were diarrhea, occurring in 7% of patients versus 2% in the placebo group, and dizziness, reported in 9% versus 4%. Discontinuation rates were similar between the treatment and placebo arms in both studies.
Lipfendra contains the active ingredient enlicitide and is classified as a macrocyclic peptide. This formulation offers a once-daily oral alternative to existing injectable PCSK9 therapies, which have historically required subcutaneous administration. Ann Marie Navar, an associate professor of medicine at UT Southwestern Medical Center and lead author of the CORALreef Lipids study, noted that high LDL-C is a major risk factor for atherosclerotic cardiovascular disease.
