FDA clears Merck’s oral PCSK9 drug LIPFENDRA

The U.S. Food and Drug Administration has approved Merck’s (MRK) LIPFENDRA (enlicitide) 20 mg tablets as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol in adults with hypercholesterolemia. The indication includes patients with heterozygous familial hypercholesterolemia, a genetic form of high cholesterol. LIPFENDRA is taken as a once-daily oral treatment, expanding options for patients who need additional LDL-C lowering beyond lifestyle changes and existing therapies.

LIPFENDRA is the first FDA-approved oral PCSK9 inhibitor. PCSK9 inhibitors are a class of medicines used to lower LDL cholesterol, and until this approval they have been available in injectable forms. The new pill formulation introduces an alternative route of administration that may be relevant for patients and clinicians managing elevated cholesterol levels.

Regulatory approval was based on two Phase 3 trials in the CORALreef clinical program. In the CORALreef Lipids study, treatment with LIPFENDRA produced a statistically significant 56% reduction in LDL-C compared with placebo at week 24. From baseline to week 24, LDL-C fell by 57% in the LIPFENDRA group, while the placebo group recorded a 3% increase.

In the CORALreef HeFH trial, which enrolled adults with heterozygous familial hypercholesterolemia, LIPFENDRA reduced LDL-C by 59% versus placebo at week 24. Baseline to week 24 data showed a 58% reduction for LIPFENDRA compared with a 3% increase for placebo. Across the program, treatment also led to reductions in non-high-density lipoprotein cholesterol and apolipoprotein B, markers associated with atherogenic lipoproteins.

The safety profile of LIPFENDRA in the CORALreef Lipids trial was described as similar to placebo. In the CORALreef HeFH study, certain adverse reactions occurred more often with LIPFENDRA than with placebo. Diarrhea was reported in 7% of patients receiving LIPFENDRA compared with 2% on placebo, and dizziness occurred in 9% of LIPFENDRA-treated patients versus 4% on placebo.

These findings outline the main tolerability considerations observed in the HeFH population, while the overall Phase 3 data supported the benefit–risk profile underlying FDA approval. No additional safety figures were highlighted beyond these commonly reported events and the placebo-comparable experience in the broader lipid trial.

Beyond the lipid-lowering trials, Merck (MRK) has advanced the CORALreef Outcomes cardiovascular outcomes study to evaluate longer-term clinical effects. The company reported that this trial has completed enrollment with more than 14,500 participants. The outcomes study is designed to further characterize the impact of LIPFENDRA on cardiovascular measures in a large patient population.

With the completion of enrollment in CORALreef Outcomes and the FDA’s approval of LIPFENDRA, Merck has established a late-stage clinical platform around an oral PCSK9 inhibitor. The newly approved medicine now becomes available as a once-daily tablet option for adults requiring substantial LDL-C reduction, including those with heterozygous familial hypercholesterolemia.