FDA Approves Merck’s LIPFENDRA as First Oral PCSK9 Inhibitor

Merck announced that the U.S. Food and Drug Administration has approved LIPFENDRA® (enlicitide) 20 mg tablets as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH). The approval marks a significant milestone as LIPFENDRA becomes the first FDA-approved oral PCSK9 inhibitor for LDL-C reduction in the United States.

LIPFENDRA is a novel macrocyclic peptide that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9) and inhibits its interaction with LDL receptors, thereby lowering circulating LDL-C levels.

Commenting on the approval, Dr. Dean Y. Li, President of Merck Research Laboratories, said LIPFENDRA combines PCSK9 inhibition with macrocyclic peptide technology to deliver substantial LDL-C reductions in a convenient once-daily oral formulation.

Approval Supported by Phase 3 CORALreef Program

The FDA approval was supported by two pivotal Phase 3 trials: CORALreef Lipids (NCT05952856) and CORALreef HeFH (NCT05952869).

In CORALreef Lipids, a randomized, double-blind, placebo-controlled study involving 2,904 patients with hypercholesterolemia, LIPFENDRA achieved a 56% placebo-adjusted reduction in LDL-C at Week 24 (95% CI: −61 to −51; p<0.001). This corresponded to a 57% reduction from baseline compared with a 3% increase in the placebo group, while a post-hoc analysis excluding biologically impossible baseline LDL-C values showed a 60% reduction. Treatment also significantly reduced other atherogenic lipoproteins, including non-HDL cholesterol by 54% and apolipoprotein B (ApoB) by 50%.

In CORALreef HeFH, which enrolled 303 adults with heterozygous familial hypercholesterolemia, LIPFENDRA produced a 59% placebo-adjusted reduction in LDL-C at Week 24 (95% CI: −66 to −53; p<0.001), representing a 58% reduction from baseline compared with a 3% increase in the placebo group. Secondary endpoints showed significant reductions in non-HDL cholesterol (52%) and ApoB (48%).

Dr. Ann Marie Navar, lead author of the CORALreef Lipids study and Associate Professor of Medicine at UT Southwestern Medical Center, noted that elevated LDL-C is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) and highlighted the substantial LDL-C reductions achieved with LIPFENDRA across both pivotal Phase 3 trials.

Safety Findings

LIPFENDRA demonstrated a favorable safety profile across both studies. In CORALreef Lipids, the incidence of adverse reactions was comparable between the LIPFENDRA and placebo groups. In CORALreef HeFH, the most common adverse reactions occurring more frequently with LIPFENDRA than placebo were diarrhea (7% vs. 2%) and dizziness (9% vs. 4%). Similar proportions of patients in both treatment groups discontinued therapy because of adverse reactions.

About the CORALreef Studies

Both Phase 3 studies evaluated LIPFENDRA 20 mg once daily for 52 weeks in patients receiving stable background lipid-lowering therapy with moderate- or high-intensity statins, with or without additional lipid-modifying treatment. Patients receiving PCSK9 inhibitors were excluded. The primary endpoint in both trials was the percent change in LDL-C from baseline to Week 24.

Ongoing Development Program

LIPFENDRA continues to be evaluated through the CORALreef clinical program, which includes more than 19,000 participants with hypercholesterolemia. The ongoing CORALreef Outcomes trial (NCT06008756) has completed enrollment of more than 14,500 participants and is evaluating whether LIPFENDRA reduces cardiovascular morbidity and mortality. Additional studies include CORALreef Extension (NCT06492291), CORALreef Pediatric (NCT07058077), and CORALreef Combination (NCT07216482). Merck noted that it has not yet been established whether LIPFENDRA reduces cardiovascular morbidity and mortality.

About LIPFENDRA

LIPFENDRA (enlicitide) is an oral PCSK9 inhibitor approved as an adjunct to diet and exercise for lowering LDL-C in adults with hypercholesterolemia, including HeFH. It is the first FDA-approved oral PCSK9 inhibitor and uses a novel macrocyclic peptide mechanism that blocks PCSK9 binding to LDL receptors. Cardiovascular outcomes studies have previously shown that LDL-C reduction lowers the risk of major adverse cardiovascular events when achieved with statins or monoclonal antibody PCSK9 inhibitors.

Regulatory Path Forward

The approval of LIPFENDRA introduces the first oral PCSK9 inhibitor for adults requiring additional LDL-C lowering despite standard lipid-lowering therapy. While the Phase 3 CORALreef studies demonstrated robust reductions in LDL-C and other atherogenic lipoproteins, whether these benefits translate into reductions in cardiovascular morbidity and mortality remains under investigation in the ongoing CORALreef Outcomes trial.

What This Means for Patients

LIPFENDRA offers a new oral treatment option for adults with hypercholesterolemia, including HeFH, who need additional LDL-C lowering despite standard lipid-lowering therapy. As the first FDA-approved oral PCSK9 inhibitor, it provides an alternative to injectable PCSK9 inhibitors for eligible patients. However, whether LIPFENDRA reduces the risk of heart attack or stroke is still being studied in the ongoing CORALreef Outcomes trial.

References

Merck’s LIPFENDRA® (enlicitide) is the First and Only Once-Daily Oral PCSK9 Inhibitor Approved by the U.S. FDA to Reduce LDL-C in Adults with Hypercholesterolemia