RAHWAY, N.J., July 16, 2026
Merck has achieved a significant milestone in cardiovascular medicine with the U.S. Food and Drug Administration (FDA) approval of LIPFENDRA® (enlicitide) 20 mg, the first and only once-daily oral PCSK9 inhibitor approved to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including patients with heterozygous familial hypercholesterolemia (HeFH). The approval introduces a first-in-class oral treatment option that combines the proven efficacy of PCSK9 inhibition with the convenience of a once-daily tablet, offering an important alternative to injectable therapies. Developed as a novel macrocyclic peptide, LIPFENDRA works by blocking the interaction between PCSK9 and LDL receptors, enhancing the body’s ability to remove harmful cholesterol from the bloodstream. The approval was supported by strong Phase 3 clinical evidence demonstrating substantial LDL-C reductions and reinforces Merck’s commitment to advancing innovative therapies for cardiovascular disease.
Phase 3 Clinical Trials Demonstrate Significant LDL-C Reduction
The FDA approval is based on positive results from the pivotal CORALreef Lipids and CORALreef HeFH Phase 3 clinical trials, which evaluated the efficacy and safety of LIPFENDRA in adults requiring additional LDL-C lowering despite standard lipid-lowering therapy. At 24 weeks, patients treated with LIPFENDRA achieved placebo-adjusted LDL-C reductions of 56% in the CORALreef Lipids study and 59% in the CORALreef HeFH trial, representing clinically meaningful improvements for patients at elevated cardiovascular risk. The treatment also significantly reduced additional atherogenic biomarkers, including non-HDL cholesterol and Apolipoprotein B (ApoB), both closely associated with atherosclerotic cardiovascular disease (ASCVD). Clinical data showed that the safety profile was generally comparable to placebo, with diarrhea and dizziness reported as the most common adverse events among patients with familial hypercholesterolemia. These findings position LIPFENDRA as a promising new therapeutic option for long-term cholesterol management.
First Oral PCSK9 Therapy Expands Treatment Options
Unlike currently available injectable PCSK9 inhibitors, LIPFENDRA offers the convenience of once-daily oral administration, potentially improving treatment adherence among patients requiring intensive LDL-C reduction. The investigational medicine is a macrocyclic peptide that specifically inhibits the binding of PCSK9 to LDL receptors, allowing the liver to remove more LDL cholesterol from circulation. High LDL-C remains one of the leading modifiable risk factors for heart attack, stroke, and other cardiovascular complications, making timely intervention critical for reducing long-term disease burden. Merck is also conducting the large-scale CORALreef Outcomes study involving more than 14,500 participants to determine whether LDL-C reductions achieved with LIPFENDRA translate into lower rates of cardiovascular morbidity and mortality. Additional ongoing studies continue to evaluate the therapy in pediatric patients, combination treatment strategies, and long-term extension programs, reflecting Merck’s commitment to expanding the clinical evidence supporting this first-in-class therapy.
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Merck Strengthens Leadership in Cardiometabolic Innovation
The approval of LIPFENDRA represents a major advancement in cardiometabolic medicine and strengthens Merck’s growing portfolio of innovative therapies targeting cardiovascular disease. With cardiovascular disease remaining the leading cause of death globally, the introduction of the first FDA-approved oral PCSK9 inhibitor addresses a significant unmet need by providing physicians and patients with an effective, convenient cholesterol-lowering option. The approval also reflects continued progress in precision drug design, with macrocyclic peptide technology enabling highly targeted inhibition of disease-driving biological pathways. As healthcare systems increasingly focus on preventing cardiovascular events through aggressive lipid management, LIPFENDRA has the potential to become an important addition to standard treatment strategies for adults with hypercholesterolemia. Supported by robust Phase 3 evidence and an extensive ongoing clinical development program, the therapy reinforces Merck’s position as a leader in developing innovative medicines that improve long-term cardiovascular health outcomes.
Source: Merck press release
