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

At week 24 in the CORALreef Lipids and CORALreef HeFH trials, LIPFENDRA significantly reduced LDL-C by a placebo-adjusted 56% and 59%, respectively

LIPFENDRA is a novel macrocyclic peptide that binds to PCSK9 and inhibits the interaction of PCSK9 with LDL receptors

Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced the U.S. Food and Drug Administration (FDA) has approved LIPFENDRA^® (enlicitide) tablets 20 mg as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). LIPFENDRA is a novel macrocyclic peptide and is the first FDA-approved oral PCSK9 inhibitor shown to lower LDL-C, also known as bad cholesterol.

"By harnessing the innovative science of PCSK9 inhibitors and novel macrocyclic peptide technology, LIPFENDRA was designed to significantly lower LDL-C in the form of a convenient once-daily pill," said Dr. Dean Y. Li, president, Merck Research Laboratories. "This is a pivotal moment as we bring the first U.S. FDA-approved oral PCSK9 inhibitor to adults with high LDL-C, offering patients an important new option. We’re proud of our work with regulators on this rigorous and efficient review process."

The approval is based on two Phase 3 trials from the CORALreef clinical program: CORALreef Lipids and CORALreef HeFH. In CORALreef Lipids, LIPFENDRA reduced LDL-C by 56% compared to placebo at week 24. A 60% decrease from baseline in LDL-C was observed with LIPFENDRA when biologically impossible baseline LDL-C values were removed according to revised data handling rules (post-hoc). In CORALreef HeFH, LIPFENDRA reduced LDL-C by 59% at week 24 compared to placebo. Results from these Phase 3 trials showed treatment with LIPFENDRA resulted in reductions across other atherogenic lipoproteins associated with atherosclerotic cardiovascular disease (ASCVD) risk including non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB). The safety profile of LIPFENDRA in CORALreef Lipids was similar to placebo. In CORALreef HeFH, the most common adverse reactions in adults with HeFH treated with LIPFENDRA that occurred at higher frequencies compared to placebo were diarrhea (LIPFENDRA 7%, placebo 2%) and dizziness (LIPFENDRA 9%, placebo 4%). In both trials, similar proportions of LIPFENDRA-treated patients and placebo-treated patients discontinued treatment because of an adverse reaction. For additional information on results from the CORALreef trials, see "Clinical data supporting FDA approval" below.

"High LDL-C is a major risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death globally," said Dr. Ann Marie Navar, a lead author of the CORALreef Lipids study and associate professor of medicine in the Division of Cardiology at UT Southwestern Medical Center. "In two Phase 3 trials, LIPFENDRA led to impressive reductions in LDL-C. Now, for the first time, patients have an oral PCSK9 inhibitor for LDL lowering."

An ongoing clinical trial is studying the effect of LIPFENDRA on cardiovascular morbidity and mortality. It is not yet known if LIPFENDRA can reduce the risk of cardiovascular morbidity and mortality.

"One of the greatest opportunities to help manage the risk of ASCVD lies in the timely identification and appropriate treatment of risk factors, such as LDL-C," said Katherine Wilemon, CEO of the Family Heart Foundation. "We are encouraged by the approval of a new oral PCSK9 inhibitor option for adults who need additional LDL-C lowering."

Clinical data supporting FDA approval

LIPFENDRA was approved based on results from two pivotal Phase 3 trials from the CORALreef clinical trial program:

• At week 24, in the CORALreef Lipids trial, treatment with LIPFENDRA resulted in:
  • A statistically significant and clinically meaningful reduction in LDL-C of 56% compared to placebo at week 24 (95% CI: -61, -51; p<0.001), with a reduction from baseline (primary endpoint) in LDL-C of 57% for LIPFENDRA compared to an increase of 3% for placebo;
  • When LDL-C values ≤0 were removed according to revised data handling rules (post-hoc), a statistically significant and clinically meaningful reduction in LDL-C of 60% for LIPFENDRA compared to an increase of 3% for placebo at week 24 (95% CI: -62, -57%).
  • Statistically significant reductions in secondary endpoints from baseline to week 24 compared to an increase of 3% for placebo:
    • 54% mean reduction in non-HDL-C for LIPFENDRA;
    • 50% mean reduction in ApoB for LIPFENDRA.

• At week 24, in the CORALreef HeFH trial, treatment with LIPFENDRA resulted in:
  • A statistically significant and clinically meaningful reduction in LDL-C of 59% compared to placebo (95% CI: -66, -53; p<0.001), with a reduction from baseline (primary endpoint) in LDL-C of 58% for LIPFENDRA compared to an increase of 3% for placebo;
  • Statistically significant reductions in secondary endpoints from baseline to week 24 compared to an increase of 2% for placebo:
    • 52% mean reduction in non-HDL-C for LIPFENDRA;
    • 48% mean reduction in ApoB for LIPFENDRA.

In CORALreef Lipids, the frequencies of adverse reactions in adults with hypercholesterolemia were similar between those treated with LIPFENDRA and those receiving placebo. Similar proportions of LIPFENDRA-treated patients and placebo-treated patients discontinued treatment because of an adverse reaction. In CORALreef HeFH, the most common adverse reactions in adults with HeFH treated with LIPFENDRA that occurred at higher frequencies compared to placebo were diarrhea (LIPFENDRA 7%, placebo 2%) and dizziness (LIPFENDRA 9%, placebo 4%). Similar proportions of LIPFENDRA-treated patients and placebo-treated patients discontinued treatment because of an adverse reaction. The safety profile observed in adults with HeFH in CORALreef HeFH was otherwise generally consistent with that observed in adults with hypercholesterolemia in CORALreef Lipids.

About CORALreef Lipids and HeFH

CORALreef Lipids (NCT05952856) was a Phase 3, multicenter, double-blind, randomized, placebo-controlled study in which 2,904 patients with hypercholesterolemia (including those with and without HeFH) and a history of a major ASCVD event or increased risk for development of a first major ASCVD event were randomized in a 2:1 ratio to receive LIPFENDRA 20 mg orally once daily (n=1,935) or placebo (n=969) for 52 weeks. Patients required additional LDL-C reduction despite stable lipid-lowering treatment with moderate- or high-intensity statins (unless statin intolerance was documented) with or without other lipid-modifying therapy. Patients taking PCSK9 inhibitors were excluded from the trial. The primary efficacy outcome measure was the mean percent change from baseline to week 24 in LDL-C.

CORALreef HeFH (NCT05952869) was a Phase 3, multicenter, double-blind, randomized, placebo-controlled study in which 303 patients with HeFH were randomized in a 2:1 ratio to receive LIPFENDRA 20 mg orally once daily (n=202) or placebo (n=101) for 52 weeks. Patients required additional LDL-C reduction despite stable lipid-lowering treatment with moderate- or high-intensity statins, with or without other lipid-modifying therapy. The diagnosis of HeFH was made by clinical criteria or genotyping. The primary efficacy outcome measure was the mean percent change from baseline to week 24 in LDL-C.

About CORALreef clinical trial program

The efficacy and safety profile of LIPFENDRA continues to be evaluated through the comprehensive CORALreef Clinical Trial program evaluating over 19,000 participants who have hypercholesterolemia. LIPFENDRA was FDA approved based on two pivotal Phase 3 studies: CORALreef Lipids (NCT05952856) and CORALreef HeFH (NCT05952869). LIPFENDRA is continuing to be evaluated in the large cardiovascular outcomes trial, CORALreef Outcomes (NCT06008756), which has completed enrollment with over 14,500 participants. Additional CORALreef clinical trials include CORALreef Extension (NCT06492291), CORALreef Pediatric (NCT07058077), and CORALreef Combination (NCT07216482).

About LIPFENDRA^® (enlicitide) tablets 20 mg

LIPFENDRA is an oral proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor FDA-approved as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). Cardiovascular outcomes trials have demonstrated that reducing LDL-C lowers the risk for major adverse cardiovascular events (MACE) in adults at increased risk, when treated with statins or monoclonal antibody PCSK9 inhibitors as an add-on to statin therapy. LIPFENDRA is the first oral PCSK9 inhibitor approved to reduce LDL-C and is a novel macrocyclic peptide that inhibits the binding of PCSK9 to LDL receptors.

Selected Safety Information

In the CORALreef Lipids trial the frequencies of adverse reactions were similar between adults treated with LIPFENDRA and those receiving placebo. Similar proportions of LIPFENDRA-treated patients and placebo-treated patients discontinued treatment because of an adverse reaction.

In the CORALreef HeFH trial the most common adverse reactions that occurred at higher frequencies compared to placebo were diarrhea (LIPFENDRA 7%, placebo 2%) and dizziness (LIPFENDRA 9%, placebo 4%). Similar proportions of LIPFENDRA-treated patients and placebo-treated patients discontinued treatment because of an adverse reaction. The safety profile was otherwise generally consistent with that observed in adults with hypercholesterolemia in the CORALreef Lipids trial.

Merck’s focus on cardiometabolic and respiratory diseases

Merck has a long history of developing treatments for cardiometabolic and respiratory diseases. Building on a legacy that began nearly 70 years ago with the introduction of our first cardiovascular therapy, we are committed to advancing research for patients impacted by cardiometabolic and respiratory diseases. Our focus spans a range of diseases, including atherosclerotic cardiovascular disease, heart failure, pulmonary hypertension and chronic obstructive pulmonary disease (COPD).

Advancements in the treatment of cardiometabolic and respiratory diseases can make a critical difference for patients and health systems around the world. At Merck, we strive for scientific excellence and innovation in all stages of research, from discovery through approval and life cycle management.

About Merck

At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.

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Please see Prescribing Information for LIPFENDRA (enlicitide) at https://www.merck.com/product/usa/pi_circulars/l/lipfendra/lipfendra_pi.pdf and Patient Information/Medication Guide for LIPFENDRA (enlicitide) at https://www.merck.com/product/usa/pi_circulars/l/lipfendra/lipfendra_ppi.pdf.

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