RAHWAY, NEW JERSEY — The U.S. Food and Drug Administration approved Merck's oral PCSK9 inhibitor drug enlicitide, marketed as Lipfendra, on Thursday. The approval offers a new treatment option for adults with high cholesterol or heterozygous familial hypercholesterolemia who have not reached their LDL cholesterol goals with existing therapies.

Lipfendra is the first oral PCSK9 inhibitor approved for lowering cholesterol. It is approved as an adjunct to diet and exercise to reduce LDL cholesterol in adults with high cholesterol or heterozygous familial hypercholesterolemia. The once-daily 20-mg tablet must be taken on an empty stomach—after a 6- to 8-hour fast—and patients must avoid eating for 30 minutes after ingestion.

Lipfendra works by blocking the PCSK9 protein, which limits the body's ability to clear cholesterol from the blood. In contrast, statins work by blocking a liver enzyme involved in cholesterol production. The FDA approval was based on data from two phase III clinical trials: CORALreef Lipids and CORALreef HeFH, which together included 3,207 participants.

In the CORALreef Lipids trial, Lipfendra reduced LDL cholesterol by 56% compared to placebo at week 24. In the CORALreef HeFH trial, the reduction was 59% at the same time point.

Clinical trials showed Lipfendra can lower LDL cholesterol levels by up to 60%. In one study of approximately 3,000 patients, those taking Lipfendra saw LDL cholesterol levels drop more than 55% after six months. In a second study, patients averaged a 59% reduction in LDL cholesterol compared to those receiving a placebo. Some participants in the trials were able to reduce their LDL levels to below 50 mg/dL, a target aligned with current treatment guidelines for very high-risk patients.

Merck stated that Lipfendra will be available within weeks. The list price is $10.50 per day, or approximately $315 for a 30-day supply. Merck expects out-of-pocket costs for Lipfendra to be lower for many patients depending on insurance coverage.

By comparison, injectable PCSK9 inhibitors currently cost between $500 and $600 per month. Amgen produces an injectable PCSK9 inhibitor called Repatha, and Regeneron and Sanofi jointly produce another called Praluent. The first PCSK9 inhibitor was approved in 2015.

Dr. Puja Banka, associate vice-president for global clinical development at Merck, emphasized the unmet need in cholesterol management. "Seventy per cent of patients are not getting to their LDL goal," she said. Banka also stated that the side effects of Lipfendra were like the placebo.

"Its side-effects... were like the placebo," she added. In the CORALreef Lipids trial, no excess safety events occurred with enlicitide compared to placebo. However, in the CORALreef HeFH trial, diarrhea and dizziness occurred more frequently with enlicitide than with placebo.

Dr. Ann Marie Navar, a cardiologist at UT Southwestern Medical Center, supported the significance of the approval. "Although we have a number of lipid-lowering therapies that effectively lower LDL cholesterol, the majority of patients, even our highest-risk patients with atherosclerotic cardiovascular disease, fail to reach LDL cholesterol goals," she said. Navar added, "But none come close to the degree of LDL cholesterol-lowering that we see with enlicitide." She also noted that while injectable PCSK9 inhibitors are among the most powerful agents available after statins, they remain "remarkably underutilized" due to practical barriers in clinical practice.

Cardiologist and professor Erin Michos of Johns Hopkins School of Medicine described the approval as transformative for patient care. "This is a game changer. I have a number of patients who are anxiously waiting for the oral one. They didn’t want to go on an injection. I have to give them a call and say it’s out now," Michos said.

Her remarks highlight a key advantage of an oral formulation over current injectable alternatives. Heart disease is the leading cause of death in the U.S., and high LDL cholesterol levels contribute to atherosclerotic cardiovascular disease, or plaque buildup in arteries. About one in four adults in the U.S. have high LDL cholesterol, according to the American Heart Association. More than 40 million Americans take statins, which were the most prescribed drugs in the U.S. in 2023. Despite this, a large proportion of patients fail to reach recommended LDL targets.

The American College of Cardiology and the American Heart Association issued new guidelines in March 2024 recommending LDL cholesterol levels below 100 mg/dL for those at borderline or intermediate risk, below 70 mg/dL for those at high risk, and below 55 mg/dL for individuals with atherosclerotic cardiovascular disease at very high risk. An ongoing clinical trial is studying the effect of Lipfendra on cardiovascular morbidity and mortality. The CORALreef AddOn phase III trial previously showed enlicitide’s cholesterol-lowering efficacy compared with ezetimibe, bempedoic acid, or both. Following the approval announcement, Merck shares rose 4% in morning trading.