Merck & Co. has taken a significant step forward in its pursuit to introduce the first oral PCSK9 inhibitor to the market. The pharmaceutical company announced successful outcomes from two phase 3 clinical trials evaluating its candidate, enlicitide decanoate, in patients with high cholesterol.
The first study, known as the CORALreef HeFH trial, focused on patients with heterozygous familial hypercholesterolemia (HeFH) who either had atherosclerotic cardiovascular disease or were at risk for it and were already on statin therapy. According to Merck's June 9 press release, the trial achieved its primary endpoint by demonstrating a clinically meaningful reduction in low-density lipoprotein cholesterol (LDL-C) levels at Week 24 compared to placebo.
Merck also reported positive results from the CORALreef AddOn study, which involved patients with hypercholesterolemia. This trial met its key endpoint by showing a significant reduction in LDL-C at Week 8 when compared to approved non-statin cholesterol-lowering agents such as ezetimibe and bempedoic acid.
While detailed data from both trials have not been disclosed, Merck confirmed that there were “no clinically meaningful differences in incidences of adverse events” between the treatment and control groups. These trials are part of Merck's broader CORALreef development program, which encompasses approximately 17,000 patients and includes ongoing phase 3 trials CORALreef Lipids and CORALreef Outcomes.
Currently, the hypercholesterolemia market is largely dominated by injectable PCSK9 inhibitors, including Amgen's Repatha and the Sanofi-Regeneron collaboration on Praluent. Additionally, Novartis markets Leqvio, which uses small-interfering RNA technology to reduce PCSK9 production in the liver.
Enlicitide shares the mechanism of action with these monoclonal antibody-based PCSK9 inhibitors but offers a distinct advantage as an oral therapy. This route of administration could improve patient adherence and appeal compared to injectable options.
Merck's advancement places it ahead of rival AstraZeneca in the race to bring the first oral PCSK9 inhibitor to regulatory approval. AstraZeneca's candidate, AZD0780, demonstrated a 50% reduction in cholesterol in a phase 2 dyslipidemia study reported in March.
Dean Li, M.D., Ph.D., president of Merck Research Laboratories, expressed optimism about the program, stating, “We are thrilled to bring forward the first phase 3 results from our clinical development program evaluating enlicitide, which, if approved, would be the first marketed oral PCSK9 inhibitor in the U.S.”
Li further described enlicitide as “a novel macrocyclic peptide that has the potential to deliver antibody-like efficacy and specificity for the validated PCSK9 mechanism in the form of a daily oral pill,” adding that Merck is working with urgency to make this therapy available worldwide.
Citi analysts characterized the data as “encouraging” and anticipate potential approval by 2027. They noted, “We believe enlicitide could be a key player in the hyperlipidemia space, where an oral administration along with a positive efficacy and safety profile could be differentiating.”
