Merck's Oral PCSK9 Inhibitor Shows Promise in Phase 3 Trials

Merck & Co. has taken a significant step forward in the race to develop the first oral PCSK9 inhibitor, announcing positive results from two phase 3 trials for its candidate, enlicitide decanoate. The studies, part of the company's CORALreef development program, demonstrated the drug's efficacy in reducing cholesterol levels in patients with high cholesterol, potentially offering a more convenient alternative to current injectable treatments.

Phase 3 Trial Results

The CORALreef HeFH trial, which focused on patients with heterozygous familial hypercholesterolemia at risk of atherosclerotic cardiovascular disease, met its primary endpoint. Enlicitide decanoate showed a clinically meaningful reduction in baseline levels of low-density lipoprotein cholesterol (LDL-C) at Week 24 compared to placebo in patients already being treated with statins.

Similarly, the CORALreef AddOn study, which evaluated patients with hypercholesterolemia, achieved its key endpoint. The trial demonstrated a reduction in LDL-C at Week 8 compared to approved non-statin cholesterol medicines ezetimibe and bempedoic acid.

Merck reported that both trials showed no clinically meaningful differences in the incidence of adverse events, suggesting a favorable safety profile for enlicitide decanoate.

Market Implications and Competition

The hypercholesterolemia market is currently dominated by injectable PCSK9 inhibitors, including Amgen's Repatha and Sanofi-Regeneron's Praluent. Novartis' Leqvio, which uses small-interfering RNA technology to decrease PCSK9 production in the liver, is also a key player in this space.

Enlicitide decanoate, if approved, would be the first oral PCSK9 inhibitor to reach the market, potentially offering a more convenient option for patients. The drug uses the same mechanism as approved monoclonal antibody injectable PCSK9 inhibitors but in an oral formulation.

Merck's progress keeps it ahead of competitor AstraZeneca, whose oral PCSK9 inhibitor candidate, AZD0780, showed promising results in a phase 2 dyslipidemia study earlier this year.

Future Outlook

Dean Li, M.D., Ph.D., president of Merck Research Laboratories, expressed enthusiasm about the results, 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 emphasized the potential of enlicitide as a novel macrocyclic peptide that could deliver antibody-like efficacy and specificity for the PCSK9 mechanism in a daily oral pill form.

The CORALreef development program, which includes these two successful trials, spans a total of 17,000 patients. Ongoing studies in the program include the CORALreef Lipids and CORALreef Outcomes phase 3 trials.

Citi analysts described the data as "encouraging" and anticipate potential approval for enlicitide in 2027. They believe the drug "could be a key player in the hyperlipidemia space, where an oral administration along with a positive efficacy and safety profile could be differentiating."

The news of these positive trial results led to a 2% increase in Merck's stock price in premarket trading on Monday morning, reflecting investor optimism about the potential of enlicitide decanoate in the competitive cholesterol management market.