Merck's Oral PCSK9 Inhibitor Shows Promise in Cholesterol-Lowering Studies

Merck & Co.'s experimental oral PCSK9 inhibitor, enlicitide, has demonstrated significant efficacy in lowering cholesterol levels, potentially rivaling existing injectable treatments. The drug's performance in recent Phase 3 trials has sparked optimism among analysts and researchers about its potential to reshape the cholesterol management landscape.

Impressive Clinical Trial Results

In two pivotal Phase 3 trials presented at the American Heart Association's 2025 Scientific Sessions, enlicitide showed remarkable ability to reduce low-density lipoprotein cholesterol (LDL-C) levels. The CORALreef Lipids trial, which enrolled over 2,900 patients with or at risk of atherosclerotic cardiovascular disease, reported a 59.7% reduction in LDL-C compared to placebo after 24 weeks of treatment.

Similarly, the CORALreef HeFH study, focusing on patients with heterozygous familial hypercholesterolemia, demonstrated a 59.4% LDL-C reduction versus placebo at 24 weeks. These results are comparable to the efficacy seen with injectable PCSK9 inhibitors like Amgen's Repatha and Regeneron's Praluent.

Dr. Ann Marie Navar, a medical professor at UT Southwestern Medical Center and study investigator, highlighted the significance of these findings: "It's really hard to get patients to [LDL-C goals] without using injectable therapies now. It will be nice to get an oral therapy that's going to get us there."

Potential Advantages Over Injectables

Analysts from Leerink Partners suggest that enlicitide holds a "significant advantage" over injected biologics due to its oral administration, room-temperature storage, and potentially lower pricing. This could lead to increased uptake in primary care settings where injectable hesitation is high.

The drug's performance is particularly noteworthy given that 97% of patients in the CORALreef Lipids trial were already on background statin therapy. Enlicitide's ability to further lower LDL-C levels in this context underscores its potential as an additional tool in managing cardiovascular risk.

Challenges and Uncertainties

Despite the promising results, some challenges remain. Enlicitide's dosing instructions require it to be taken on an empty stomach after an eight-hour fast and 30 minutes before breakfast, which could affect real-world adherence. However, in clinical trials, patients reported a 97% adherence rate.

The drug's long-term cardiovascular outcomes are yet to be determined. Merck is currently conducting the CORALreef Outcomes study, involving over 14,700 patients, with primary completion projected for late 2029. This study will be crucial in establishing enlicitide's ability to reduce major adverse cardiovascular events, a benchmark set by injectable PCSK9 inhibitors.

As the pharmaceutical landscape evolves, enlicitide's development represents a significant step towards more convenient and potentially more accessible cholesterol management options. With Merck planning to share data from all three Phase 3 trials with regulatory authorities worldwide, the industry eagerly awaits the next steps in bringing this innovative treatment to market.