Merck's Oral PCSK9 Inhibitor MK-0616 Demonstrates Significant LDL-C Reduction in Phase IIb Trial

On March 6, MSD announced that MK-0616 significantly reduced low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia in a Phase IIb study, positioning it to potentially become the world’s first oral PCSK9 inhibitor.

MK-0616 is a macrocyclic peptide designed to increase the clearance of LDL-C in the blood by inhibiting PCSK9. If left untreated, high LDL-C can lead to a high risk of atherosclerotic cardiovascular disease (ASCVD) events, such as heart attacks and strokes.

MK-0616-008 (NCT05261126) is a randomized, double-blind, placebo-controlled Phase IIb trial designed to evaluate the efficacy and safety of MK-0616 taken daily compared to placebo in adult patients with hypercholesterolemia who have a broad risk of atherosclerotic cardiovascular disease (ASCVD). The study enrolled 381 patients, with the primary efficacy endpoint being the change in LDL-C from baseline at week 8.

Results showed that, compared with placebo, all doses of MK-0616 significantly reduced LDL-C in patients at week 8, and the results were generally consistent across pre-specified subgroups. After placebo adjustment, the reductions in LDL-C levels from baseline in the four dose groups were as follows (P<0.001 for all dose groups): 41.2% in the 6mg group, 55.7% in the 12mg group, 59.1% in the 18mg group, and 60.9% in the 30mg group.

A similar full efficacy was achieved by Week 2, with the effect persisting throughout the 8-week treatment period. By Week 8, secondary endpoints improved across all MK-0616 dose groups, with patients showing reductions in apolipoprotein B levels by 32.8% (6mg) to 51.8% (30mg), and non-high-density lipoprotein cholesterol (non-HDL-C) levels by 35.9% (6mg) to 55.8% (30mg). Additionally, 80.5% (6mg) to 90.8% (30mg) of patients reached the pre-specified LDL-C target, compared to only 9.3% in the placebo group.

MK-0616 was well-tolerated, with discontinuation rates or adverse events similar across treatment groups at week 16, and no serious adverse events related to MK-0616 treatment were observed.

"These data bolster our confidence that MK-0616 could become the first oral PCSK9 inhibitor, with the potential to transform the treatment paradigm for patients with hypercholesterolemia, enabling more patients to reach their LDL-C treatment goals," said Dr. Joerg Koglin, Vice President of Global Clinical Development at Merck Sharp & Dohme AG. "We look forward to advancing this program into Phase III development in the second half of this year."

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