Oral PCSK9 Inhibitor, MK-0616, Demonstrates Significant LDL-C Reduction in Phase 2b Trial

The experimental oral PCSK9 inhibitor MK-0616 was associated with a significant reduction in LDL-C in patients with hypercholesterolemia and was well tolerated, according to a phase 2b, randomized international trial presented at ACC.23/WCC and simultaneously published in JACC.

Christie M. Ballantyne, MD, FACC, et al., randomized participants with clinical atherosclerotic cardiovascular disease (ASCVD) plus LDL-C ≥70 mg/dL and ≤160 mg/dL, intermediate or higher risk for ASCVD, and borderline risk for ASCVD to placebo or one of four doses of MK-0616 (6 mg, 12 mg, 18 mg or 30 mg).

A total of 381 adults were enrolled (49% women, median age 62 years). Their mean LDL-C was 119.5 mg/dL and 38.6% had clinical ASCVD, and about 60% were taking a statin at study entry, with about a quarter receiving high-intensity statin therapy.

Researchers assessed the change in LDL-C from baseline at eight weeks – the primary endpoint – when participants stopped the study drug and followed them for another eight weeks to assess adverse events.

The results showed a significant reduction in the primary outcome with each dose of MK-0616 (6 mg, 12 mg, 18 mg and 30 mg, respectively) compared with placebo, as measured by the least squares mean percent change in LDL-C: –41.2%, –55.7%, –59.1% and –60.9% (p<0.001 for all).

A similar proportion of adverse events was observed across the MK-0616 treatment groups (39.5% to 43.4%) vs. placebo (44.0%). Premature discontinuation of medication was low and comparable between each dose of MK-0616 and placebo.

The secondary endpoint of percent change from baseline in apolipoprotein B at Week 8 was –32.8%, –45.8%, –48.7% and 51.8% for each dose respectively vs. placebo; the percent change in non–HDL-C ranged from –35.9% to –55.8%. The proportion of patients who attained LDL-C goals ranged from 80.5% to 90.8%.

The investigators concluded that oral inhibition of PCSK9 with MK-0616 in participants with hypercholesterolemia led to clinically meaningful reductions in LDL-C superior to placebo. “This is a highly effective compound that was well tolerated,” said Ballantyne. “MK-0616 could offer another potential option. Between this and statins and the other therapies we have, we should be able to basically treat almost everybody in terms of LDL cholesterol.”

The study authors acknowledge that while these findings are promising, the number of patients and duration of treatment for this trial were limited, stating: “Larger studies of longer duration will be needed to appropriately assess the efficacy, durability, and safety of MK-0616 in various subgroups in the context of available treatments.”

Clinical Topics: Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Novel Agents

Keywords: ACC Annual Scientific Session, ACC23, Hypercholesterolemia, PCSK9 protein, human, Proprotein Convertase 9, Hyperlipidemias, Enzyme Inhibitors, Peptides, Secondary Prevention

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