Oral PCSK9 inhibitor significantly lowers LDL-C

The experimental oral PCSK9 inhibitor MK-0616 demonstrated statistically significant and robust, dose-dependent reductions in LDL-cholesterol (LDL-C) in patients with hypercholesterolemia and was well tolerated in a phase 2b, randomised, international trial. All doses were statistically superior to placebo, and the results were consistent across subgroups.

Prof. Christie Ballantyne (Baylor College of Medicine, TX, USA) explained that injectable treatments targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have been shown to provide “excellent” reductions in LDL-C and the risk of atherosclerotic cardiovascular disease, but they have been poorly adopted due to access barriers and the need for multiple injections [1]. “An oral PCSK9 inhibitor may widen access and improve the attainment of guideline-recommended treatment goals.”

An oral PCSK9 inhibitor with the provisional name of MK-0616 was subjected to a phase 2b randomised controlled trial (NCT05261126) [1]. The straightforward primary objective was per cent change from baseline in LDL-C at week 8 in participants with hypercholesterolemia. A total of 381 adults were enrolled; 49% were women, and the median age was 62 years. They had a mean LDL-C of 119.5 mg/dL and 38.6% had clinical atherosclerotic cardiovascular disease; about 60% were taking a statin at study entry. Participants were randomised to placebo or one of the 4 doses of MK-0616 for 8 weeks, after which treatment was withdrawn to assess adverse events in the following 8 weeks.

All doses of MK-0616 demonstrated statistically superior and dose-dependent reductions in LDL-C versus placebo (P<0.001). Efficacy was nearly complete after 2 weeks, and a persistent effect over the 8-week treatment period was observed, as measured by the least squares mean percentage change in LDL-C. The Figure shows the primary endpoint results for the efficacy population.

Figure: LDL-C significant percent change from baseline versus placebo at week 8 for the efficacy population [1]



Apolipoprotein-B (ApoB) was also significantly lowered at week 8, with a mean difference versus placebo of 32.8% (6 mg group) to 51.8% (30 mg group). The reduction versus placebo in non-HDL-C was between 35.9% and 55.8%, in these dosage groups. The proportion of patients who attained LDL-C goals ranged from 80.5% to 90.8%, versus 9.3% in the placebo group.

MK-0616 was well tolerated; the proportion of participants with ≥1 adverse event was between 39.5% and 43.4% in the treatment arms and 44.0% in the placebo arm.

1. Ballantyne CM. Efficacy and safety of the oral PCSK9 inhibitor MK-0616: a phase 2b randomized controlled trial. Session 410-16, ACC Scientific Session 2023, 4–6 March, New Orleans, USA.

 

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Posted on 7 June, 202323 April, 2024