Novel oral PCSK9 inhibitor shows promising results for hypercholesterolaemia

MK-0616, an oral PCSK9 inhibitor in development, was efficacious in lowering LDL cholesterol in patients with hypercholesterolaemia treated with statins and showed a favourable safety profile across two phase 1 trials. An oral PCSK9 inhibitor could help to overcome treatment barriers, providing cardiovascular risk reductions for patients with hypercholesterolaemia in an earlier phase.

Dr Douglas Johns (Merck & Co., NJ, USA) mentioned that many patients with hypercholesterolaemia do not reach their LDL cholesterol treatment goals [1]. Although injectable PCSK9 inhibitors demonstrated LDL cholesterol reductions of 50–60%, these therapies are often administered as a last resort only. An oral PCSK9 inhibitor could remove the barriers associated with injectable treatments.

A first randomised, double-blind, placebo-controlled, in-human trial assessed the safety and tolerability of single doses of MK-0616 ranging from 10 mg to 300 mg in 60 male participants (aged 18–50 years). MK-0616 was generally safe and well tolerated in this population. No serious adverse events (AEs) were reported and only 1 treatment-related discontinuation was observed, a case of maculopapular rash. Drug-related AEs were mostly abdominal discomfort, diarrhoea, dyspepsia, and headache. Free PCSK9 was reduced by more than 80%, regardless of the administered dose of MK-0616. This effect lasted for approximately 24 hours. Free PCSK9 levels returned to baseline levels in 96 hours. In addition, the authors observed that a permeation enhancer (i.e. sodium caprate) improved the absorption of MK-0616 and noted a negative pre-dose food effect.

A second double-blind, placebo-controlled, phase 1 trial evaluated the LDL-cholesterol lowering capacities of MK-0616 in 40 men and women (aged 18–65 years) treated with statin therapy. Patients were randomised 3:1 to 1 of 3 dosing regimens of MK-0616 or placebo (see Figure). The 14-day result displayed no serious AEs, deaths, or discontinuations. Treatment-related AEs were similar to the reported AEs in the first trial, demonstrating a favourable safety profile of the agent. LDL cholesterol was reduced by a maximum of 65% in all experimental conditions, except for the pre-dose food condition (see Figure). This result suggests that low-dose MK-0616 plus low-dose sodium caprate can achieve a major reduction in LDL cholesterol. Larger clinical trials need to confirm the safety and efficacy of MK-0616 in a diverse population.

Figure: MK-0616 dosing and LDL-cholesterol change from baseline [1]



LDL-C, low-density lipoprotein cholesterol; PBO, placebo.

 

1. 
   
   1. Johns DG, et al. The Clinical Safety, Pharmacokinetics, and LDL-Cholesterol Lowering Efficacy of MK-0616, an Oral PCSK9 Inhibitor. LBS06, AHA Scientific Sessions 2021, 13–15 November.

 

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Posted on 14 January 202213 June 2024