Gene editing may change the treatment landscape of hypercholesterolaemia 

The first-in-human study to investigate VERVE-101, a novel CRISPR base editing medicine, showed successful inactivation of hepatic PCSK9 in the liver by changing a single DNA base pair. Furthermore, durable, dose-dependent reductions of LDL-cholesterol profile were observed in the first assessed patients with heterozygous familial hypercholesterolaemia (HeFH). 

“Patients with HeFH need daily pills or intermittent injections over decades,” said Dr Andrew Bellinger (Verve Therapeutics, MA, USA) [1]. “This is a heavy burden on patients, providers, and the healthcare system.” Dr Bellinger and colleagues wondered whether a single-course treatment that mimics PCSK9 variants protecting against atherosclerotic cardiovascular disease can be developed.

The phase 1b heart-1 study (NCT05398029) tested the CRISPR base editing medicine VERVE-101 for patients with HeFH and a high risk of cardiovascular events. The first 10 participants (8 men and 2 women; mean age 54 years) were allocated to 4 single-infusion dose groups: 0.1 mg/kg (n=3), 0.3 mg/kg (n=3), 0.45 mg/kg (n=3), and 0.6 mg/kg (n=1). “The patients had severe atherosclerotic cardiovascular disease (ASCVD) and a high risk for cardiovascular events,” added Dr Bellinger. The primary endpoint was the safety and tolerability of the agent.

“In the higher dose cohorts, we saw blood PCSK9 protein level reductions of 47%, 59%, and 84%,” noted Dr Bellinger. Also, blood LDL-cholesterol level reductions of 39%, 48%, and 55% were reported in 3 participants in the higher dose groups. “The patient in the highest dose group had the 55% reduction and this reduction was maintained up to day 180,” added Dr Bellinger.

As for safety, 4 infusion-site reactions were noted and some transient, reversible increases in ALT levels in the higher dose groups. “Mean bilirubin levels remained below the upper limit of normal,” according to Dr Bellinger. Finally, there was 1 serious cardiovascular event, a myocardial infarction, that may have been related to treatment.

The heart-1 trial will keep enrolling patients in the 2 highest dose groups for an expansion cohort planned for 2024 to complete the dose-escalation phase. A phase 2 trial is scheduled for 2025. “These preliminary results suggest that single-course gene editing medicines may become an option in patients who require deep LDL-cholesterol reductions over decades,” decided Dr Bellinger.

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   1. Bellinger AM, et al. Safety and pharmacodynamic effects of VERVE-101: an investigational DNA base editing medicine designed to durably inactivate the PCSK9 gene and lower LDL cholesterol - interim results of the phase 1b heart-1 trial. LB05, AHA Scientific Sessions 2023, 11–13 November, Philadelphia, USA.

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Posted on 29 January 202426 July 2024