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Verve-101: Where are we up to with PCSK9 gene editing?

VERVE-101 is a novel CRISPR base editing agent designed to knock out expression of the PCSK9 gene by changing a single DNA base, thereby turning off PCSK9 protein production in hepatocytes and lowering LDL-C. VERVE-101 consists of an mRNA for an adenine base editor and a guide RNA that targets the PCSK9 gene, all contained in a lipid nanoparticle system administered as a single i.v. infusion.1  

Development of this technology was initiated following research linking loss-of-function mutations in the PCSK9 gene with reductions in LDL-C reduction and coronary events.2,3 In nonhuman primates treated with a 1.5 mg/kg dose, VERVE-101 was well tolerated and resulted in an 83% reduction in PCSK9 protein and a 69% fall in LDL-C, for up to 476 days after dosing.1

Interim results were recently reported from 10 patients in the Phase 1b, heart-1 trial who had heterozygous familial hypercholesterolaemia (HeFH), severe advanced atherosclerotic cardiovascular disease (ASCVD), and uncontrolled hypercholesterolaemia, and received single doses of VERVE-101 at 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) via i.v. infusion.4

Good tolerability and safety were observed in the six patients on the lowest doses of VERVE-101 (0.1 mg/kg and 0.3 mg/kg) though, in line with expectations from preclinical data, there was little effect on PCKS9 or LDL-C. However, in two patients treated with VERVE-101 0.45 mg/kg, PCSK9 was reduced by 59% and 84% respectively, and LDL-C by 39% and 48%. The patient treated with VERVE-101 0.6 mg/kg had a PCSK9 reduction of 47%, and an LDL-C reduction of 55%. In this single participant in the highest dose cohort, the 55% reduction in LDL-C was durable out to 180 days, with follow-up ongoing. One patient who received VERVE-101 0.45 mg/kg dose had not reached day 28 when the efficacy analysis was carried out and was not included in the efficacy analysis.

Three cardiovascular serious adverse events occurred in two participants, and two were determined unrelated to treatment. In one patient, a myocardial infarction that occurred one day after treatment was considered potentially related to treatment (VERVE-101 0.45 mg/kg), but non-sustained ventricular tachycardia which occurred more than four weeks after treatment was not. In a second patient, a fatal cardiac arrest about five weeks after infusion (VERVE-101 0.3 mg/kg) was also not considered related to treatment.

The independent data and safety monitoring board (DSMB) agreed that SAEs were consistent with a severe, advanced ASCVD patient population and recommended continuing dosing.

Professor Steve Humphries is a consultant to Verve Therapeutics, the company developing VERVE-101 and is an author in the heart-1 trial. Statements are made in his personal capacity and not on behalf of Verve Therapeutics. Professor Humphries’ opinions reflect his own beliefs and do not necessarily reflect the opinions and beliefs of Verve Therapeutics.

 

 

References

  1. Lee RG, Mazzola AM, Braun MC et al. Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models. Circulation. 2023 Jan 17;147(3):242-253
  2. Zhao Z, Tuakli-Wosornu Y, Lagace TA et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006;79:514–523.
  3. Cohen JC, Boerwinkle E, Mosley TH et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–1272.
  4. Bellinger AM, Vafai SB, Gladding PA et al. Safety and Pharmacodynamic Effects of VERVE-101, an Investigational DNA Base Editing Medicine Designed to Durably Inactivate the PCSK9Gene and Lower LDL Cholesterol - Interim Results of the Phase 1b heart-1 Trial. Presented at American Heart Association Scientific Sessions 2023 (11-13 November, Philadelphia, USA); Session LBS.06 - Late-Breaking Science: Future of Lipid Lowering Therapy - Novel Mechanisms and Approaches

 

14 December 2023