UK Medicines Regulator Awards Innovation Passport to Base-Editing Candidate for Heart Disease

Verve Therapeutics announced yesterday in a press release that its lead base-editing therapeutic candidate VERVE-101 has been awarded the Innovation Passport for the treatment of heterozygous familial hypercholesterolemia (HeFH) under the Innovative Licensing and Access Pathway by the UK Medicines and Healthcare products Regulatory Agency (MHRA).

VERVE-101 is designed as a single-dose gene-editing medicine that uses a base editor to permanently switch off the PCSK9 gene in the liver, to durably lower disease-driving low-density lipoprotein cholesterol (LDL-C). Elevated LDL-C levels lead to clogged arteries in the heart and are a driver of a number of cardiovascular conditions including HeFH , a prevalent and potentially life-threatening subtype of atherosclerotic cardiovascular disease.

The Innovation Passport was awarded to VERVE-101 under the Innovative Licensing and Access Pathway (ILAP). This pathway aims to accelerate time to market and facilitate patient access to innovative medicines. Innovation Passports may be awarded to medicinal products that address a condition that is life-threatening or seriously debilitating and where there is a significant patient or public health need.

VERVE-101 is designed to permanently lower low-density lipoprotein cholesterol

VERVE-101 consists of an adenine base editor (ABE) messenger RNA (licensed from Beam Therapeutics Inc.) and an optimised guide RNA (gRNA) targeting the PCSK9 gene, both of which are packaged in an engineered lipid nanoparticle. This cargo is administrered in vivo via blood infusion and it gets taken up by the liver.

Once inside the liver, the gRNA and ABE-encoding mRNA are released, leading to translation of the base editor and its migration, along with the gRNA, to the nucleus, followed by disruption of the PCSK9 gene.

By making a single A-to-G change in the DNA genetic sequence of PCSK9, VERVE-101 inactivates the target gene. This has been shown to up-regulate LDL receptor expression, which leads to lower LDL-C levels, thereby reducing the risk for ASCVD.

The heart-1 clinical trial

VERVE-101 is currently being evaluated in the Phase 1 heart-1 clinical trial, which is ongoing in the UK and New Zealand. The trial is designed to evaluate the safety and tolerability of VERVE-101 in individuals with HeFH, with additional analyses for pharmacokinetics and reductions in blood PCSK9 protein and LDL-C. The first patient was dosed in July 2022.

CRISPR Medicine News spoke with Verve Therapeutics’ CEO, Sekar Kathiresan, shortly after dosing of the first individual with VERVE-101 last year. He discussed VERVE-101's mechanism of action and how it may transform the lives of individuals with cardiovascular disease. You can read that interview here.

According to the press release published yesterday, Verve expects to report initial clinical data from the dose escalation portion of the heart-1 clinical trial including safety parameters, blood PCSK9 level, and blood LDL-C level in the second half of 2023. We will continue to provide further updates on VERVE-101 and the heart-1 trial as they emerge.

We strive to keep you updated with clinical and pre-clinical news from the CRISPR Medicine field. For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.