Single-course in vivo base editing therapy proven to lower cholesterol

Gene therapy

A Phase Ib trial has shown low-density lipoprotein cholesterol (LDL-C) reductions up to 55% and blood PCSK9 protein reductions up to 84% after a single infusion of Verve Therapeutics’ Verve-101.

The trial participants have heterozygous familial hypercholesterolemia (HeFH), a life-threatening inherited disease characterised by lifelong elevations in blood LDL-C and accelerated atherosclerotic cardiovascular disease (ASCVD).

FH is one of the most common genetic conditions, affecting around one in 300 people globally. It is caused by a single gene mutation that impairs the body’s ability to mediate LDL cholesterol. Since the mutation only affects a single gene, it makes it a prime candidate for genome editing treatments.

Verve-101 is an investigational, in vivo base editing medicine designed to be a single-course treatment that inactivates the PCSK9 gene in the liver to durably lower blood LDL-C.

“Of the more than three million people with HeFH in the US and Europe, very few are currently at LDL-C goal, due in part to a care model that requires lifetime therapies. This model puts a strain on the healthcare system and is failing our patients,” said Deepak Bhatt, Director of the Mount Sinai Fuster Heart Hospital and the Dr Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine in New York.

“I am very encouraged by the initial data from the heart-1 trial that demonstrated the potential for single-course gene editing as a new approach to treat patients with HeFH. The data showed that Verve-101 could meaningfully and durably lower LDL-C in these patients. We’re at an exciting moment for cardiovascular prevention where the management of ASCVD may fundamentally change.”

heart-1 clinical trial

According to the trial data, following a single infusion of Verve-101, dose-dependent reductions in pharmacodynamic measures of blood PCSK9 protein levels were observed, suggesting successful editing at the intended genomic target.

Dose-dependent LDL-C reductions, a validated measure of clinical efficacy for this patient population, were observed one month after treatment.

The two patients treated with 0.45mg/kg had a time-averaged blood PCSK9 protein reduction of 59% and 84%. The patient treated with 0.6mg/kg had a time-averaged blood PCSK9 protein reduction of 47%. The two patients treated with 0.45mg/kg had a time-averaged LDL-C reduction of 39% and 48%. The patient treated with 0.6mg/kg had a time-averaged LDL-C reduction of 55%, which was durable up to 180 days, with follow-up ongoing.

The safety profile observed in the heart-1 trial supports continued development of Verve-101, and the company says the adverse events have been consistent with the severe, advanced ASCVD patient population enrolled.

“Our goal is to fundamentally disrupt the chronic care model for cardiovascular disease and provide a new single-course treatment option for patients,” said Andrew Bellinger, Chief Scientific Officer of Verve. “These data confirm our hypothesis that a single-course gene editing medicine has the potential to induce meaningful and durable reductions in LDL-C when administered at therapeutic doses.”

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