Gene therapy for cholesterol: Initial test results cheer

Mumbai: For millions of heart patients struggling with elevated levels of cholesterol, there is a ray of hope. A one-time intravenous infusion of a drug coded VERVE-102, being tested by global pharmaceutical giant Eli Lilly, showed significant reductions in a liver-produced protein called PCSK9.

VERVE-102 is an early investigational in vivo (inside the body) gene editing medicine designed to make a single, precise DNA base pair change to PCSK9 gene. It is created to mimic naturally occurring cardioprotective PCSK9 variants and lower LDL-C (‘bad’ cholesterol) over time, with a single infusion.

The US Food and Drug Administration has granted fasttrack designation for VERVE-102 to reduce LDL-C in participants with hyperlipidaemia and high lifetime cardiovascular risk. In India, 60-80 million are estimated to be living with heart conditions, while reports suggest three million cases of heart attacks annually.


“In an interim analysis of 35 patients, a single infusion of VERVE-102 resulted in dose-dependent mean reductions in PCSK9, ranging from 51% to 88%, at 0.3 mg/kg or 1.0 mg/kg, respectively. Corresponding reductions in LDL-C ranged from 9% to 62%, at 0.3 mg/kg or 1.0 mg/kg, respectively,” an Eli Lilly India spokesperson told ET. “These early data give us encouraging evidence,” said Riyaz S Patel, cardiologist at Barts Health NHS Trust and professor of cardiology at University College London. “Many patients with elevated LDL-C struggle to achieve sustained control… putting them at significant risk. With coronary artery disease still one of the leading causes of death worldwide, the need for new approaches is real.”

Indianapolis-headquartered Eli Lilly, known for its blockbuster weight-loss drugs Mounjaro and Zepbound, announced interim results for VERVE-102 on May 25. The early-stage data was presented at the European Atherosclerosis Society Congress and simultaneously published in The New England Journal of Medicine. ET explains:

WHAT IS VERVE-102?

VERVE-102 is an early investigational in vivo gene editing medicine designed to make a single, precise DNA base pair change to the PCSK9 gene. VERVE-102 is designed to mimic naturally occurring cardioprotective PCSK9 variants and durably lower LDL-C after a single infusion.

HOW DOES THE DRUG WORK IN THE BODY?

VERVE-102 has a messenger RNA (ribonucleic acid–responsible for protein synthesis and gene regulation) for an adenine base editor (a type of gene editing tool) and a guide RNA targeting PCSK9, encapsulated in a lipid nanoparticle designed to target the liver. Inside the liver cells, the PCSK9 gene is precisely edited and turned off by the drug.

WHAT IS PCSK9 AND WHY IS IT THE TARGET OF GENE EDITING?

PCSK9 is a protein produced by the liver that breaks down LDL receptors, which clears bad cholesterol from the blood. People born with naturally inactive PCSK9 are known to have lifelong low LDL-C and up to 88% lower lifetime risk of coronary artery disease, with no apparent adverse effects. This indicates the longer LDL-C stays low, the greater is the protection.

ARE THERE OTHER DRUGS TO CUT PCSK9?

Some drugs known as PCSK9 inhibitors include Praluent (alirocumab), Repatha (evolocumab) and Leqvio (inclisiran). But they are not gene editing drugs. These are administered every few weeks to twice a year. Lilly has another drug called lepodisiran in advanced stages of clinical trials and requires once-a-year infusion. US-based Merck is developing an oral pill targeting PCSK9 called Enlicitide.

WHAT ARE THE EFFICACY RESULTS OF THE PHASE 1B DATA FOR VERVE-102?

In this interim analysis of 35 patients, a single infusion of VERVE-102 resulted in dosedependent mean reductions of 51-88% in PCSK9. As of the data cut-off date earlier this year, median follow-up duration was approximately nine months, with 15 of the patients followed for at least one year. Durability was observed up to 18 months in participants with the longest follow-up.

WHAT DO THESE RESULTS MEAN?

In India, 60-80 million patients are estimated to be living with heart conditions, while reports suggest three million cases of heart attacks annually. Treatment exists but patients struggle to maintain long-term adherence to chronic cholesterol issues. VERVE-102 can be the first in vivo gene-editing medicine, which could transform cardiovascular care from chronic management to a one-time treatment. Larger trials of VERVE-102 are expected to help broader efforts aimed at one-time treatments for chronic diseases.

WHAT’S NEXT FOR THE VERVE-102 CLINICAL PROGRAMME?

Eli Lilly says it will continue to enrol participants and persist with follow-ups. All participants are expected to participate in a long-term, follow-up study for up to 15 years. Based on the positive interim phase 1b results, the company says it will initiate the phase II clinical trial of VERVE-102 before the end of the year.

IS VERVE-102 ONLY FOR SELECT PATIENTS WITH PREMATURE HEART CONDITIONS, OR COULD IT EVENTUALLY BE USED MORE BROADLY?

VERVE-102 is being evaluated in people with heterozygous familial hypercholesterolemia and premature coronary artery disease, two populations where durable LDL-C reduction is critical. There may be potential in the future to extend this approach to broader populations with high cardiovascular risk.

HOW DOES VERVE-102 FIT INTO ELI LILLY’S BROADER GENETIC MEDICINE RANGE?

It is a key part of Lilly’s growing genetic medicines portfolio, which now accounts for more than one-third of the company’s R&D roster.