The trial, which is ongoing in the U.K. and New Zealand, has been on hold in the U.S. since late last year as the FDA sought more details from Verve.

Verve Therapeutics plans to soon start testing a gene editing therapy for heart disease in the U.S. after federal regulators lifted an order that had blocked the biotechnology company from enrolling people into its study.

Verve, which specializes in a cutting-edge form of genetic medicine known as base editing, said Monday that it had resolved questions raised by the Food and Drug Administration last fall when it first requested clearance to begin U.S. testing. The study, dubbed Heart-1, has been underway in the U.K. and New Zealand since last summer, and Verve plans to present the first data from it at a medical meeting next month.

“We were able to comprehensively address all of the preclinical questions, provide the clinical data, and then got our [application] cleared,” said company CEO Sek Kathiresan, a cardiologist and geneticist who formed Verve five years ago to develop a one-time treatment for heart disease.

The regulatory green light for Verve comes less than a week after the FDA cleared Intellia Therapeutics to begin a late-stage trial of a gene editing treatment for the rare disorder transthyretin amyloidosis. Intellia conducted an earlier study of the therapy at sites in Europe, the U.K. and New Zealand.

Both treatments work “in vivo,” meaning the gene editing caused by the therapies happens inside the body, rather than in cells edited in a laboratory, or “ex vivo.” The FDA has so far been cautious in permitting testing of in vivo treatments to move ahead quickly.

Verve’s treatment, dubbed VERVE-101, uses a form of CRISPR gene editing, base editing, that allows drugmakers to make edits to a single DNA letter, or base. In Verve’s case, its treatment changes an “A” in the sequence for a gene called PCSK9 to a “G,” inactivating the gene. Turning off PCSK9 could powerfully lower LDL cholesterol, high levels of which are closely intertwined with cardiovascular disease.

VERVE-101, a single-course in vivo liver base editing medicine, is currently being evaluated in our Phase 1b heart-1 clinical trial in patients with high-risk heterozygous familial hypercholesterolemia (HeFH), established atherosclerotic cardiovascular disease (ASCVD), and uncontrolled LDL-C levels on oral standard-of-care therapy.

HeFH is characterized by extremely high LDL-C levels in the blood that, over time, cause plaque to build up in the arteries, resulting in reduced blood flow or blockage. This significantly increases an individual’s risk for heart attack and stroke. Inactivation of the PCSK9 gene in the liver can be effective in lowering LDL-C levels.

We believe that VERVE-101 has the potential to treat a broad population of patients and plan to take a stepwise approach for its clinical development. If our Phase 1b heart-1 clinical trial to evaluate the safety and efficacy of VERVE-101 in patients with high-risk HeFH is successful, we plan to expand into the broader HeFH population, and then ultimately target larger patient groups with established ASCVD. 

Encouraging Preclinical Results 
In an ongoing long-term study in 36 non-human primates (NHP), we administered 1.5 mg/kg of VERVE-101 (n=22) and 0.75 mg/kg (n=4), with a control group (n=10). The study was designed to measure whole liver editing, blood PCSK9 protein levels and blood LDL-C levels.

At the 1.5 mg/kg dose level, we observed an average of 70% whole liver editing at the PCSK9 target site at day 15, which we believe represents editing of the majority of hepatocytes. We also observed a PCSK9 protein reduction of approximately 79% and a robust LDL-C reduction of approximately 62% at two weeks following treatment, which improved to 89% and 68%, respectively, at one year following treatment. At the 0.75 mg/kg dose level, we observed a PCSK9 protein reduction of approximately 54% and a robust LDL-C reduction of approximately 38% at two weeks following treatment, which improved to 69% and 50%, respectively, at one year following treatment.

VERVE-101 was generally well tolerated in NHP studies, with only mild elevations in liver function tests that resolved within two weeks. These findings are consistent with observations from nonclinical studies performed for an approved LNP-based product that is administered intravenously.

“The current model, which is daily pills and intermittent injections, does not really work that well,” said Kathiresan in an interview. “The hope is that a medicine like VERVE-101 can address that unmet need with a one-time therapy [that produces] deep and durable lowering of LDL.”

Verve is testing the drug first in people with heterozygous familial hypercholesterolemia, or HeFH, an inherited condition that causes extremely high LDL levels and early-onset atherosclerotic cardiovascular disease. It later hopes to test its base editing approach in broader groups of people with heart disease, and with other gene targets linked to heart risk.

The data Verve plans to present next month will give an early indication of how well VERVE-101 might work in people with HeFH. The results will include data from trial participants outside of the U.S. who received one of four different doses of VERVE-101, and are the same as what Verve submitted to the FDA.

According to Kathiresan, the FDA had also wanted to see data from the company comparing the treatment’s potency in animal tests to those in humans, and data showing whether VERVE-101 caused edits in sperm or egg cells — a key concern for in vivo therapies.

“This is a drug that’s given systemically and so, theoretically, could go to different parts of the body. Almost all of it goes to the liver, and they wanted us to check on whether it’s going to sperm cells or egg cells,” the CEO said. “And that’s what we did and adequately addressed their concerns.”

Kathiresan declined to say how many clinical trial sites Verve plans to open in the U.S. now that the FDA has lifted its hold, but confirmed there would be multiple.

He added that Verve’s interactions with the FDA on VERVE-101 will be a “template” to help it advance other of its treatments into human testing. “Now we know what it takes,” Kathiresan said. 

News of Verve’s and Intellia’s regulatory progress could give a lift to a field that’s been battered this year by a down market for biotech. At least 11 developers of gene editing or gene replacement therapies have laid off staff in 2023, including Beam Therapeutics, from which Verve licenses its technology.

More good news may be ahead. The FDA is currently reviewing an ex vivo treatment from Vertex Pharmaceuticals and CRISPR Therapeutics that could become the first CRISPR-based medicine approved by the agency. A decision is expected by Dec. 8.

“The regulatory path has been uncertain in some ways,” said Kathiresan. “There’s a better trodden path for ex vivo [therapies]. But for the in vivo path — that’s just being laid now.”

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