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Enrolment in a trial investigating a novel gene editing therapy in patients with heterozygous familial hypercholesterolemia (HeFH) has been paused after laboratory abnormalities, including a grade 3 transient increase in alanine aminotransferase (ALT), were detected in one participant.

The open-label Heart-1 phase 1b clinical trial is testing the safety and tolerability of VERVE-101, a single-course CRISPR-based gene editing treatment given by intravenous infusion that permanently turns off the PCSK9 gene in the liver to reduce low-density lipoprotein cholesterol (LDL-C).Study participants are a dults with HeFH, atherosclerotic cardiovascular disease, and uncontrolled hypercholesterolemia.

"The Heart-1 study continues to support proof-of-concept for in vivo base editing of the PCSK9 gene in the liver, with a meaningful and durable lowering of LDL-C," Sekar Kathiresan, MD, co-founder and chief executive officer of Verve Therapeutics, Inc., the company behind the therapy, said in a press release.

"However, at potentially therapeutic dose levels of VERVE-101, we have observed certain asymptomatic laboratory abnormalities, which we believe are attributable to the LNP [lipid nanoparticle] delivery system. The safety of patients in our clinical trials is of the utmost importance," Kathiresan continued.

VERVE-101 is an LNP encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor. Researchers have been testing four different doses: 0.1, 0.3, 0.45,and 0.6 mg/kg.

Interim results in the first 10 patients treated in the study, presented at last year's annual Scientific Sessions of the American Heart Association (AHA), showed reductions in blood proprotein convertase subtilisin kexin 9 levels across all dosing groups at 4 weeks, but reductions were most pronounced with the two highest doses.

Effective and Durable

Now, a total of 13 participants have been dosed with VERVE-101, with six dosed at 0.45 mg/kg. In the first five participants in the 0.45 mg/kg cohort with follow-up to at least 28 days, there were time-averaged LDL-C reductions ranging from 21% to 73% and averaging 46% (as of March 18, 2024).

In the two patients with the longest follow-up in the 0.45 mg/kg or 0.6 mg/kg cohorts, LDL-C lowering has been durable out to 9 months, with follow-up ongoing.

However, the sixth participant treated in the 0.45 mg/kg cohort experienced a grade 3 drug-induced transient increase in serum ALT, as well as a serious adverse event of grade 3 drug-induced thrombocytopenia, within the first 4 days after dosing. The participant did not experience any bleeding or other symptoms related to the laboratory abnormalities, and the abnormalities resolved fully within a few days.

In light of these laboratory abnormalities, though, Verve announced it has paused enrollment in the Heart-1 trial after consulting with the study's independent data and safety monitoring board. The company said it is conducting an investigation into the laboratory abnormalities and, on the basis of those results, expects to work with regulatory authorities to define a path forward for VERVE-101.

These safety events were reported to the US Food and Drug Administration, the UK Medicines and Healthcare products Regulatory Agency (MHRA), and the New Zealand Medicines and Medical Devices Safety Authority. The VERVE-101 Investigational New Drug Application and other clinical trial applications (CTAs) remain active, according to the press release.

In safety findings reported at last year's AHA meeting, two patients had serious cardiovascular events. One in the 0.3-mg/kg arm died of cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia 4 weeks later.

However, an independent review panel determined that the cardiovascular events were in line with outcomes for high-risk patients and were not directly related to treatment.

Verve Therapeutics is now prioritizing initiation of the Heart-2 clinical trial of VERVE-102, which is expected to start this year. VERVE-102 is a gene editing therapy with editor and guide components similar to VERVE-101 but an LNP delivery system that includes a different ionizable lipid and liver-targeting ligand.

The company announced clearance of its CTA by the MHRA and Health Canada for VERVE-102.