CRISPR Editing Therapy Reduces LDL-C in Familial Hypercholesteremia in Small Trial


One serious AE of myocardial infarction may have been related to VERVE-101 therapy while other AEs of fatal cardiac arrest and tachycardia were determined to be unrelated to the therapy.

VERVE-101 CRISPR base editing therapy significantly reduced low-density lipoprotein cholesterol (LDL-C) in people with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic cardiovascular disease (ASCVD) treated in the phase 1b heart-1 clinical trial (NCT05398029).1

Data from the first-in-human trial were presented at the American Heart Association’s (AHA) Scientific Sessions 2023, held November 10-13 in Philadelphia, Pennsylvania, by Andrew M Bellinger, MD, PhD, chief scientific officer, Verve Therapeutics.

HeHF, which affects around 3 million people in the United States and Europe, involves lifelong severe elevations in LDL-C and accelerated ASCVD. The disease is currently treated under a chronic care model consisting of daily pills and intermittent injections over decades, leading to a large treatment burden on patients. VERVE-101 uses CRISPR/Cas9 to inactivate the PCSK9 gene in hepatic cells via a single base pair change. PCSK9 is a cholesterol-raising gene and naturally occurring gene variants that turn off PCSK9 yield lifelong lowering of LDL-C and ASCVD with no apparent deleterious effects.

“Instead of daily pills or intermittent injections over decades to lower bad cholesterol, this study reveals the potential for a new treatment option – a single-course therapy that may lead to deep LDL-C lowering for decades,” Bellinger said in a press briefing.2

READ MORE: Verve’s Hypercholesterolemia Gene-Editing Therapy VERVE-101 Cleared for US Trial After Rocky Start

heart-1 is evaluating the safety and tolerability of VERVE-101 and has treated 10 participants across 4 dose cohorts - 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3), 0.45 mg/kg (n = 3), and 0.6 mg/kg (n = 1) - as of October 16, 2023.1 Enrolled patients were male and female with uncontrolled hypercholesteremia on the maximally-tolerated oral lipid lowering therapy. Participants received dexamethasone and antihistamine predications before receiving a single, peripheral intravenous infusion of VERVE-101. The trial is also assessing pharmacokinetics of the therapy as well as blood PCSK9 and LDL-C change from baseline up to 1 year.

The enrolled participants, from the United Kingdom and New Zealand, had a mean age of 54 years (range, 29-69) and most were male (n = 8). They had a mean LDLC of 193 mg/dL (range, 107-373); 9 had prior coronary revascularization; 4 had more than 1 prior myocardial infarction; and 1 had prior cardiac arrest. Eight were on statin therapy and 2 had prior PCSK9-targeted therapy.1

Investigators found that blood PCSK9 percentage decreased from baseline in 2 of 3 participants in cohort 1 (+2; -9; -11) and all evaluable participants in cohorts 2 (-7; -24; -40), 3 (-59; -84) and 4 (47) from baseline at last available follow-up. Similarly, blood LDL-C decreased from baseline in 1 of 3 participants in cohort 1 (+8; +3; -3) and all evaluable participants in cohorts 2 (-9; -9; -10), 3 (-39; -48), and 4 (-55). While durability data are limited, the 55% reduction in cohort 4 has been sustained for 180 days after treatment.1

In terms of safety, there were 2 treatment related grade 3 or higher (serious) adverse events (AEs), which were 1 case each of cardiovascular events and increased liver transaminases. Alanine aminotransferase elevations were transient and reversible and were below the upper limit of normal. In addition, there were 2 unrelated serious cardiovascular events. Common mild AEs included infusion-related reactions and upper respiratory infections or COVID-19.1

Clinical Takeaways

  • In the heart-1 trial, VERVE-101, a CRISPR-based gene therapy, achieved a high of a 55% reduction in LDL-C in a patient with HeFH and ASCVD.
  • VERVE-101 uses CRISPR/Cas9 to inactivate PCSK9, in a potential shift from chronic care models.
  • There were treatment-related serious adverse events of transient ALT elevations and myocardial infarction.

The cardiovascular events occurred in 2 participants. One, in cohort 2, experienced fatal cardiac arrest about 5 weeks after infusion that was determined to be related to ASCVD and not VERVE-101. The second participant, in cohort 3, had myocardial infarction the day after infusion that was potentially related to therapy and then non-sustained ventricular tachycardia over 4 weeks after infusion determined to be unrelated to therapy. The independent data and safety monitoring board reviewed these events and recommended the trial and dosing continue. The trial is continuing to dose patients in cohorts 3 and 4, with a dose expansion cohort planned for 2024. Verve also plans to initiate a randomized and placebo-controlled phase 2 trial in 2025

"I think [the data] Verve therapeutics announced... in a relatively small number of patients was amazing. The first use of human gene editing to lower cholesterol levels where they were targeting PCSK9 [showed] at the higher doses about a 50 percent reduction in LDL-C that was durable out to 6 months. So to me, that concept of editing genes in humans in a way that will hopefully be safe and durable, we need more patients followed for longer, but so far, looks like a really promising approach and opens the door for that approach for a variety of cardiovascular disease conditions and risk factors... So, to me, that's really exciting,” Deepak L. Bhatt, MD, MPH, director, Mount Sinai Heart, Dr. Valentin Fuster Professor of Cardiovascular Medicine, Icahn School of Medicine, Mount Sinai, said while discussing the top cardiac news of 2023 with our sister site HCPLive at the AHA meeting.

1. Vafai SB, Gladding PA, Scott R, et al. Safety and pharmacodynamic effects of VERVE-101 an investigational DNA Base editing medicine designed to durably inactivate the PCSK9 gene and lower LDL cholesterol – interim results of the phase 1b heart-1 trial. Presented at: AHA Scientific Sessions 2023; November 10-13; Philadelphia, Pennsylvania.
2. A single infusion of a gene-editing medicine may control inherited high LDL cholesterol. News release. AHA.
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