Verve Therapeutics said Sunday it has generated the first human proof-of-concept data for its in vivo base editing therapy VERVE-101—the first base editing treatment to reach the clinic—in patients with heterozygous familial hypercholesterolemia (HeFH).

At the American Heart Association Scientific Sessions 2023, Verve announced data from its Phase Ib heart-1 trial (NCT05398029) showing that one month after treatment with VERVE-101, HeFH patients showed dose-dependent reductions of disease-causing low-density lipoprotein cholesterol (LDL-C).

Also, following a single infusion of VERVE-101, patients showed dose-dependent reductions in pharmacodynamic measures of blood PCSK9 protein levels—an outcome that according to Verve suggests successful editing at the intended genomic target.

“Can we precisely rewrite the genetic code—make a single DNA spelling change—in the liver of a human being for clinical effect? YES!” Sekar Kathiresan, MD, Verve’s co-founder and CEO, who led the trial, exclaimed in a post on X, formerly Twitter.

“Clinical implication: It’s early but could open the way for an entirely new way to treat heart disease,” Kathiresan elaborated. “Instead of daily pills/intermittent injections, a one-time intravenous infusion procedure to durably (possibly lifelong) lower LDL cholesterol; “surgery without a scalpel.”

Heart-1 is an open-label trial in patients living with HeFH, established accelerated atherosclerotic cardiovascular disease (ASCVD), and uncontrolled hypercholesterolemia.

Making history

Verve dosed the first patient last year, making history by advancing the first base edited therapy into the clinic. Investigators treated three patients with VERVE-101 at single doses of 0.1 mg/kg, three patients at 0.3 mg/kg, three at 0.45 mg/kg, and one at 0.6 mg/kg.

“Notably, the doses used in humans were lower than those in NHP [non-human primates], but led to the same level of PCSK9 and LDL reductions, suggesting good translation from preclinical models to humans,” Jefferies equity analyst Michael Yee observed in a research note.

One 0.45 mg/kg patient had not reached day 28 as of the data cut-off date and was not included in the efficacy analysis, leaving two 0.45 mg/kg patients, and one 0.6 mg/kg patient that were evaluable. The two patients treated with 0.45 mg/kg of VERVE-101 had a time-averaged blood PCSK9 protein reduction of 59% and 84%, and a time-averaged LDL-C reduction of 39% and 48%.

One of the two 0.45 mg/kg patients experienced a myocardial infarction (Grade 3) the day after treatment—an event considered potentially related to treatment due to the proximity to dosing. Verve said the event followed unstable chest pain symptoms prior to dosing that were unreported to investigators. Coronary angiography taken after the event showed critical left main equivalent coronary artery disease.

The same patient also experienced non-sustained ventricular tachycardia (Grade 2) more than four weeks after dosing, which was determined to be unrelated to treatment.

The sole patient treated with 0.6 mg/kg showed a time-averaged blood PCSK9 protein reduction of 47% and a time-averaged LDL-C reduction of 55%, a reduction that was durable out to 180 days, with follow-up ongoing. Blood PCSK9 protein and LDL-C reductions are quantified as percent change from baseline using the time-weighted average from day 28 through the last available follow-up.

“An exciting moment”

“This trial enrolled patients with advanced coronary disease, and the cardiovascular adverse events were consistent with what might be expected in this patient population. We’re at an exciting moment for cardiovascular prevention where the management of ASCVD may fundamentally change,” stated Deepak L. Bhatt, MD, MPH, 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.

Another six patients were treated at sub-therapeutic doses of 0.1 mg/kg and 0.3 mg/kg. One patient dosed in the 0.3 mg/kg cohort had a fatal cardiac arrest approximately five weeks after treatment due to underlying ischemic heart disease, which was determined not to be related to treatment by the trial’s investigator and independent data and safety monitoring board (DSMB).

The trial’s DSMB reviewed all safety events and recommended continuation of trial enrollment with no protocol changes required, Verve said.

Based on the favorable initial findings in heart-1, Verve is continuing to enroll patients in the trial’s potentially therapeutic dose cohorts of 0.45 mg/kg and 0.6 mg/kg, added Verve’s CSO Andrew Bellinger, MD, PhD.

VERVE-101 is a single-course treatment designed to treat HeFH by inactivating the PCSK9 gene in the liver to durably lower blood LDL-C. VERVE-101 consists of an adenine base editor messenger RNA that Verve has licensed from another base editing therapy developer, Beam Therapeutics, as well as an optimized guide RNA targeting the PCSK9 gene packaged in an engineered lipid nanoparticle.

By making a single A-to-G change in the DNA genetic sequence of PCSK9, VERVE-101 aims to inactivate that target gene. Verve reasons that inactivation of the PCSK9 gene has previously been shown to up-regulate LDLR expression, leading to lower LDL-C levels and thus reducing the risk for ASCVD, of which HeFH is a subtype.

Base editing is a pinpoint method for engineering base substitutions without cleaving the DNA double helix backbone. The underlying technology was developed in the lab of Harvard University chemist David Liu, PhD—who co-founded Beam with Feng Zhang, PhD, and Keith Joung, MD—with research led by two postdocs, Alexis Komor, PhD, and Nicole Gaudelli, PhD.

“What a fantastic way to start the week! Congrats to the @VerveTx team and @kiranmusunuru for leading the clinical application of base editing for heart disease, Gaudelli posted on X, calling out Verve co-founder Kiran Musunuru, MD, PhD, professor of cardiovascular medicine and genetics, Perelman School of Medicine at the University of Pennsylvania. “It’s an exciting time, and I can’t wait to see what more you’ll achieve.”

“It works!”

In a thread posted on X, Musunuru characterized the first in human data as “the culmination of 10+ years of work to use #CRISPR gene editing to fight heart disease!”

“IT WORKS!” Musunuru declared. “One (of many) big implications for the field: The [door] is wide open for precise corrective editing to definitively treat grievous genetic diseases centered in the liver, including inborn errors of metabolism. Stay tuned!”

Added Fyodor Urnov, PhD, director of technology & translation at the Innovative Genomics Institute: “Gene editing with #CRISPR has crossed a Rubicon—into important new territory of, we all hope, becoming a treatment for… and ultimately a vaccine AGAINST, heart disease.”

“I admire @VerveTx courage and persistence—full Gregorspeed ahead!”

“Today’s first-in-human data on gene editing for heart disease from @VerveTx is a good time to salute the inventors of base editing,” Urnov added.

The heart-1 trial has enrolled patients in the U.K. and New Zealand. The FDA last year placed a clinical hold blocking U.S. enrollment—“a frustrating development,” one analyst said at the time. Last month the agency lifted the hold, clearing Verve’s IND for the study. The FDA lifted the hold after Verve submitted interim clinical data from the trial’s dose-escalation portion addressed preclinical questions posed by the agency.

As a result, Verve said, it plans to activate and open U.S. sites. Next year, the company plans to select a single dose from the dose escalation phase, begin an expansion cohort, and complete that expansion cohort of the heart-1 clinical trial.

Lilly beams up

VERVE-101 is among PCSK9-targeting Verve therapies for which Eli Lilly last month agreed to acquire opt-in rights held by Beam to Verve-developed base editing therapies through an up-to-$600 million collaboration—$250 million upfront, up to $350 million tied to achieving clinical, regulatory, and alliance milestones. Lilly also agreed to acquire opt-in rights to Verve-developed programs focused on two other cardiovascular targets—ANGPTL3, and an undisclosed third target that was only described as “liver-mediated.”

Verve said it plans to initiate a Phase I trial of Verve’s other PCSK9-inactivating in vivo base editing therapy VERVE-102 (now in IND-enabling phase) in the first half of 2024, subject to regulatory clearance. VERVE-101 and VERVE-102 share an identical guide RNA targeting PCSK9 as well as similar messenger RNA expressing an adenine base editor. Unlike VERVE-101, VERVE-102 is delivered using the company’s proprietary GalNAc-LNP delivery technology.

Following completion of the heart-1 trial and the VERVE-102 trial, Verve said, it plans to launch a randomized, placebo-controlled Phase II trial of either VERVE-101 or VERVE-102 in 2025.

ANGPTL3 is targeted by VERVE-201, being developed for both homozygous familial hypercholesterolemia (HoFH) and refractory hypercholesterolemia.

Lilly has also agreed to co-develop a base editing program for an undisclosed ASCVD. The pharma giant added to rights it acquired in June for up to $525 million-plus to co-develop Verve’s “LPA” program, indicated for ASCVD with high lipoprotein a [Lp(a)] and using a novel editor.

Discussing the importance of Verve’s research on VERVE-101, CEO Kathiresan added a postscript to his post on X placing the work within the context of the holiday known as Diwali or Deepvali: “Deepavali celebrates new knowledge, and so thrilled to add today to our knowledge on the intersection of gene editing technology and cardiovascular disease.”

Alex Philippidis is senior business editor of GEN.

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