Sekar Kathiresan, MD, Verve Therapeutics co-founder and CEO

Verve Therapeutics has dosed its first patient with what it said today was the first in vivo base editing therapy to reach the clinic, a potential treatment for Heterozygous Familial Hypercholesterolemia (HeFH).

Verve, which specializes in gene editing therapies for cardiovascular disease, said that its VERVE-101 is a single-course gene editing treatment designed to reduce the low-density lipoprotein cholesterol (LDL-C) that drives HeFH.

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 atherosclerotic cardiovascular disease (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.

Beam is also expected to enroll its first patient later this year in its first clinical trial for one of its base editing therapies, BEAM-101 for the treatment of sickle cell disease (SCD). Beam also plans two IND applications this year—one for its second SCD candidate BEAM-102, and the other for BEAM-201, a treatment for relapsed/refractory T cell acute lymphoblastic leukemia/T cell lymphoblastic lymphoma.

“The dosing of the first human with such an investigational base editing medicine represents a significant achievement by our team and for the field of gene editing,” Sekar Kathiresan, MD, Verve’s co-founder and CEO, said in a statement.

“Preclinical data suggest that VERVE-101 has the potential to offer people with HeFH a game-changing treatment option, transforming the traditional chronic care model to a single-course, life-long treatment solution,” Kathiresan added.

Andrew Bellinger, MD, PhD, Verve’s chief scientific and medical officer, added that VERVE-101 is intended to improve upon current standard of care treatment for HeFH. He stated that less than 20% of patients achieve LDL-C goal levels due to the limitations of the chronic model, which include requirements for rigorous patient adherence, regular health care access, and extensive health care infrastructure.

‘A key inflection point’

“Our ultimate goal with VERVE-101 is to bring a new option to the millions of people with ASCVD around the world, and dosing participants in the Phase I study for this first indication, HeFH, is a key inflection point to achieving that goal,” Bellinger said.

Publicly traded Verve’s stock rose 8% on Tuesday, closing at $22.20.

VERVE-101 is under study in the Phase Ib heart-1 trial (NCT05398029), designed to assess the safety and tolerability of VERVE-101 with additional analyses for pharmacokinetics and reductions in blood PCSK9 protein and LDL-C.

The trial is designed to enroll approximately 40 adults and includes three parts: A single ascending dose portion, followed by an expansion single-dose cohort where additional participants will receive the selected potentially therapeutic dose, and an optional second-dose cohort, in which eligible participants in lower dose cohorts in Part A have the option to receive a second treatment to reach the selected potentially therapeutic dose.

Verve is conducting the trial at a pair of clinical sites in New Zealand, according to

The company has said it plans to submit both a clinical trial application (CTA) in the United Kingdom and an IND application in the U.S., both in the second half of this year.

Interim clinical data for the heart-1 trial—which will include safety parameters, blood PCSK9 level and blood LDL-C level—are expected in 2023, Verve said.

“Given the once-and-done treatment potential for very large CV [cardiovascular] market opportunities, we see first human proof-of-concept data in 2023 for lead VERVE-101 as a key inflection point for the shares,” Eun Yang, PhD, an analyst with Jefferies, wrote July 7 in a research note.

In January during a presentation at the 40th Annual J.P Morgan Healthcare Conference, Verve described its market opportunity in CV as potentially hundreds of millions of patients worldwide, including 31 million with a genetic form of ASCVD. Verve presented figures also cited by the National Organization for Rare Disorders (NORD) showing that HeFH affects 1 in 250 people, while HoFH is much rarer, affecting 1 in 250,000, the company said.

“VERVE-101 has the potential to change the way cardiovascular disease is cared for by lowering LDL-C as low as possible for as long as possible after a single treatment,” Bellinger added.

“Given the once-and-done treatment potential for very large CV [cardiovascular] market opportunities, we see first human proof-of-concept data in 2023 for lead VERVE-101 as a key inflection point for the shares,” Eun Yang, PhD, an analyst with Jefferies, wrote July 7 in a research note.

Verve is also developing a second program designed to lower blood lipids such as LDL-C by permanently turning off the ANGPTL3 gene in the liver, in order to treat homozygous familial hypercholesterolemia (HoFH), a rare genetic subtype of ASCVD characterized by extremely high blood LDL-C, as well as for patients with ASCVD who have not achieved goal LDL-C lowering with oral therapy and a PCSK9 inhibitor.

The company expects to identify its base editing development candidate targeting ANGPTL3 and begin IND-enabling studies later this year.

Verve, Beam Amend Agreement

Since 2019, Verve had licensed Beam’s technology for human therapeutics against PCSK9 and three other liver-mediated, cardiovascular disease targets, including ANGPTL3, plus two undisclosed gene targets.

Just last week, Verve and Beam amended their agreement to develop and commercialize products targeting another liver-mediated, cardiovascular disease target, though that target and development timeline have not been disclosed.

Verve agreed to oversee development and commercialization of products targeting that gene, with Beam holding options to co-develop them after the final dosing of a patient in a Phase I clinical trial. If Beam opts in, it would share 35% of worldwide development expenses for the product, as well as jointly commercialize and share 35% of the profits and expenses of commercializing that product worldwide.

But if Beam doesn’t opt in, it would be entitled to receive milestones and royalties as called for in the companies’ original agreement.

The amended agreement does not change Beam’s co-development option for Verve’s programs targeting PCSK9 and ANGPTL3. BEAM has the option to co-develop those programs at the end of Phase I. If Beam exercises that option, it would fund 33% of major market development costs and 50% of U.S. commercialization costs—but in return would receive 50% of U.S. profits, while Verve would retain ex-US rights. For those ex-U.S. opt-in products, on a product-by-product basis, Verve agreed to pay Beam clinical and regulatory milestones of up to $5.6 million and sales-based milestones of up to $7.5 million.

If Beam declines to opt in, it would be eligible instead for $11.3 million per product in payments tied to achieving development milestones, $15 million per product in sales milestone payments and royalties in the low single digits.

Verve finished the first quarter with cash, cash equivalents and marketable securities of $323.3 million as of March 31, 2022, down 10% from $360.4 million as of December 31, 2021.

“Based on current operating plans, Verve expects its existing cash, cash equivalents and marketable securities will enable the company to fund its operating expenses and capital expenditure requirements into 2024,” Verve said in May when it reported Q1 results.

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