Verve Therapeutics Presents Comprehensive Analyses of Off-target Editing Risk for VERVE-101 at Precision Genome Engineering Keystone Symposia
Extensive Analyses in Multiple Human Cell Types Demonstrate Minimal to No Off-target Editing Following VERVE-101 Treatment, Supporting its Planned Clinical Initiation in 2022
Whole Genome Sequencing at 500X Coverage of Primary Human Liver Cells Treated with VERVE-101 Demonstrated No Increased Frequency of Adenine Editing Compared to Untreated Controls
CAMBRIDGE, Mass., April 26, 2022 (GLOBE NEWSWIRE) -- Verve Therapeutics, a biotechnology company pioneering a new approach to the care of cardiovascular disease with single-course gene editing medicines, announced new findings from a comprehensive off-target assessment of its lead product candidate, VERVE-101, demonstrating minimal to no off-target editing and supporting the favorable tolerability profile observed across multiple non-human primate studies conducted to date. The data will be presented at the Precision Genome Engineering Keystone Symposia in Keystone, Colorado on April 29.
VERVE-101 is designed to precisely edit a single base pair in the PCSK9 gene without creating double-stranded DNA breaks, and permanently turn off the gene in the liver, the target tissue, to reduce disease-driving low density lipoprotein cholesterol (LDL-C). Verve plans to investigate VERVE-101 initially as a treatment for heterozygous familial hypercholesterolemia (HeFH), a genetic form of atherosclerotic cardiovascular disease (ASCVD).
Consistent with recent industry guidance from the U.S. Food and Drug Administration (FDA), Verve researchers employed multiple orthogonal methods, including a sensitive biochemical method called ONE-seq, an unbiased genome-wide analysis called ABE-digenome-seq, and an in silico method, to identify more than 3,000 potential sites of off-target editing across the genome, i.e., those with the greatest experimental or bioinformatic similarity to the on-target site. Verve researchers then applied a highly sensitive and customized next-generation sequencing assay to verify bona fide off-target editing at those 3,000 potential sites in primary human liver cells from multiple donors. After treatment with the VERVE-101 batch made under Good Manufacturing Practices (GMP), no sites were observed to have statistically significant off-target editing.
Extensive additional evaluation in non-target cells (spleen cells, adrenal cells, and hematopoietic stem cells) and in other cellular contexts (pediatric human liver cells and human liver cell lines) identified only two potential sites with statistically significant editing above untreated controls in any cell type and with any batch. The two instances of off-target editing occurred at doses greater than those expected to achieve saturation for on-target editing. Based on these data, Verve believes that VERVE-101 has a low risk of off-target genomic modifications that would be expected to have an associated clinical adverse effect.
In addition, in order to assess for potential guide-independent off-target effects on a genome-wide scale, a whole genome sequencing analysis of human liver cells treated with VERVE-101 was performed at a very high coverage depth of 500 sequencing reads per base. This analysis demonstrated no increase in adenine editing compared to untreated controls. Finally, in order to assess for genomic integrity, including chromosomal rearrangements and large insertions or deletions, Verve researchers performed whole genome optical mapping in primary human liver cells and observed no additional structural variants after VERVE-101 treatment when compared with untreated controls.
“Based on our interactions with regulatory agencies and as part of our clinical development path for VERVE-101, we have conducted rigorous analyses to ensure that we are advancing a therapy predicted to be both effective and safe,” said Andrew Bellinger, M.D., Ph.D., chief scientific and medical officer of Verve. “These updated findings, leveraging industry-leading and highly sensitive off-target analysis tools, continue to demonstrate minimal to no off-target editing and support our plans to initiate global clinical development with VERVE-101 for later this year.”
Precision Genome Engineering Keystone Symposia Presentation Details
Title: Comprehensive approach to evaluate off-target editing for an in vivo liver base editing medicine targeting the PCSK9 gene
Presented by: Hari Jayaram, Ph.D., Vice President, Editing and Discovery, Verve
Track: Workshop 2: Therapeutic Applications (Joint) Session
Date/Time: April 29, 2022, 2:30 – 2:45 p.m. MT (4:30 – 4:45 p.m. ET)
About Verve Therapeutics
Verve Therapeutics, Inc. (Nasdaq: VERV) is a genetic medicines company pioneering a new approach to the care of cardiovascular disease, transforming treatment from chronic management to single-course gene editing medicines. The company’s initial two programs target PCSK9 and ANGPTL3, genes that have been extensively validated as targets for lowering blood lipids such as low-density lipoprotein cholesterol (LDL-C), a root cause of cardiovascular disease. Verve’s lead product candidate, VERVE-101, is designed to permanently turn off the PCSK9 gene in the liver in order to disrupt blood PCSK9 protein production and thereby durably reduce blood LDL-C levels, with the goal of reducing a patient’s risk for cardiovascular disease. VERVE-101, currently in IND-enabling studies, is being developed initially for the treatment of patients with heterozygous familial hypercholesterolemia, a potentially fatal genetic heart disease. For more information, please visit www.VerveTx.com.
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