VERVE-101 / Eli Lilly, Verve Therapeutics - LARVOL DELTA

Gene Therapy for Cardiovascular and Cerebrovascular Disease: Mechanisms, Translational Barriers, and the Road Ahead. (PubMed, Biomedicines) - "For atherosclerosis, RNA-based agents, notably inclisiran, alongside in vivo editing strategies such as VERVE-101, offer durable lipid reduction and attenuation of vascular inflammation. Collectively, these approaches position gene therapy as a meaningful complement to standard care, capable of addressing root molecular pathology rather than downstream consequences. This review synthesises current mechanistic understanding, translational obstacles, and emerging directions across these three disease domains, arguing that, delivery and safety challenges notwithstanding, gene therapy stands to substantially reshape how cardiovascular and cerebrovascular diseases are prevented and treated."

Journal • Review • Atherosclerosis • Cardiovascular • CNS Disorders • Gene Therapies • Inflammation • Ischemic stroke • Vascular Neurology • BDNF • KCNH2 • KCNQ1OT1 • NEUROD1 • STING

RNA-Targeted Therapeutics for Lipid Metabolic Disorders: From Bench to Bedside. (PubMed, Research (Wash D C)) - "Examples include inclisiran (targeting proprotein convertase subtilisin/kexin type 9 [PCSK9]) and agents against apolipoprotein C-III (APOC3), lipoprotein(a) [Lp(a)], and angiopoietin-like protein 3 (ANGPTL3)...Additionally, mRNA lipid nanoparticle-based in vivo base editing (e.g., VERVE 101/102 targeting PCSK9) has entered clinical trials, offering potential for permanent genetic correction with a single infusion...The recent 2026 American College of Cardiology/American Heart Association dyslipidemia guideline emphasizes the clinical importance of targeting PCSK9, APOC3, Lp(a), and ANGPTL3. This review provides a state-of-the-art overview of RNA-targeted therapeutics in hyperlipidemia and discusses future research directions in this emerging field."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • ANGPTL3

Cholesterol metabolism: molecular mechanisms, biological functions, diseases, and therapeutic targets. (PubMed, Mol Biomed) - "Emerging therapeutic strategies extend beyond conventional statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to include transformative modalities: CRISPR-based in vivo gene editing (e.g., VERVE-101 targeting PCSK9), small interfering RNA (siRNA) therapeutics (inclisiran), and microbiota-directed interventions. Pioneering approaches against targets Such as angiopoietin-like 3 (ANGPTL3), lipoprotein(a) [Lp(a)], and asialoglycoprotein receptor 1 (ASGR1)-alongside repurposed natural agents (berberine, probiotics)-offer promise for mitigating residual cardiovascular risk and advancing precision cardiometabolic medicine. By integrating mechanistic insights with clinical advancements, this review underscores the transition from broad-spectrum therapies to personalized, multi-target regimens, offering a roadmap for mitigating cholesterol-related diseases in the era of genomic and metabolic medicine."

Journal • Review • Atherosclerosis • Cardiovascular • CNS Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • ANGPTL3 • ASGR

A Study of VERVE-101 in Patients With Familial Hypercholesterolemia and Cardiovascular Disease (clinicaltrials.gov) - P1 | N=13 | Completed | Sponsor: Verve Therapeutics, Inc. | Active, not recruiting ➔ Completed | N=44 ➔ 13 | Trial completion date: Jun 2025 ➔ Feb 2025 | Trial primary completion date: Jun 2025 ➔ Feb 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders

CRISPR-Cas9 Targeting PCSK9: A Promising Therapeutic Approach for Atherosclerosis. (PubMed, J Cardiovasc Transl Res) - "Early clinical studies of gene editing therapies like VERVE-101 have yielded encouraging results, highlighting both the feasibility and potential efficacy of this technology...Additionally, the establishment of ethical and legal regulatory frameworks will be critical for the safe adoption of this technology. With the continued advancement of gene editing technology, CRISPR-Cas9 may become an important tool for treating atherosclerosis and other complex diseases."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia

A Study of VERVE-101 in Patients with Familial Hypercholesterolemia and Cardiovascular Disease (clinicaltrials.gov) - P1 | N=44 | Active, not recruiting | Sponsor: Verve Therapeutics, Inc. | Trial completion date: Dec 2024 ➔ Jun 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders

VERVE-101, a CRISPR base-editing therapy designed to permanently inactivate hepatic PCSK9 and reduce LDL-cholesterol. (PubMed, Expert Opin Investig Drugs) - No abstract available

Journal

Characterization of Guide RNA Site Consistency Across Ancestries and the Potential for Off-Target Editing with the Clinical-Stage Base Editing Medicine, VERVE-101 (ASGCT 2024) - "VERVE-101 is the first in vivo base editing medicine to demonstrate proof-of-concept in humans. The consistency of the gRNA target site across populations suggests the potential therapeutic benefits of VERVE-101 should apply broadly across individuals with diverse ancestries. Comprehensive off-target assessment in different cellular contexts demonstrated VERVE-101 to be highly specific with a low risk for clinically relevant off-target edits."

Clinical • Dyslipidemia • Oncology • PCSK9

A Study of VERVE-101 in Patients With Familial Hypercholesterolemia and Cardiovascular Disease (clinicaltrials.gov) - P1 | N=44 | Active, not recruiting | Sponsor: Verve Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2023 American Heart Association Scientific Sessions. (PubMed, Curr Atheroscler Rep) - "Included studies assessed semaglutide and cardiovascular outcomes in overweight or obese patients without diabetes (SELECT); dapagliflozin in patients with acute myocardial infarction without diabetes (DAPA-MI); effects of dietary sodium on systolic blood pressure in middle-aged individuals (CARDIA-SSBP); long-term blood pressure control after hypertensive pregnancy with physician guided self-management (POP-HT); effect and safety of zilebesiran, an RNA interference therapy, for sustained blood pressure reduction (KARDIA-1); recaticimab add-on therapy in patients with non-familial hypercholesterolemia and mixed hyperlipidemia (REMAIN-2); efficacy and safety of lepodisiran an extended duration short-interfering RNA targeting lipoprotein(a); safety and pharmacodynamic effects of an investigational DNA base editing medicine that inactivates the PCSK9 gene and lowers LDL cholesterol (VERVE-101); automated referral to centralized pharmacy services for evidence-based statin..."

Journal • Review • Acute Coronary Syndrome • Cardiovascular • Diabetes • Dyslipidemia • Genetic Disorders • Metabolic Disorders • Myocardial Infarction • Obesity • PCSK9

A Study of VERVE-101 in Patients With Familial Hypercholesterolemia and Cardiovascular Disease (clinicaltrials.gov) - P1 | N=44 | Recruiting | Sponsor: Verve Therapeutics, Inc. | Phase classification: P1b ➔ P1

Phase classification • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders

VERVE-101: a promising CRISPR-based gene editing therapy that reduces LDL-C and PCSK9 levels in HeFH patients. (PubMed, Eur Heart J Cardiovasc Pharmacother) - No abstract available

Journal • Dyslipidemia • Heterozygous Familial Hypercholesterolemia

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 (AHA 2023) - P1b | "After pre-medication with dexamethasone and antihistamines, VERVE-101 is delivered as a single peripheral intravenous infusion. These interim data will be the first reported results for any in vivo DNA base editing medicine administered to human trial participants. Proof-of-concept demonstration of a clinically meaningful and durable reduction in LDL-C would support further investigation of single-course editing approaches to inactivate PCSK9 for the treatment of ASCVD."

Clinical • Late-breaking abstract • P1 data • PK/PD data • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders • PCSK9

Discussion with VERVE-101 Trialist (AHA 2023) - "There is no abstract associated with this presentation."

MTT.03. Meet the Trialist - VERVE-101 (AHA 2023) - No abstract available

VERVE-101—An Investigational Single-Course Gene Editing Medicine Targeting PCSK9—Durably and Potently Lowers PCSK9 and LDL-C Concentrations in Non-Human Primates (AHA 2022) - "A single intravenous infusion of VERVE-101 in non-human primates was well-tolerated and led to 89% lower blood PCSK9 protein and 68% lower blood LDL-C at one year after dosing. These results support initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease, with initial patient dosing anticipated in mid-2022."

Atherosclerosis • Cardiovascular • Dyslipidemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • PCSK9

"When should we expect Verve to respond to the FDA hold on Verve 101?" (,@Cap_ital_Gains)

New Approaches for Targeting PCSK9: Small-Interfering Ribonucleic Acid and Genome Editing. (PubMed, Arterioscler Thromb Vasc Biol) - "In this review, we discuss the history of targeting PCSK9 with the use of mRNA and small-interfering ribonucleic acid. We also shed light on targeting PCSK9 with genome editing, including discussion of the VERVE-101 clustered regularly interspaced short palindromic repeats-base editing medicine currently being evaluated in a clinical trial and others in development."

Journal • Cardiovascular • Coronary Artery Disease • Dyslipidemia

"Any timeline for US FDA Verve-101 approval?" (,@seekerweb)

FDA event

"$VERV VERVE-101 IND Placed on Hold by the FDA" (,@BioStocks)

"For serious, undruggable diseases where quality of life is affected or a terminal prognosis is given, I can understand the risk. But for non-serious, druggable diseases where an effective alternative exists, it's way too dangerous and outright unethical. Verve-101 @skathire $VERV" (,@BioBoyScout)

HEOR

Efficacy and Safety of an Investigational Single-course CRISPR Base Editing Therapy Targeting PCSK9 in Non-human Primate and Mouse Models. (PubMed, Circulation) - "VERVE-101 was well-tolerated in in non-human primates and led to 83% lower blood PCSK9 protein and 69% lower LDL-C with durable effects up to 476 days following dosing. These results have supported initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders • PCSK9

"VERVE-101 - durable, potent Mean 83% reduction in blood PCSK9 protein & 69% reduction in LDL-C was observed in NHPs treated with 1.5 mg/kg of VERVE-101, durable out to 476 days" (,@skathire)

A Study of VERVE-101 in Patients With Familial Hypercholesterolemia and Cardiovascular Disease (clinicaltrials.gov) - P1b | N=44 | Recruiting | Sponsor: Verve Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders • LDLR

"U.S. IND and U.K. CTA clearances expected in 2H 2022 for VERVE-101 https://t.co/ewQeWXpN5P" (,@skathire)