Shyam Bhakta, MD, MBA
Contributing Editor, Editorial Board, Telegraft Member Newsletter
Member, Cardiovascular Interdisciplinary Program and Working Group, National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio, USA
High cholesterol, both genetic/hereditary and acquired, is a major risk factor for cardiovascular disease, which is the leading cause of death and disability globally. Acute vascular events, such as myocardial infarction, known colloquially as heart attack, as well as stroke, often times occur in apparently healthy individuals without previous symptoms or signs of impending heart disease. Data from the landmark Framingham Heart Study demonstrated a linear, proportionate increase in heart attack and stroke with increasing blood levels of total cholesterol and low-density lipoprotein (LDL), the latter of which has a strong association with cardiovascular disease.
While a healthy lifestyle consisting of a diet low in cholesterol and saturated fat accompanied by regular exercise and weight management can lower cholesterol, lifestyle modifications can lower cholesterol by only 15 percent, leaving many patients with residual high cholesterol and risk for heart disease. Conventional oral medications for the treatment of high cholesterol have been available for almost a half-century. While these drugs are generally safe, many patients either refuse to initiate medications altogether or discontinue them after several weeks, months, and even years due to real or purported adverse effects. As many as 50 percent of patients discontinue medication within one year following initiation (2).
While newer, novel, injectable medications are available that are very safe, they are not as effective as older, less-expensive, and more widely available generic cholesterol-lowering medications. In addition, high out-of-pocket costs of newer, novel, injectable medications due to co-insurance, high-deductible health plans, and other out-of-pocket expenses place such medications out of reach for many patients, including those in developing and/or lower-income nations.
LDL cholesterol binds to the LDL receptor (LDL-R) in the liver, is internalized, and metabolized. Many patients with premature heart disease, defined as the diagnosis or development of heart disease before the age of 65, have either increased endogenous production of LDL cholesterol and/or reduced or inadequate clearance of LDL cholesterol from the blood, leading to high residual cholesterol and risk for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) receptor, expressed constitutively by the liver, downregulates LDL-R, thus reducing LDL clearance from the bloodstream. Individuals homozygous recessive for PCSK9 were found to have very low LDL levels and low risk for cardiovascular disease.
Currently approved medications targeting PCSK9 include alirocumab (Praluent®; Regeneron®) and evolocumab (Repatha®; Amgen®), both of which are humanized monoclonal antibodies and administered either once or twice monthly. Inclisiran (Leqvio®; Novartis®) is a small interfering RNA (siRNA) oligonucleotide against PCSK9 and administered just once every six months during the maintenance treatment phase. The monoclonal antibody medications lower LDL cholesterol by 40 percent, whereas the siRNA agent lowers cholesterol by over 50 percent. Alirocumab and evolocumab both have been shown to reduce the risk of first and recurrent heart attack. While such endpoint data for inclisiran is not currently available, these trials are ongoing and expected to demonstrate reductions in cardiovascular events as well.
Despite the safety, efficacy, and infrequent dosing of these agents, cost and adherence remain challenges. Alirocumab and evolocumab require patient self-injection, and inclisiran requires patients to visit an infusion center. Hence, the need for novel, “one-stop-shopping” agents remains for this pervasive problem.
VERVE-102 (Verve Therapeutics) is an mRNA encoding an adenine base editor and guide RNA (gRNA) targeting PCSK9 and packaged in a novel GalNAc lipid nanoparticle (LNP). VERVE-102 consists of an A->G DNA edit, creating a premature stop codon that inactivates PCSK9 within hepatocytes. DNA sequence analysis of 784,318 individuals from diverse ethnic and racial backgrounds identified homology of this sequence targeted by the gRNA in 99.97 percent of screened individuals. LNP hepatocyte delivery occurs through either endogenous LDL-R uptake or GalNAC-medicated endocytosis via the asialoglycoprotein receptor (1). The drug is administered over two to four hours (2).
The Heart-2 study is a phase 1b trial in which a single escalating dose of VERVE-102 was given to men and women between the ages of 18 and 65 with either heterozygous familial hypercholesterolemia (HeFH) or premature coronary disease requiring multiple cholesterol-lowering medications. HeFH is a common Mendelian disease in which patients are deficient in LDL-R and have high circulating LDL cholesterol, increasing risk for heart attack and/or stroke in their 30s or 40s. Homozygous familial hypercholesterolemia (HoFH), a more severe form of this entity, leads to even higher circulating LDL levels and leads to heart attacks and other cardiovascular events in patients in their teens or 20s. Currently, the only curative treatment for HoFH remains liver transplantation, a safe and effective procedure but out of reach for many patients due to limited donor organ availability, patient selection, and long-term health concerns post-transplantation as well as adverse effects from immunosuppressive medications.
The Heart-2 study administered VERVE-102 to three cohorts of patients at doses consisting of 0.3, 0.45, and 0.6 mg/kg. Endpoints included safety as well as reductions in LDL and PCSK9 blood levels. VERVE therapeutics announced recently the results of the dose-escalating study in the first 14 patients (2). Average total RNA dose across the three dose groups was 20, 37, and 45 mg and resulted in reductions in LDL from baseline of 21, 41, and 59 percent, respectively. Study drug administration was well-tolerated with no serious treatment-associated adverse effects reported. VERVE Therapeutics’ Investigational New Drug (IND) application was approved by the United States Food and Drug administration. A Phase 2 clinical trial will be initiated soon.
While these results are preliminary and the sample size is small, this strategy presents a very exciting strategy to the treatment of heart disease. As stated earlier, cardiovascular disease remains the leading cause of death and disability globally. Premature coronary artery disease is an especially daunting problem, afflicting younger patients during peak periods of labor force participation, productivity, and wealth accumulation. Cardiovascular disease also accounts for 20 – 40 percent of government health expenditures. Currently in the United States, important debates continue on regarding the long-term sustainability of the landmark Medicare program, and proposed cuts to the Medicaid program are being considered that will affect healthcare access for millions. Safe and effective treatments that are well-tolerated by patients and demonstrate good adherence present a potential solution to both the prevention of first events of heart disease as well as secondary prevention of recurrent events throughout one’s lifetime. These preliminary findings demonstrate the amazing and exciting potential of cell, gene, and regenerative therapies for the treatment of severe diseases that present a risk to so many.
References
- Vafai, S et al. Abstract 4139206: Design of Heart-2: a phase 1b clinical trial of VERVE-102, an in vivo base editing medicine delivered by a GalNAc-LNP and targeting PCSK9 to durably lower LDL cholesterol. Circulation, 11 November 2024; 150(S1).
- Verve Therapeutics Announces Positive Initial Data from the Heart-2 Phase 1b Clinical Trial of VERVE-102, an In Vivo Base Editing Medicine Targeting PCSK9. 14 April 2025; https://ir.vervetx.com/news-releases/news-release-details/verve-therapeutics-announces-positive-initial-data-heart-2-phase; accessed 20 April 2025.