CGTLive's Pillars of Progress 2023: Top News in Cardiology

For all of 2023, the CGTLive^™ team was following along the clinical development of targeted and novel engineered approaches to the treatment of patients with various medical disorders. These efforts included holding in-depth conversations with experts in the clinical care of these individuals, as well as in cell and gene therapy development, culminating in our coverage of each step of progress that the most exciting cellular and genetic treatments have made along the pipeline.

From major data publications and presentations to FDA decisions and major medical meetings, the team spent all year bringing the latest information to the website's front page.

Among our areas of focus in 2023 has been cardiology. Several gene therapies for cardiology indications made progress in the pipeline this year and notable data from some of these programs were presented at the American Heart Association’s (AHA) Scientific Sessions 2023, held November 10-13 in Philadelphia, Pennsylvania. The major news items appeared among the top pieces our team produced—but sometimes smaller stories reach those heights as well because of their clinical impact, their inventive mechanisms, or otherwise. Whatever the reason for the attention these stories got, their place here helps provide an understanding of the themes in cardiology over the course of 2023.

Here, we'll highlight some of the most-read content on CGTLive's cardiology page this year. Click the buttons to read further into these stories.

1. Patients With Congestive Heart Failure Show Clinically Meaningful Improvements After Gene Therapy

• AskBio presented data from a phase 1/2 trial of AB-1002 gene therapy at the AHA Scientific Sessions 2023 meeting.
• Investigators found that 3 of 6 patients in cohort 1, those that completed 12-month follow-up, showed clinically meaningful improvements in left ventricular ejection fraction, NYHA Functional Class, Minnesota Living with Heart Failure Questionnaire, cardiopulmonary exercise test (VO2 max), and 6-minute walk test compared to baseline
• AB-1002 is a cardiotropic adeno-associated virus (AAV) vector gene therapy, administered via injection to the heart, designed to promote increased production of a therapeutic protein inhibitor 1 and block protein phosphatase 1, which has been linked to CHF.

November 18, 2023 — Patients with congestive heart failure (CGF) treated with AB-1002 (AskBio; NAN-101) gene therapy showed clinically meaningful improvements in multiple functional outcomes in a phase 1/2 clinical trial (NCT04179643). Data from the trial were presented at the AHA Scientific Sessions 2023.

"We believe these encouraging early results in patients with advanced heart failure are important for the congestive heart failure community, as they bring hope to a sub-population where treatment options are needed."

– Litsa G. Kranias, PhD, of University of Cincinnati

2. PKP2 Gene Therapy Cleared for Cardiomyopathy Trial

• LX2020 is an AAVrh10-based gene therapy candidate designed to intravenously deliver a functional PKP2 gene to cardiac muscle to increase PKP2 protein levels in the cardiac desmosome.
• LEXEO plans to initiate the phase 1/2 HEROIC-PKP2 first-in-human trial, which will be an open-label, dose-escalating, 52-week trial.
• The study will evaluate the safety and tolerability of LX2020 in adult patients with PKP2-ACM as well as efficacy measures including myocardial protein expression, biomarkers measuring cardiac structure and function, and arrhythmia burden.

August 1, 2023 — The FDA has granted investigational new drug (IND) clearance to LEXEO Therapeutics’ LX2020 for the potential treatment of arrhythmogenic cardiomyopathy (ACM) caused by variants in the PKP2 gene (PKP2-ACM).

“This IND clearance marks an important step in advancing a potential one-time treatment for individuals with PKP2-ACM, who are in need of more effective options for this devastating disease. Current clinical management strategies are only marginally effective and primarily focus on symptom management.”

– Eric Adler, MD, of LEXEO

3. Hypertrophic Cardiomyopathy Gene Therapy Receives IND Clearance

• TN-201 is meant to provide a functional copy of MYBPC3 with the intention of halting or reversing disease progression via restoration of MYBPC3 protein production to normal levels.
• The planned phase 1b clinical trial will aim to enroll 6 or more adult patients with New York Heart Association class II or III symptomatic MYBPC3-associated nonobstructive HCM who have an implantable cardioverter defibrillator.
• The study will evaluate safety, markers of cardiac transduction and transgene expression in right ventricular biopsy samples, changes in circulating cardiac biomarkers, imaging biomarkers (via echocardiogram and changes in exercise capacity), symptom burden, and quality of life.

January 13, 2023 — Tenaya Therapeutics’ TN-201, an investigational AAV-vector based gene therapy intended to treat hypertrophic cardiomyopathy (HCM) caused by mutations in the MYBPC3 gene, has received clearance of its IND by the FDA.

“TN-201 is being developed by Tenaya to correct the underlying genetic cause of HCM after a single dose, offering the hope of restoring normal contractility and preventing the serious complications associated with this disease.”

– Whit Tingley, MD, PhD, of Tenaya Therapeutics

4. CRISPR Editing Therapy Reduces LDL-C in Familial Hypercholesteremia in Small Trial

• HeHF, which affects around 3 million people in the United States and Europe, involves lifelong severe elevations in LDL-C and accelerated ASCVD.
• The disease is currently treated under a chronic care model consisting of daily pills and intermittent injections over decades, leading to a large treatment burden on patients.
• VERVE-101 uses CRISPR/Cas9 to inactivate the PCSK9 gene in hepatic cells via a single base pair change.

November 13, 2023 — VERVE-101 CRISPR base editing therapy significantly reduced low-density lipoprotein cholesterol (LDL-C) in people with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic cardiovascular disease (ASCVD) treated in the phase 1b heart-1 clinical trial (NCT05398029). Data from the first-in-human trial were presented at the AHA Scientific Sessions 2023.

“Instead of daily pills or intermittent injections over decades to lower bad cholesterol, this study reveals the potential for a new treatment option – a single-course therapy that may lead to deep LDL-C lowering for decades."

– Andrew M Bellinger, MD, PhD, of Verve Therapeutics

5. Single RNAi Therapy Injection Controls Mild-to-Moderate Hypertension for 6 Months

• Zilebesiran targets angiotensinogen, a hormone produced predominantly in the liver that contributes to blood pressure regulation.
• One injection of zilebesiran significantly reduced blood pressure in adults with mild-to-moderate hypertension for up to 6 months.
• The therapy was well-tolerated, with a few cases of mild, treatment adverse events, the most of which were infusion site reactions.

November 14, 2023 — A single injection of the investigational RNA interference therapy zilebesiran (Alnylam) lowered blood pressure in adults with mild-to-moderate hypertension for up to 6 months with a favorable safety profile. Data on zilebesiran, from the phase 2 KARDIA-1 trial (NCT04936035), were presented at the AHA Scientific Sessions 2023.

“Uncontrolled high blood pressure is a leading cause of death and disease, so there is a need for new treatments that provide sustained blood pressure control over longer periods of time. This will improve outcomes for people with hypertension."

– George Bakris, MD, of University of Chicago Medicine