PKP2 Gene Therapy Cleared for Cardiomyopathy Trial


LEXEO also recently completed dosing in the first cohort of a trial for Friedreich’s ataxia cardiomyopathy.

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).1

“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, chief scientific officer, LEXEO, said in a statement.1 “LX2020 seeks to address the underlying cause of this disease by delivering a functional PKP2 gene to halt progression and reverse the disease phenotype. We look forward to initiating the Phase 1/2 clinical trial and rapidly advancing the program through the clinic.”

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. The program is based on research led by Farah Sheikh, PhD, at the University of California, San Diego School of Medicine. Sheikh’s lab developed a mouse model of ACM that better models the disease phenotype in humans and evaluated LX2020 in these models. The therapy demonstrated restored desmosomal and cell-cell junction integrity, leading to improvements in cardiac tissue composition and integrity; alleviation of arrhythmias; and improvements in right and left ventricular function resulting in increased survival in preclinical models.

“I think this is an innovative finding, because everyone always thinks you have to add all of these different genes back together to get this complex to form and anchor back together, and we showed that a single gene is able to do that particular function,” Sheikh told CGTLive about her work in delivering PKP2 via gene therapy in mouse models.

WATCH NOW: Farah Sheikh, PhD, on Modeling Arrhythmogenic Right Ventricular Cardiomyopathy

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. It 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. The trial will have 2 dose-ascending cohorts of 3 patients each. The trial will evaluate participants for long-term safety and efficacy for an additional 4 years after the initial 52-week period.

LEXEO recently announced that it had completed dosing in the first cohort of the SUNRISE-FA trial (NCT05445323) of LX2006 in patients with Friedreich’s ataxia (FA) cardiomyopathy.2 The trial has started dosing in its second cohort based off a positive Data Safety Monitoring Board recommendation after the first dose was well-tolerated with no unexpected events or toxicities observed.

“New treatment approaches, like LEXEO’s LX2006 gene therapy candidate, are critical for individuals and caregivers confronted with the debilitating realities of FA,” Jennifer Farmer, chief executive officer, Friedreich’s Ataxia Research Alliance, said in a statement at that time.2 “Cardiomyopathy is the leading cause of death in individuals diagnosed with FA, so we are incredibly encouraged by the work that LEXEO has undertaken to try to address this life-threatening complication through gene therapy. We are grateful to all the individuals in the FA community who volunteer and participate in research studies and clinical trials.”

1. LEXEO Therapeutics Announces FDA Clearance of IND for LX2020, an AAV-based Gene Therapy Candidate for PKP2 Arrhythmogenic Cardiomyopathy. News release. LEXEO Therapeutics. August 1, 2023.
2. LEXEO Therapeutics announces completion of first cohort and dosing in second cohort in SUNRISE-FA, a phase 1/2 clinical trial of LX2006 for the treatment of Friedreich’s ataxia cardiomyopathy. News release. LEXEO Therapeutics. June 13, 2023.
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