Gene Therapy Improves Some Disease Biomarkers of Friedreich Ataxia Cardiomyopathy
Despite the improvements, Lexeo was unable to discern a benefit on cardiovascular fitness and Peak VO2 from LX2006 with current measurements.
Jonathan W. Weinsaft, MD,
Credit: Weill Cornell Medicine
LX2006 gene therapy (Lexeo Therapeutics) improved some disease biomarkers in treated patients with Friedreich Ataxia (FA) cardiomyopathy, according to interim data from the Lexeo SUNRISE-FA Phase 1/2 clinical trial (NCT05445323) and the Weill Cornell Medicine investigator-initiated phase 1A trial (NCT05302271) evaluating the therapy.1
LX2006 is an adeno-associated virus (AAV) vector gene therapy designed to deliver a functional frataxin gene to promote frataxin protein expression and restore mitochondrial function in myocardial cells.
“We're particularly excited by the potential of gene therapies to address rare conditions. We're doing active research that is funded by NIH, focused on FA, which is a rare condition that can affect both the neurologic system as well as the cardiovascular system. And in fact, cardiovascular clauses are a leading cause of death in that patient population,” Jonathan W. Weinsaft, MD, chief of cardiology and professor of medicine at Weill Cornell Medical College, told CGTLive®.
“We are very encouraged by these data and the potential of LX2006 to treat FA cardiomyopathy, a devastating and fatal condition with no currently approved therapies,” Eric Adler, MD, the chief medical officer and head of research at Lexeo Therapeutics, said in a statement.1 “Based on the favorable safety profile and clinical benefits observed to date, we are excited to explore expedited clinical development of LX2006, including potential for accelerated approval of this possibly life-saving treatment.”
WATCH NOW: Farah Sheikh, PhD, on Preclinical Research on Arrhythmogenic Cardiomyopathy Gene Therapy LX2020
Investigators found that LX2006 was well tolerated with no treatment-related serious adverse events (AEs), complement activation or other immunogenicity, cardiac or hepatic safety signals observed to date. All AEs were transient and resolved, and no participants discontinued from either study.
Interim clinical data were presented in a webcast from 8 participants with over 6 months of follow-up. Most participants with elevated left ventricular mass index (LVMI) at baseline, 75% achieved over a 10% reduction at 12 months (n = 4), with a mean reduction of 11.4% at 12 months (n = 4) and 18.3% at 18 months (n = 2). Of all participants, 50% achieved over 10% reduction in LVMI at 12 months (n = 6). Overall, participants had a 13.6% mean reduction in left ventricular (LV) lateral wall thickness at 12 months (n = 6) and a 53.3% reduction in high-sensitivity Troponin I at 12 months (n = 5). Investigators also observed increases in frataxin levels from baseline in all evaluable participants on liquid chromatography mass spectrometry and immunohistochemistry.
Investigators also measured peak VO2 but were not able to show a conclusive benefit on the cardiovascular fitness measure. Three participants were unable to achieve the maximal exercise capacity level needed to reliably interpret peak VO2. The other 5 participants had mean improvements of 1% after 6 months and 4% after 12 months. Lexeo stated that neurologic symptoms of FA interfered with the Upper Limb Cardiopulmonary Exercise Test and noted that it will look into other cardiopulmonary exercise test measures that may be able to better demonstrate a benefit.
“The interim data shared today demonstrate clinically meaningful improvements across multiple cardiac biomarkers of hypertrophy, a hallmark of FA cardiomyopathy,” Sandi See Tai, MD, the chief development officer at Lexeo, added.1 “Together with the increases in frataxin protein expression observed in SUNRISE-FA cardiac biopsies to date, these results further highlight the potential of LX2006 to positively impact outcomes for people with FA cardiomyopathy. I would like to thank the participants, caregivers, and investigators participating in these trials who have helped to achieve this important milestone.”
Across both trials, 13 participants have been dosed as of July 15, 2024, in cohorts 1 (1.8 x 1011 vg/kg; n = 6), 2 (5.6 x 1011 vg/kg; n = 6), and 3 (1.2 x 1012 vg/kg; n = 1). Lexeo will share further data from the trials at a scientific conference in the latter half of 2024.
Lexeo also has a gene therapy in its pipeline for another type of cardiomyopathy, arrhythmogenic cardiomyopathy. The therapy, LX2020, is currently being evaluated in a first-in-human trial after the FDA cleared its investigational new drug application in August 2023.2
