FDA Grants Fast Track Designation for Gene Therapy Candidate LX2006 in Friedreich Ataxia Cardiomyopathy


In recent news, Lexeo Therapeutics' gene therapy candidate LX2006 received FDA fast track designation for patients with Friedreich ataxia cardiomyopathy.

R. Nolan Townsend, chief executive officer at Lexeo Therapeutics

R. Nolan Townsend

Credit: Mass General Brigham

According to a recent announcement, the FDA has granted fast track designation to Lexeo Therapeutics’ LX2006, an adeno-associated virus (AAV) gene therapy candidate, for the treatment of Friedreich ataxia (FA) cardiomyopathy. LX2006, a therapy aimed to deliver a functional frataxin gene to promote frataxin protein expression and restore mitochondrial function in myocardial cells, received this designation based on available preclinical data.1

SUNRISE-FA (NCT05445323), an ongoing phase 1/2, dose-ascending, open-label trial, will assess the safety and tolerability, as well as preliminary efficacy, of LX2006 in patients with FA cardiomyopathy. In June 2023, the company announced the completion of patient dosing in the first cohort of the SUNRISE-FA and initial dosing of the first patient in the second cohort.2 SUNRISE-FA includes approximately 9 individuals with FA-associated cardiomyopathy who are followed for a 52-week period. Thus far, preliminary data from the first dose cohort indicated that the therapy was well tolerated, with no unexpected events or toxicities.

Top Clinical Takeaways

  • FDA's fast track designation highlights the urgent need for effective treatments for Friedreich ataxia cardiomyopathy.
  • LX2006, a gene therapy candidate, shows promise in restoring mitochondrial function in myocardial cells.
  • SUNRISE-FA trial aims to assess the safety, tolerability, and preliminary efficacy of LX2006 in patients with FA-associated cardiomyopathy.

“FA cardiomyopathy is the leading cause of death among FA patients, and there are currently no approved treatment options. The FDA’s fast track designation for LX2006 underscores the significant unmet need for effective treatment options to address the cardiac impact of this debilitating disease,” R. Nolan Townsend, chief executive officer at Lexeo Therapeutics, said in a statement.1 “We believe today’s fast track designation, along with the previously announced Rare Pediatric Disease and Orphan Drug designations granted to LX2006, will allow for enhanced regulatory interactions and the potential for this life-improving therapy to reach FA patients more quickly.”

READ MORE: Nanopore Long-Read Sequencing Facilitates Diagnosis of Atypical Ataxia-Telangiectasia

FA is a rare, autosomal recessive disease caused by a mutation in the autosomal frataxin (FXN) gene. Currently, there is no approved therapy that alters the progression of cardiomyopathy in FA, which is responsible for 59% of FA-related deaths. In the study, LX2006 will be administered as a one-time intravenous infusion to patients with FA in at least 2 ascending-dose cohorts with the potential for a third cohort. Investigators will assess the long-term safety and efficacy of LX2006 for an additional 4 years following completion of the initial year of the trial, totaling 5 years of follow-up.1

"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.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."

The 3 cohorts of the trial will assess LX2006 in low, mild, and high doses, with safety, as demonstrated through treatment-emergent adverse events (TEAEs) and treatment-emergent serious events, as the primary outcome. Patients included in the trial are between 18 and 40 years of age, have a confirmed genetic diagnosis of FA, and met protocol specified ranges for antibodies and measures for FA cardiomyopathy. Those with uncontrolled diabetes, abnormal liver function, active infection of any time, and a contraindication to cardiac MRI, were excluded from the study.3

The cardiac involvement seen in FA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and dilated cardiomyopathy. Dilated cardiomyopathy and arrythmia are associated with mortality in patients with FA, whereas hypertrophic cardiomyopathy is not.4

In 2014, a consensus statement for the multidisciplinary treatment of patients with FA recommended that electrocardiogram and echocardiography should be performed at the initial presentation and that patients should be referred to a cardiologist only for cardiac symptoms or abnormal cardiac testing.5 Cardiac MRIs, which can detect remodeling and decreased myocardial perfusion reserve, may be a useful tool in the early detection of disease and/or monitoring the therapeutic response.

1. Lexeo Therapeutics Granted FDA Fast Track Designation for LX2006, an AAV-Based Gene Therapy Candidate for the Treatment of Friedreich Ataxia Cardiomyopathy. News Release. Lexeo Therapeutics. Published April 16, 2024. Accessed April 26, 2024. https://ir.lexeotx.com/news-releases/news-release-details/lexeo-therapeutics-granted-fda-fast-track-designation-lx2006-aav
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. Accessed April 26, 2024. https://www.lexeotx.com/post/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-friedreichs-ataxia-cardiomyopathy/
3. Gene therapy for cardiomyopathy associated with Friedreich’s ataxia. Clinicaltrials.gov. Updated May 10, 2023. Accessed April 26, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05445323
4. Hanson E, Sheldon M, Pacheco B, Alkubeysi M, Raizada V. Heart disease in Friedreich’s ataxia. World J Cardiol. 2019;11(1):1-12. doi:10.4330/wjc.v11.i1.1
5. Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB; Clinical Management Guidelines Writing Group. Consensus clinical management guidelines for Friedreich ataxia. Orphanet J Rare Dis. 2014;9:184. Published 2014 Nov 30. doi:10.1186/s13023-014-0184-7
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