Lexeo Shares Positive Interim Data for FA Cardiomyopathy Gene Therapy

The maker of a gene therapy candidate for the treatment of Friedreich ataxia (FA) cardiomyopathy has released interim data suggesting the therapy is well tolerated and is associated with improvement in key clinical parameters.

Lexeo Therapeutics, which has been working on gene therapies for genetically defined cardiovascular diseases and APOE4-associated Alzheimer disease, released data from a phase 1/2 clinical trial this week. The release also included data from a Weill-Cornell Medicine investigator-initiated phase 1A trial. Taken together, the data suggest the therapy, known as LX2006, is well tolerated and associated with a reduction in mean left ventricular mass index (LVMI) in patients with elevated LVMI at baseline.¹

FA is a rare genetic condition that leads to progressive nervous system damage. It can cause muscle weakness and discoordination, among other symptoms. However, the most common cause of death among people with the disease is cardiac complications, such as cardiomyopathy.

Eric Adler, MD | Image Credit: Lexeo Therapeutics

Eric Adler, MD, Lexeo’s chief medical officer and head of research, said in a conference call with reporters and investors that patients with FA cardiomyopathy have few options.

“Treatment options for FA cardiomyopathy are extremely limited,” he said. “Medical therapy has not been shown to be effective, and cardiac transplantation is rarely an option given the comorbidities associated with the disease.”

Only one therapy is currently approved to treat FA: omaveloxolone (Skyclarys; Biogen). In clinical trials, it led to meaningful improvement in modified FA rating scale (mFARS) scores.² However, Adler said it has not been evaluated for the treatment of cardiac dysfunction associated with FA.

LX2006 is specifically focused on cardiac manifestations of FA. The therapy delivers a functional frataxin gene, which promotes the expression of the frataxin protein. The frataxin protein is deficient in patients with FA; these individuals have an estimated 2% or less of the normal level of frataxin in the heart. The company believes improving frataxin levels in the heart can help restore mitochondrial function in myocardial cells.

Adler said it is not yet clear just how much frataxin restoration is needed to improve the cardiac health of people with FA, but he pointed to a newly developed murine model that suggested that achieving even 5% of normal frataxin levels in the heart led to near normal cardiac output.³

“As such, we believe a modest amount of frataxin restoration may be sufficient to restore cardiac function or translate to clinical benefit in FA,” he said.

The company’s new interim data are based on 8 patients with at least 6 months of follow-up. Authors said all participants exhibited increased levels of frataxin compared with baseline following treatment with LX2006. They found that three-quarters of patients with elevated LVMI at baseline achieved a reduction of at least 10% at 12 months; there were also mean reductions of 11.4% at 12 months and 18.3% at 18 months. Left ventricular lateral wall thickness was reduced at 12 months, by an average of 13.6% in all patients, they said. High-sensitivity troponin levels, which indicate myocardial injury, were reduced by an average of 53.3% at 12 months.

In terms of safety, the company said neither study has identified any treatment-related serious adverse events thus far, and all adverse events were transient and resolved. The company said there are no signs of complement activation, nor are there any cardiac or hepatic safety signals thus far. No patients have discontinued either study.

Adler said Lexeo is “very encouraged” by the early results and hopes to explore expedited clinical development of the therapy. The press release said the company expects to share further details of their interim results in the fall of this year. Meanwhile, the Weill-Cornell investigator-initiated trial is currently enrolling a second cohort of patients.

References

1. Lexeo Therapeutics announces positive interim phase 1/2 clinical data of LX2006 for the treatment of Friedreich ataxia cardiomyopathy. News release. Lexeo Therapeutics. July 15, 2024. Accessed July 16, 2024. https://ir.lexeotx.com/news-releases/news-release-details/lexeo-therapeutics-announces-positive-interim-phase-12-clinical

2. Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann Neurol. 2021;89(2):212-225. doi:10.1002/ana.25934

3. Gérard C, Archambault AF, Bouchard C, Tremblay JP. A promising mouse model for Friedreich Ataxia progressing like human patients. Behav Brain Res. 2023;436:114107. doi:10.1016/j.bbr.2022.114107