Benefits seen with Friedreich’s ataxia heart disease gene therapy
LX2006 led to improvements in cardiac biomarkers, functional measures
The investigational gene therapy LX2006 was well tolerated and led to clinically meaningful improvements in cardiac biomarkers and functional measures in people with Friedreich’s ataxia (FA) and a type of heart disease called cardiomyopathy, the results from two clinical trials show.
The findings informed the design of a planned registrational clinical trial that Lexeo Therapeutics seeks to start by early next year, with a potential efficacy data readout in 2027. Registrational means the results would support applications toward LX2006’s regulatory approval, if they’re positive.
“These data provide strong evidence that LX2006 is acting as a beneficial disease-modifying treatment candidate, supporting its continued development as a potential first- and best-in-class therapy for FA cardiomyopathy,” Eric Adler, MD, chief medical officer and head of research at Lexeo, said in a company press release.
FA is caused by mutations in the FXN gene, leading to a deficiency in frataxin, a protein important for cellular energy production. Nerve and muscle cells, which are particularly vulnerable to frataxin loss, become damaged. Most people with FA develop heart problems, usually manifesting as cardiomyopathy, a disease of the heart’s muscle that affects its ability to pump blood to the rest of the body.
Studying LX2006
LX2006 is designed to deliver a working version of FXN to heart muscle cells, thereby enabling them to make frataxin and restore more normal energy production, in turn improving heart function. It’s being tested in two open-label trials — the Lexeo-sponsored SUNRISE-FA Phase 1/2 trial (NCT05445323) and another investigator-initiated Phase 1 study (NCT05302271) sponsored by Weill Cornell Medicine. Both involve adults with FA, ages 18-50, who have signs of cardiomyopathy. SUNRISE, which finished recruiting last year, enrolled eight participants. The other study, which may still be recruiting, seeks to enroll 25 people.
The participants are receiving a single infusion of LX2006 into the bloodstream at one of three doses and are being monitored initially for a year. The main goal is to evaluate safety, with indicators of cardiac and physical function as secondary outcomes. Long-term safety and efficacy will be monitored for four years thereafter.
Previous interim analyses found LX2006 to be well tolerated with signs of improvement in key cardiac parameters.
Lexeo reports that as of March 25, 16 people have been treated across the two studies. At the start, six had an elevated left ventricular mass index (LVMI), which reflects the presence of cardiac hypertrophy, where the heart’s main pumping chamber is thickened and enlarged.
Safety data indicated the gene therapy has been well tolerated, with no severe adverse events. There also haven’t been signs of abnormal immune activation or excessive frataxin levels in heart tissue. One observed case of inflammation in the heart muscle may have been related to treatment.
Efficacy data covered 12 participants who had at least six months of follow-up.
Among the six people with an abnormal baseline LVMI, results showed a 27% mean improvement as of the latest visit, with five participants achieving a normal range LVMI measurement. Higher doses were linked to greater improvements.
Most of the six people with normal baseline LVMI exhibited an LVMI improvement or stabilization over time, according to Lexeo. Most participants also saw improvements in other indicators of cardiac health, and in measures of functional status.
Heart tissue biopsies collected in SUNRISE-FA showed that all participants achieved an increase in cardiac frataxin levels after three months, with the greatest increases in those given the highest dose.
“We believe these data show LX2006 exceeding the thresholds aligned with the U.S. Food and Drug Administration (FDA) to support accelerated approval in the planned registrational study,” noted Sandi See Tai, MD, chief development officer at Lexeo.
Goals of planned LX2006 trial
The planned trial will enroll 12-16 adults with FA and abnormal LVMI who will receive the highest dose of LX2006 tested in the previous trials.
In conversations with the FDA, Lexeo has settled on two primary goals — to achieve a more than 10% improvement in LVMI after a year and to see an increase in frataxin levels after three months. LX2006’s safety will also be evaluated in smaller groups of adolescents and children.
The company also plans to soon start enrolling participants with FA cardiomyopathy in a natural history study called CLARITY-FA (NCT06865482) that will serve as an external control arm for the registrational trial.
“We are eager to advance this promising candidate as quickly as possible to support adults and children living with the devastating and fatal impacts of FA cardiomyopathy,” See Tai said.
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