Gene therapy safe, may help heart health in FA, new data show
2 early trials find improvements with heart-targeted treatment LX2006
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Use of the experimental gene therapy LX2006 is generally safe and appears to improve or stabilize markers of heart health among people with Friedreich’s ataxia (FA).
That’s according to newly published data from two early clinical trials that tested the one-time infusion therapy in a small number of FA patients with cardiomyopathy, or disease of the heart muscles. The results overall demonstrated that LX2006 was well tolerated, with early signs of effectiveness seen in both trials, according to Lexeo Therapeutics, the gene therapy’s developer.
The study, “AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich Ataxia A Nonrandomized Clinical Trial,” was published in the journal JAMA Cardiology. The work was funded in part by Lexeo; five of the study’s 25 authors are employed by the developer.
“These positive Phase [1/2] data demonstrate clinically meaningful improvements across both cardiac and neurologic measures of Friedreich ataxia and this publication in JAMA Cardiology further underscores the significance of these results and the potential of this therapy for individuals living with this devastating disease,” Narinder Bhalla, MD, Lexeo’s chief medical officer and a coauthor of the study, said in a company press release.
The developer is now preparing to launch a pivotal trial to further test its therapy candidate.
A genetic disease, FA is marked by abnormally low levels of the protein frataxin. In the heart, a lack of frataxin can lead to cardiomyopathy, and indeed, heart disease is the leading cause of death among people with FA. However, there are no approved therapies for cardiomyopathy specific to the rare condition.
LX2006 increased frataxin protein levels in trial participants
LX2006, also known as AAVrh.10hFXN, is designed to deliver a gene encoding the frataxin protein to heart cells, allowing the heart to produce healthy amounts of the protein. The therapy delivers its genetic payload using a viral vector — basically, a virus that’s been engineered to deliver a therapeutic gene instead of causing infection.
The new study covers outcomes from two early clinical trials testing LX2006: the Phase 1/2 SUNRISE-FA study (NCT05445323), sponsored by Lexeo, and an investigator-initiated Phase 1 study (NCT05302271) funded by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health in the U.S.
Across both trials, 17 adults with FA-related cardiomyopathy received a one-time infusion of LX2006 at one of three doses. Starting prior to the gene therapy infusion, all of the patients received immune-suppressing steroids to reduce the risk of a problematic immune response to the viral vector.
The main goal of the studies was to evaluate the safety of the gene therapy candidate. Four serious safety issues were documented; three of these — a bacterial infection, pneumonia, and severe chest pain — were judged as possibly related to the immune-suppressing steroid regimen.
There was also one case of myocarditis, or heart muscle inflammation, that developed a year after gene therapy and was judged to be possibly related to the viral vector. This heart inflammation did not cause overt symptoms, but it was judged to be serious.
All of the serious safety issues were resolved with appropriate care, and all other safety issues related to the experimental treatment were nonserious and temporary, according to the developer.
Heart biopsies taken three months after gene therapy were available from eight patients. Analyses of these samples showed that LX2006 treatment increased frataxin protein levels as intended in all eight patients, per Lexeo.
New trial to test gene therapy in FA patients with heart disease
A hallmark of FA cardiomyopathy is that the left ventricle — the chamber of the heart responsible for pumping oxygen-rich blood out to the body’s tissues — becomes enlarged. This is reflected by an increased left ventricular mass index (LVMI), a measurement that looks at the size of the left ventricle relative to the size of a person’s body.
In nine patients, LVMI decreased by at least 10% following treatment with LX2006. In another seven patients, LVMI was stable over time — a contrast to the typical progression of FA cardiomyopathy, in which LVMI increases over time as heart disease worsens. The one patient with worsening LVMI was the individual who experienced myocarditis; the researchers noted that it was not possible to tease out the effects of gene therapy versus the impact of this side effect.
All save two patients experienced a decrease of at least 10% in a heart damage marker called serum high-sensitivity troponin I following LX2006 treatment. The two outliers experienced increases of at least 10% in this heart damage marker; one of these patients was the individual with myocarditis.
Taking these data collectively, the researchers concluded that LX2006 “was well tolerated and is a potential treatment for FA cardiomyopathy, as evidenced by preliminary improvement in exploratory efficacy end points.”
In addition to improvements in heart health markers, LX2006 treatment was associated with stabilization over time in the modified Friedreich Ataxia Rating Scale (mFARS), which measures neurological impacts of FA. Again, this contrasts with typical disease development, where mFARS scores worsen over time as the disease progresses. Lexeo said these data suggest that the heart-targeted gene therapy also may provide additional benefits beyond heart health.
Lexeo will now conduct a Phase 2 study, expected to launch soon, to further test LX2006. Assuming results are positive, the company plans to use the trial as a basis for applying for regulatory approval of the gene therapy.
The developer noted that nine trial participants were treated at Weill Cornell Medicine in New York as part of the investigator-initiated study.
“We are grateful to Weill Cornell Medicine and the study investigators for helping advance this program to the next stage of clinical development,” Bhalla said.
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