Gene Therapy 4D-310 Boosts Heart Health in 3 Patients After 1 Year

Phase 1/2 trials of the gene therapy are ongoing in the US, Taiwan, and Australia

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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One year after treatment with 4D-310, an experimental gene therapy for Fabry disease, measures of heart health have improved in the first three participants in a clinical trial, according to new data announced by the therapy’s developer, 4D Molecular Therapeutics (4DMT).

“4D-310 holds promise as a potential first-in-class treatment for Fabry disease-associated cardiomyopathy [heart disease], the leading cause of death in this patient population, as demonstrated by the cardiac clinical data announced today,” Eric Adler, MD, a professor at the University of California at San Diego and trial investigator, said in a press release.

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4D-310 uses a viral vector to deliver a healthy copy of the GLA gene

Fabry disease is caused by mutations in the GLA gene. 4D-310 is designed to use a viral vector to deliver a healthy copy of this gene to cells in the body.

“Utilizing a novel vector invented at 4DMT with the goal of achieving increased delivery and transduction within the heart in humans, 4D-310 is designed to enable [GLA gene] expression and disease correction directly within cardiomyocytes [heart cells],” Adler said.

4DMT is currently conducting two Phase 1/2 clinical trials testing 4D-310 in patients with Fabry disease: one is being run in the U.S. (NCT04519749), the other in Taiwan and Australia (NCT05629559). According to the company, a total of six patients have so far been given the gene therapy across the two studies.

All six patients received a dose of 10 trillion vector genomes per kilogram of body weight. Participants also received immune-suppressing corticosteroids to help prevent an immune response against the viral vector that could diminish the therapy’s efficacy or cause side effects.

4D-310 holds promise as a potential first-in-class treatment for Fabry disease-associated cardiomyopathy [heart disease], the leading cause of death in this patient population

3 patients developed atypical hemolytic uremic syndrome

Three of the six patients developed atypical hemolytic uremic syndrome (aHUS), a disorder characterized by the destruction of red blood cells that carry oxygen through the bloodstream.

One of the cases was severe and qualified as a dose-limiting toxicity event, meaning the therapy’s dose was likely too toxic for clinical use in that case. The patient experiencing this severe event, a 69-year-old man with underlying kidney disease, required temporary hemodialysis, which was not needed in the other two patients.

In all three patients who developed aHUS, the complication was resolved within two to four weeks. No other serious side effects or safety problems have been documented, and there have been no clinically significant toxicities detected by lab tests, according to 4DMT.

As of January 2023, no new participants will be enrolled in the two Phase 1/2 trials, the company has announced. The studies will continue to collect data on the six enrolled patients, and 4DMT will be evaluating next steps for the gene therapy later this year, once one-year data is available for all six patients.

Future trials of the gene therapy likely will not use the corticosteroid-based immune suppression regimen used in these studies, the company noted. 4DMT is currently evaluating another immune-suppressing treatment regimen — a combination of rituximab and sirolimus — which may potentially help prevent toxicity-related events and complications like aHUS.

“We look forward to working with the 4D team to design and evaluate potential treatment regimens based on rituximab and sirolimus which in our clinical experience is effective at preventing aHUS,” Adler said.

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One-year data available for three patients in US trial

As of late 2022, one-year data was available for three of the patients, all of whom participated in the U.S. trial.

Results showed that two of the three patients experienced improvements in peak VO2, a measure of how well the heart and lungs can provide oxygen to body tissues during exercise.

Before treatment with 4D-310, two of the three patients had abnormally low scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ), a measure of heart health-related quality of life. Scores improved in both of these patients after one year. In the third patient, scores were normal at the study’s start and remained stable after one year.

Heart imaging (echocardiography) done to assess the function of the left ventricle — one of the heart’s lower chambers that pumps oxygen-rich blood out to the rest of the body — showed improvements after one year in all three patients. MRI of heart tissue showed improvements in two of the patients; MRI data was not yet available for the third patient at the time of this analysis.

Full data from the trial are expected to be presented at a conference in late February, according to 4DMT.

The company also announced that it has communicated with the U.S. Food and Drug Administration about measures that could be used to test the efficacy of 4D-310 in a potential pivotal clinical trial. The proposed trial would use peak VO2 and KCCQ as the main efficacy measures, with echocardiography of the left ventricle as an additional measure. The federal agency has “communicated alignment” with these endpoints, according to the company.