Measures of heart function improved one to two years after treatment with 4D-310, an investigational gene therapy for Fabry disease, according to new trial data from 4D Molecular Therapeutics (4DMT), the company that developed the treatment.

“We are pleased that 4D-310 continues to consistently demonstrate clinical activity across multiple important cardiac endpoints, including cardiac function, exercise capacity, and quality of life,” said 4DMT’s Chief Medical Officer. Dr. Robert Kim said in the company’s press release. .

The data was presented at the latest session of WORLDSymposium 2024 in San Diego.

Fabry disease is caused by a genetic mutation. G.L.A. This enzyme breaks down fat molecules, primarily globotriaosylceramide (Gb3 or Gl-3). Without enough alpha-GLA, the molecule can accumulate to toxic levels, causing tissue and organ damage, especially in the kidneys and heart.

Enzyme replacement therapy (ERT) is a standard Fabry treatment that delivers functional, laboratory-made α-Gal A enzyme to the bloodstream. Although ERT can improve renal function, it does not completely address cardiac dysfunction.

“Current treatments do not adequately address the cardiovascular symptoms associated with Fabry disease, making cardiovascular disease the most common cause of death in these patients,” Professor Kim said.

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What does 4D-310 do for Fabry disease?

The 4D-310 uses a vector called C102 to G.L.A. A single, low dose into the bloodstream introduces genes into heart muscle cells, called cardiomyocytes. Engineered on 4DMT’s Therapeutic Vector Evolution platform, it restores α-Gal A levels through a dual mechanism of action.

This treatment is being tested in two Phase 1/2 clinical trials. One for the United States (NCT04519749) and one for Taiwan and Australia (NCT05629559). Six patients have received this treatment so far.

Initial data from the first three participants in the United States showed improvements in measures of heart function one year after treatment. However, three patients developed atypical hemolytic uremic syndrome (aHUS), in which red blood cells are destroyed.

All patients recovered within two to four weeks, but the company suspended enrollment in both trials. Shortly after, the U.S. Food and Drug Administration (FDA) put clinical trials in the United States on hold. However, the Asia-Pacific program continued.

Late last year, 4DMT reached an agreement with the FDA to lift its hold on non-human primates ( A single safety study was initiated in NHPs. aHUS. 4DMT plans to submit results to the FDA by the end of June.

“To address clinical reservations, we are launching a non-clinical study evaluating 4D-310 in NHPs receiving R/S immunosuppressive therapy,” said David Kahn, MD, co-founder and CEO. We are on track to submit results to the FDA in the second quarter of 2024.” 4DMT.

As of the latest data cutoff of December 5, 2023, no clinically significant cardiac or hepatic toxicities were reported in either study, greater than grade 1 (mild) with up to 33 months of follow-up No new treatment-related side effects occurred.

“4D-310 continues to be well tolerated, with previously reported aHUS cases fully resolving, and no new drug-related adverse events above grade 1 reported,” Kim said.

Improving heart function, exercise, and quality of life

Based on echocardiographic evaluation, ventricular function improved in all five evaluable patients 1 year after treatment. Two patients who reached 2 years of follow-up showed clinically meaningful improvement, with changes of -2.8% and -2.9%, exceeding the minimum detectable difference of -1.5%. This was assessed using total longitudinal strain measurements, a method that focuses on measuring the contraction of myocardial fibers.

Three out of four evaluable patients showed clinically meaningful improvements in exercise capacity as measured by peak VO2, the highest amount of oxygen consumed during peak exercise, after one year of treatment (+ 1.8, +2.0, +7.0). At the end of the two-year follow-up, one participant continued to show an improvement of +7.8%.

Heart-related quality of life remained stable or improved after treatment, as assessed using the Kansas City Cardiomyopathy Questionnaire. Two of her patients who had low scores before treatment had significant improvements in quality of life, while three remained stable during her 1-2 years.

Cardiac biopsies at 6 and 26 weeks in one patient showed sustained treatment-related activity of the donated functional heart G.L.A. All samples are shown to be positive for α-Gal A enzyme. Average levels of Gb-3 decreased by 15% between weeks 6 and 26, and by 61% when compared to historical samples taken about 7 years before the study.

“Cardiac biopsies showed robust and durable delivery and transgene expression from 4D-310 and, surprisingly, also a reduction in Gb3 substrate in cardiomyocytes,” Kirn said. “There are no approved treatments that reliably remove accumulated Gb3 from cardiomyocytes in patients with Fabry disease. These promising clinical results highlight the potential of our therapeutic vector evolution platform and his C102 vector for targeted therapy. will continue to verify. [into-the-vein] delivered to cardiac muscle cells. ”