FDA Puts Fabry Gene Therapy 4D-310 on Fast Track

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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4D-310, a new gene therapy for Fabry disease that is being developed by 4D Molecular Therapeutics (4DMT), has been granted fast track designation by the U.S. Food and Drug Administration (FDA).

This designation is given to investigational therapies that the FDA deems to have potential to markedly improve care for serious conditions. The designation gives the therapy’s developer (in this case, 4DMT) access to more frequent communication with the FDA during the therapy’s development. Medications given the fast track designation also can, if other criteria are met, be designated for accelerated approval and/or priority review.

“We’re pleased that the FDA has granted Fast Track designation for 4D-310,” David Kirn, MD, co-founder, chairman and CEO of 4DMT, said in a press release.

Fabry disease is caused by mutations in the GLA gene, which provides instructions for making the enzyme alpha-galactosidase A (AGA). These mutations result in the enzyme being absent or otherwise non-functional, which leads to the toxic accumulation of molecules that this enzyme usually is responsible for breaking down.

The current standard treatment for Fabry disease is enzyme replacement therapy (ERT); as its name suggests, this involves regular treatment with alpha-galactosidase A to “replace” the enzyme that is absent. However, ERT has numerous drawbacks: it requires regular treatments over the course of a person’s lifetime, and it may not be as effective at delivering replacement enzyme to certain tissues, such as the heart.

Gene therapies such as 4D-310 work by delivering a non-mutated version of the GLA gene to the body’s cells, allowing them to make their own functional enzyme. 4D-310 accomplishes this by use of a viral vector, specifically an attenuated form of adeno-associated virus (AAV), called 4D-C102.

Preclinical studies in mice have shown that 4D-C102 is better at delivering genetic payloads to cells in the heart than other AAV vectors. This is of particular relevance to Fabry, in which heart disease is a major cause of mortality.

“In contrast to ERT and other medicines in development, 4D-310 is designed to drive high level AGA enzyme expression directly within the diseased target tissues themselves, including the heart, kidney and blood vessels, in addition to driving high and stable blood concentrations. We believe this differentiation has the potential to benefit a broad range of patients with Fabry disease, including those with significant cardiomyopathy [heart disease],” said Kirn.

“To date, ERT correction of the enzyme deficiency in critical tissues, beyond endothelial cells, has been a challenge. A one time therapy that corrects AGA deficiency directly in organs and tissues where substrate accumulates may more completely and durably address the disease process in Fabry, particularly in the heart,” added Raphael Schiffman, MD, 4DMT senior clinical advisor, lysosomal storage diseases.