Fabry Disease Gene Therapy Shows Encouraging Effect on Cardiac End Points


The dual-mechanism of the therapy helps address both systemic and organ-specific deficits.

New data presented at the 18th Annual WORLDSymposium, February 7-11, 2022 in San Diego, CA, demonstrated encouraging effects of an investigational gene therapy for Fabry disease.1 The interim data suggest that the therapy from 4D Molecular Therapeutics may address cardiovascular disease—among other end points—in this patient population, which is the leading cause of death.

Study investigator Jerry Vockley, MD, PhD, division director, Genetic and Genomic Medicine, Cleveland Family Endowed Chair in Pediatric Research, professor of pediatrics and human genetics, and director, Center for Rare Disease Therapy at University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, presented the latest findings from the ongoing phase 1/2 clinical trial (NCT04519749) of 4D-310, an intravenous, C102 adeno-associated virus vector-based gene therapy that includes a functional copy of the GLA gene with a nonspecific promotor, allowing for both systemic and organ-specific effects. The trial consists of 2 dose level cohorts (1x1013 and 3x1013) as well as a dose-expansion cohort, with a primary end point of safety and tolerability and secondary end points that include change from baseline in serum anti-α-gliadin (AGA) activity as well as serum globotriaosylsphingosine (lyso-Gb3). The data presented included 3 patients enrolled in the 1E13 vg/kg cohort with post-treatment follow-up of 13 to 37 weeks as of the January 12, 2022 data cutoff.

Notably, all 3 patients had mean serum AGA enzyme activity within or significantly above normal range following infusion with 4D-310; this was despite anti-AGA antibody positivity in all 3 patients prior to treatment. After standard of care enzyme replacement therapy (ERT) ceased at week 3 posttreatment, serum AGA levels remained stable at 14 times the mean normal at week 37 in Patient 1 and at 10 times the mean normal at week 20 in Patient 3. These data were not available for Patient 2 as of the data cutoff. Notably, Patient 2, who entered the trial already off ERT and had high lyso-Gb3 levels, saw significant increase in serum AGA activity within normal range and also had a more than 50% decrease in lyso-Gb3 within 4 weeks posttreatment.

Additional exploratory cardiac end points were also reached, including improvement on cardiac MRI consistent with glycosphingolipid substrate reduction as well as improvement beyond the minimal detectable difference on cardiac function as assessed by echocardiography in Patient 1. Notably, all 3 patients had improved quality of life scores as assessed by the Kansas City Cardiomyopathy Questionnaire, including improvement beyond the minimal clinically important difference in Patient 2 and Patient 3 reaching that minimum. Patient one did not reach the minimum; however, the patient had mild symptoms at baseline.

Notably, no dose-limiting toxicities or cardiac toxicity have been observed, and no clinically significant liver toxicity has been reported to date. There was a single episode of atypical hemolytic uremic syndrome in Patient 2 which resolved fully without use of a complement inhibitor or dialysis.

“The evidence of AGA clinical activity and tolerability of 4D-310, as well as the initial encouraging effects on cardiac endpoints, strengthen our belief that 4D-310 represents a promising therapeutic approach for a broad range of patients with Fabry disease,” said Raphael Schiffmann, MD, senior vice president and therapeutic area head, lysosomal storage diseases and cardiology at 4DMT.2

1. Vockley J. An open-label, phase 1/2 trial of gene therapy 4D-310 in adult males with Fabry disease. Presented at: WORLDSymposium. February 7-11, 2022; San Diego, CA.
2. 4D Molecular Therapeutics announces updated interim results from the 4D-310 phase 1/2 clinical trial in patients with Fabry disease at the 18th annual WORLDSymposium. News release. 4D Molecular Therapeutics. https://www.biospace.com/article/releases/4d-molecular-therapeutics-announces-updated-interim-results-from-the-4d-310-phase-1-2-clinical-trial-in-patients-with-fabry-disease-at-the-18th-annual-worldsymposium/?s=63
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