4D Molecular Therapeutics Reports Interim Results for Fabry Disease Gene Therapy

4D Molecular Therapeutics reported updated interim clinical data from the ongoing phase 1/2 clinical trial of 4D-310 in patients with Fabry disease at the 18th Annual WORLDSymposium.

Fabry disease is a genetic disorder of the GLA gene that results in the body’s inability to produce an enzyme called alpha-galactosidase or AGA, causing the accumulation of the substrate globotriaosylceramide (Gb3) in critical organs, including the heart, kidney, and blood vessels. Such substrate accumulation can lead to life-threatening hypertrophic cardiomyopathy, heart failure, arrhythmias, various degrees of kidney dysfunction and cerebrovascular stroke. Fabry disease progression results in increased morbidity, mortality, and cost of care.

4D-310 holds promise for the treatment of Fabry by using a proprietary and optimized AAV vector to deliver a functional copy of the GLA gene, resulting in AGA production in target tissues. The proprietary vector in 4D-310 is designed for efficient, low-dose, intravenous delivery to key affected tissues in Fabry disease, including cardiac tissue, kidney, and vascular smooth muscle tissues.

“The dual mechanism-of-action design of 4D-310 opens the potential to treat target tissues through cross-correction from high and sustained blood AGA activity, as well as through direct transduction and AGA expression in target tissues such as the heart, kidney and blood vessels,” said Raphael Schiffmann, senior vice president and therapeutic area head of lysosomal storage diseases and cardiology for 4DMT. “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.”

The ongoing phase 1/2 clinical trial is being conducted in adult patients with severe Fabry disease. The primary endpoint of this trial is to determine the safety and maximum-tolerated dose. Secondary endpoints include biomarker assessments of plasma AGA activity and markers of biologic activity in the heart, including cardiac MRI.

As of the data cutoff date, three patients with Fabry disease had post-treatment follow-up ranging from 13 weeks to 37 weeks. These patients were enrolled in the 1E13 vg/kg cohort. The trial is designed to allow enrollment of up to 6 patients in the 1E13 vg/kg dose cohort.

Following 4D-310 infusion, mean serum AGA enzyme activity was within, or significantly above, the normal range in all three patients, despite pre-treatment anti-AGA antibody positivity in all patients. Serum AGA activity over time in patients off of enzyme replacement therapy was stable at 14-fold mean normal at week 37 in Patient 1, and at 10-fold mean normal at week 20 in Patient 3.

Patients 1 and 3 demonstrated an increase in serum AGA enzyme activity significantly above the normal range at all timepoints through last follow-up. Post-treatment serum AGA enzyme activity was well above the normal range at 14-fold mean normal at week 37 in Patient 1 and 10-fold mean normal at week 20 in Patient 3.

As previously reported, despite a high pre-treatment anti-AGA antibody titer, Patient 2 demonstrated a significant increase in serum AGA enzyme activity into the normal range. This patient entered the study off enzyme replacement therapy and therefore had high lyso-Gb3 levels at baseline. Lyso-Gb3 decreased significantly (>50 percent) within the first four weeks following 4D-310 treatment. Patient 2 did not have additional serum AGA activity data as of the data cut off.

Cardiac imaging and cardiac-related quality-of-life suggests encouraging effects on cardiac endpoints. Patient 1 reached the initial 6-month cardiac MRI and echocardiogram endpoint assessments. Six-month data for Patient 2 and 3 were not yet available as of data cutoff.

Patient 1 experienced encouraging improvement beyond the minimal detectable difference on the cMRI native T1 signal, which is consistent with glycosphingolipid substrate reduction. In addition, Patient 1 had encouraging improvement beyond the minimal detectable difference on cardiac function (left ventricular contractility) by GLS as assessed by echocardiography.

All three patients experienced increases in quality-of-life scores using the Kansas City Cardiomyopathy Questionnaire. Patient 2’s score increased beyond the minimal clinically important difference (last follow-up month 3). Patient 3’s score increased to the minimal clinically important difference (last follow-up month 3). Patient 1 had relatively mild symptoms at baseline, and had an increased score that was less than the minimal clinically important difference (last follow-up month 6).

4D-310 continues to demonstrate a manageable safety profile. Of note, no cardiac toxicity has been reported as of the data cutoff. Cardiac safety was evaluated based on serial assessments of multiple blood biomarkers, electrocardiograms, and echocardiograms.

“These clinical data suggest that 4D-310 is well-tolerated over time and has the potential to effectively treat a broad range of patients with Fabry disease,” said Jerry Vockley, chief of genetic and genomic medicine at the University of Pittsburgh School of Medicine and a principal investigator on the 4D-310 phase 1/2 clinical trial. “These updated data highlight encouraging trends toward stability of high levels of blood AGA activity following discontinuation of ERT. In addition, the initial effects on cardiac endpoints suggest the design of 4D-310 has potential for benefit in the heart.”

Photo: Raphael Schiffmann, senior vice president and therapeutic area head of lysosomal storage diseases and cardiology for 4DMT

Author: Rare Daily Staff