Experimental Gene Therapy May Be Safe and Effective, Early Data Shows

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by Vanda Pinto, PhD |

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Experimental gene therapy 4D-310 continues to be generally safe and has effectively increased enzyme alpha-galactosidase (Gal A) blood levels in the first three patients enrolled in 4D Molecular Therapeutics’s clinical trial.

These results were announced in the presentation “An Open-label, Phase 1/2 Trial of Gene Therapy 4D-310 in Adult Males with Fabry Disease” at the 18th Annual WORLDSymposium annual meeting, held in February in San Diego.

“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,” Raphael Schiffmann, MD, senior vice president of 4D Molecular Therapeutics (4DMT), said in a press release.

The safety, tolerability, and effects of 4D-310 are currently being investigated in the Phase 1/2 (NCT04519749) study, which intends to recruit 18 adult men with Fabry disease. It is recruiting patients, 18 or older, at several locations in the U.S. More information can be found here.

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In Fabry disease, the production of Gal A, a protein that breaks down fatty molecules, is prevented by mutations in the GLA gene. This leads to the buildup of toxic metabolites, mainly globotriaosylceramide (Gb3), in vital organs, such as the heart and kidney, as well as in blood vessels.

Enzyme replacement therapies (ERT), which deliver a lab-made version of Gal A into the bloodstream, are a treatment option for Fabry patients. However, these intravenous (into-the-vein) infusions can impact their quality of life. While ERT reduces kidney pathology, its benefits for cardiac symptoms — the leading cause of death and disability in Fabry patients — are not clear.

4D-310 uses a modified and harmless adeno-associated virus (AAV) to deliver a healthy version of the GLA gene to cells. Designed through 4DMT’s Therapeutic Vector Evolution platform, the therapy has a unique dual mechanism of action that restores Gal A levels in the tissues affected in Fabry disease.

Along with promoting high and stable blood Gal A levels that can be taken up by cells in the vicinity, 4D-310 also delivers the working GLA copy directly to target tissue cells, potentially avoiding being blocked by circulating antibodies against Gal A that some patients develop after ERT.

“The dual mechanism-of-action design of 4D-310 opens the potential to treat target tissues through cross-correction from high and sustained blood [Gal A] activity, as well as through direct transduction and AGA expression in target tissues such as the heart, kidney and blood vessels,” Schiffmann said.

The main goal of 4DMT’s trial is to assess the safety and tolerability of 4D-310. Secondary goals include evaluating changes in Gal A activity and lyso-Gb3, a form of Gb3, over time. Participants will be observed for up to one year after a single infusion.

In its first part, participants are receiving a single infusion of three escalating doses of the therapy: 1×1013, 3×1013, and 3×1012 vector genomes (vg) per kg of body weight. The goal is to determine the optimal dose to evaluate in a larger and new group of patients in the dose-expansion phase.

The new data concern the first three men treated with the lowest dose (1×1013 vg/kg), with a data cut-off date of Jan. 13, and a follow-up period ranging from 13 to 37 weeks, post-dosing.

Gal A enzyme activity was within, or significantly above, the normal range in all three patients after 4D-310 infusion, despite all having antibodies against Gal A before treatment.

While all the patients had been previously treated with ERT, patients 1 and 3 stopped after 4D-310 infusion and their mean Gal A activity levels remained stable and significantly above the normal range at week 20 and 37 — 98.8 to 139.7 nanomole per hour per milliliter (nmol/hr/mL).

Because patient 2 was already off ERT before 4D-310 treatment, Gal A activity increased into the normal range. Although his lyso-Gb3 levels were high, they significantly decreased (by more than 50%) within the first four weeks after treatment.

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The accumulation of harmful glycolipids in the heart was visualized using MRI and left ventricular contractility, a measure of heart function, was determined using echocardiography. Patient 1 showed a reduction in glycolipid accumulation and improvements in left ventricular contractility. Endpoint results for patients 2 and 3 were not available as of the data cutoff.

All three patients, responding to a Kansas City cardiomyopathy questionnaire, said their heart-related quality of life improved after 4D-310 infusion.

“These updated data highlight encouraging trends toward stability of high levels of blood [Gal A] 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,” said Jerry Vockley, PhD, a principal investigator of the trial.

According to researchers, 4D-310 continues to show a manageable safety profile with no reported serious adverse reactions. No evidence of significant toxicity has been found in the heart or liver as of the data cutoff. However, patient 2 had a single episode of atypical hemolytic uremic syndrome (aHUS) which fully resolved.

“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,” Vockley added.