Gene Therapy 4D-310 Safe, Restores Gal A Enzyme in 3 Dosed Patients

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A single dose of 4D-310, an investigational gene therapy from 4D Molecular Therapeutics (4DMT), appears generally safe and restored the levels of alpha-galactosidase A (Gal A), the faulty enzyme in Fabry disease, in the first three men enrolled in a Phase 1/2 clinical trial.

Notably, all three patients were free from enzyme replacement therapy (ERT) at their last follow-up assessment, ranging from six weeks to six months. Moreover, their levels of globotriaosylsphingosine, or Lyso-Gb3 — a biomarker of Fabry disease — either remained low or were significantly reduced, according to a company webcast.

These early findings, discussed in the webcast, “support our belief that 4D-310 is well-tolerated, and has the potential to deliver patient benefit after a single intravenous [into-the-vein] injection,” David Kirn, MD, 4DMT’s CEO and co-founder, said in a press release.

“Importantly, the post-treatment AGA [Gal A] enzyme activity in patients’ blood was within, or significantly above, the normal range despite the presence of pre-existing anti-AGA antibodies, which are a result of prior ERT in these patients,” Kirn said.

To the company’s knowledge, Kirn said, these “initial clinical data are the first demonstration of durable [blood] AGA activity within the normal and above normal range following gene therapy in a difficult to treat classic Fabry disease patient population.”

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Based on these “encouraging” early results, the company plans to press on in enrolling trial participants across a broad spectrum, according to Raphael Schiffmann, MD, 4DMT’s senior vice president and therapeutic area head of lysosomal storage diseases and cardiology. The trial is seeking both anti-AGA antibody positive and negative patients, in addition to those with classic and late-onset disease.

4D-310 uses a modified and harmless adeno-associated virus to deliver to cells a healthy version of the GLA gene, which provides the instructions for making Gal A and is mutated in Fabry patients.

Designed through 4DMT’s Therapeutic Vector Evolution platform, the therapy has “a unique dual mechanism of action,” according to Schiffmann, which restores Gal A levels in target tissues highly affected in Fabry, such as the heart, blood vessel walls, and kidneys.

Besides 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.

The latter mechanism has the potential to avoid the blocking effect of circulating antibodies against Gal A that some patients develop after ERT — which delivers a lab-made version of Gal A into the bloodstream.

“This dual [mechanism of action] opens the potential to effectively treat the broadest possible range of Fabry patient populations,” Schiffmann said.

Gal A level normalization is expected to prevent the disease-characteristic toxic accumulation of fatty molecules — Gb3 and Lyso-Gb3 — that can damage the heart, kidneys, and liver, as well as the need for regular, standard ERT.

4D-310 received fast track status in the U.S. for the treatment of Fabry disease, a designation meant to accelerate its clinical development and regulatory review.

The ongoing Phase 1/2 clinical trial (NCT04519749) is evaluating 4D-310’s one-year safety, tolerability, and preliminary effectiveness in up to 18 men with Fabry disease. Preliminary efficacy measures include assessing changes in the blood levels of Gal A and Lyso-Gb3.

To be eligible, patients on ERT must be receiving the treatment for at least one year and be on a stable dose for at least six months. The study is actively enrolling at its U.S. sites; more information can be found here.

In its first, dose-escalation 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 be evaluated in a larger, new group of patients in the dose-expansion phase.

Newly announced data concern the first three men treated with the lowest dose (1×1013 vg/kg), with a data cut-off date of Oct. 12 and a follow-up period ranging from two to six months post-dosing.

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All patients, whose ages ranged from 26 to 51, had classic Fabry. While all had been previously treated with ERT, only two (patients 1 and 3) were still receiving the therapy.

Following 4D-310 treatment, all three men achieved mean Gal A activity levels that were within or significantly above the normal range — 4.44–27.42 nanomole per hour per milliliter (nmol/hour/mL).

Specifically, patients 1 and 3 achieved mean levels 21 to 25 times higher than the normal range. Patient 2, who had the highest level of anti-Gal A antibodies, reached the normal range, with mean levels of 5.7 nmol/hr/ml.

Notably, after achieving their peak, Gal A activity levels started to drop, but remained well above the normal range in patients 1 and 3 up to six months; in patient 2, these levels only reached near-normal at last assessment (about three months post-dosing).

Blood Lyso-Gb3 levels remained low and stable in patients 1 and 3, even after ERT discontinuation (at week 2 and 3.5 months), and were significantly reduced in the second patient, who had the highest levels of the fatty molecule.

4D-310 was generally safe, with no dose-limiting toxicities or significant liver toxicity, which is common with virus-based gene therapies.

However, one week after treatment, patient 2 experienced atypical hemolytic uremic syndrome, a blood-related condition that may be caused by an immune reaction against the viral carrier. The adverse event was temporary and fully resolved on its own, but was considered serious since the patient was hospitalized for monitoring.

Notably, given the less-than-optimal response of the second patient dosed, further recruitment in the trial will exclude patients with high levels of anti-Gal A antibodies, which likely represent 5% of all Fabry patients, the company noted. The established threshold is well higher than the levels detected in patients 1 and 3, but lower than those seen in patient 2.

“These interim clinical data suggest that 4D-310 is well-tolerated and has the potential to effectively treat a broad range of patients with Fabry disease,” said Jerry Vockley, MD, PhD, chief of genetic and genomic medicine at the University of Pittsburgh School of Medicine, in Pennsylvania, and a principal investigator of the trial.

The company is planning to also launch a similar Phase 1/2 trial in the Asia/Pacific region, in which patients will undergo heart biopsy to assess gene delivery.