Higher Dose of FLT190, Fabry Gene Therapy, To Be Tested Next

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by Lindsey Shapiro PhD |

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FLT190 gene therapy | Fabry Disease News | MARVEL-1 trial | illustration for a clinical trial

The next patient to receive FLT190, an investigational gene therapy for Fabry disease, in the ongoing Phase 1/2 MARVEL-1 trial will be given a second, higher dose of therapy, accelerating an earlier trial timeline.

This person was originally intended to be included in the first, lowest dose group of 7.5×1011  vector genomes per kilogram of body weight (vg/kg). But the trial instead is moving to a second dosing level of 1.5×1012 vg/kg, with a first patient expected to be treated around mid-year at that dose.

According to the therapy’s developer, Freeline Therapeutics, a data monitoring committee (DMC) supported this change based on a review of FLT190’s safety and efficacy at low dose in one patient treated two years ago and another treated nine months ago.

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Freeline previously reported that both adults had achieved sustained increases in alpha-galactosidase A (Gal A), the faulty enzyme in Fabry, with the most recently treated patient remaining free of a need for enzyme-replacement therapy (ERT) at four months post-treatment.

Both experienced temporary, mild myocarditis, or inflammation of the heart muscle, but had no evidence of heart damage as of that November 2021 report.

“The consistency of the data, including the additional safety and efficacy data collected since our last update, and the feedback from DMC and regulatory authorities reinforce our confidence about proceeding to the second dose level without dosing a third patient at the lowest dose,” Pamela Foulds, MD, Freeline’s chief medical officer, said in a press release.

“We are also exploring potential options to further accelerate dosing based on the safety and efficacy data from this next patient,” Foulds added.

Delivered directly into the bloodstream as a one-time treatment, FLT-190 is packaged into a carrier — called an adeno-associated virus — that directs the therapy to the liver, where it aims to provide a healthy copy of the GLA gene that is mutated in Fabry patients.

In doing so, a healthy Gal A enzyme can be produced, preventing the toxic accumulation of the fatty molecules — called Gb3 and Lyso-Gb3 — that mark Fabry and damage the heart, kidneys, and liver.

FLT-190 aims to eliminate the need for standard ERT or chaperone therapy. Of note, ERT delivers a healthy Gal A enzyme, while chaperone therapy restores the function of some faulty Gal A forms.

The dose-finding and open-label MARVEL-1 trial (NCT04040049) is testing the therapy’s safety and efficacy in up to 15 men with Fabry disease across five European sites; more information can be found here.

In its first dose-escalation phase, patients previously on ERT or chaperone therapy are receiving FLT190 at increasing doses to determine the safest and most effective dose. Once an optimal dose is identified, the study’s second phase will evaluate FLT190 at that dose in patients who have never used ERT or chaperone treatment.

Four escalating doses are planned: 7.5×1011, 1.5×1012, 4.5×1012, and 1.5×1013 vg/kg.

The trial’s main goal is to assess treatment safety, with secondary goals evaluating changes in Gal A activity, and Gb3 and Lyso-Gb3 levels. Kidney and heart function, quality of life, and immune responses to the treatment’s carrier virus will also be assessed.

The first patient, dosed in September 2019, showed a sustained three-fold increase in Gal A activity that had remained steady for two years, the company reported in the last update. But these levels, ranging from 0.8-1.3 nanomole per hour per milliliter (nmol/hour/mL), were still below a normal range of 6–19 nmol/hour/mL and the man returned to ERT use less than two months post-treatment.

The second patient, treated in June 2021, also observed sustained Gal A increases that trended closer to a normal range at four months after treatment, with a mean level of 3.9 nmol/hour/mL. At the last update, he remained off ERT.

A further trial update is planned for the second half of 2022, Freeline stated.

FLT190 has been designated an orphan drug for Fabry disease in the U.S. and Europe, a status intending to speed the therapy’s development.

“Strong execution on our clinical programs has been a key pillar of delivering on our commitment to bring life-changing medicines to patients,” said Michael Parini, CEO of Freeline.

The company also plans to report full 2021 financial results and other business highlights on March 31.