After 2-year Delay, 2nd Patient Dosed in FLT190 Gene Therapy Trial

Almost two years after dosing its first participant, a Phase 1/2 clinical trial testing the gene therapy candidate FLT190 for Fabry disease has treated its second patient.

The trial, dubbed MARVEL-1 (NCT04040049), originally had been slated for completion this past March, but had been significantly impacted by the pandemic.

“Easing of COVID-19 restrictions, together with geographic expansion of study sites, should enable continued enrollment as we work to make FLT190 available to the Fabry disease patient community,” Theresa Heggie, CEO of  Freeline Therapeutics, the maker of FLT190, said in a press release.

“Dosing the second patient in the MARVEL-1 study is an important milestone for Freeline and evidence of progress in our Fabry program,” Heggie added.

Fabry disease is caused by mutations in the GLA gene that result in the absent or markedly deficient activity of an enzyme called alpha-galactosidase A, or Gal A. This leads to the toxic accumulation of fatty molecules — such as globotriaosylceramide (Gb3) and Lyso-Gb3 — inside tissues and organs, which can cause a variety of symptoms.

Freeline’s FLT190 is a gene therapy that uses a harmless adeno-associated virus to deliver a functional copy of the GLA gene and induce the production of normal Gal A in liver cells. In contrast to regular infusions of enzyme replacement therapy or chaperone therapy — which are lifelong treatments — this gene therapy is designed to be given in a single dose.

The MARVEL-1 trial is assessing the safety and efficacy of FLT190 in about 15 men with classic Fabry disease. Patients with this disease type produce little to no functional Gal A enzyme.

Enrollment is open at five sites across Europe; more information on contacts and locations can be found here.

The trial takes place in two parts. In Phase 1, the dose escalation part, participants will receive ascending doses of FLT190 to determine the safest and most effective dose.

A total of 10 patients will be enrolled in this part, starting with two patients on the lowest dose group (7.5×10¹¹ vector genomes [vg] per kg of body weight), followed by two patients on a mid-dose (1.5×10¹² vg/kg), and three patients each on higher doses of 4.5×10¹² vg/kg and 1.5×10¹³ vg/kg.

For each patient, a single intravenous (into-the-vein) infusion of FLT190 will be given at the beginning of the study, followed by nine months of outpatient follow-up visits. After this period, eligible patients will have the option of continuing in a long-term extension study.

In addition to monitoring for adverse side effects, the investigators will assess how much Gal A patients produce in response to the treatment. The team also will monitor whether participants are clearing Gb3 and Lyso-Gb3 from the blood effectively. Finally, changes in the participants’ quality of life, and in kidney and heart function also will be assessed.

Preliminary data from the first patient enrolled in the trial — who received treatment in September 2019 — demonstrated that the lowest dose of FLT190 was generally well-tolerated and increased Gal A levels by 3-4 times in about four weeks. This increase was sustained for at least one year after the FLT190 infusion.

As the first two patients have been dosed, the company now plans to begin dosing in the mid-dose group, and expects to present new data later this year. The trial is now expected to run through December 2022.

“With dosing complete in our first cohort, we look forward to advancing through the next cohorts in our dose-finding study,” said Heggie.

“We plan to present data later this year to demonstrate the potential for FLT190 to be a transformative treatment for patients with Fabry disease,” she added.