Fabry Disease Gene Therapy Clinical Trial Moves Onto Dosing Second Cohort


The FDA recently cleared Freeline Therapeutics to begin treating patients in the United States.

The phase 1/2 MARVEL-1 clinical trial (NCT04040049) of Freeline Therapeutics’ FLT190, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Fabry Disease, has dosed the first patient in its second cohort.1

FLT190 utilizes an AAVS3 capsid and is intended to deliver a functional copy of GLA, the disease-targeted gene, into the liver cells, with the goal of producing greater than normal levels of alpha galactosidase (α-Gal A), the enzyme which is insufficient in patients with Fabry disease. Early data from the trial’s first cohort, which was announced in February 2022, indicated that FLT190 showed a potential dose-dependent increase in α-Gal A levels in the plasma, with 1 of the 2 treated patients having durable α-Gal A levels sustained for up to 2 years (though this patient restarted enzyme replacement therapy 6 weeks after dosing) and the other patient continuing to remain off enzyme replacement therapy for over 26 weeks after treatment (data cut-off: December 22, 2021).2,3 

In terms of safety, FLT190 was well-tolerated with it being noted that 1 of the 2 patients treated in the first cohort at the time of the data cut-off had experienced a case of transient transaminitis.2,3 A novel prophylactic immune management regimen introduced after this event may have prevented vector-related transaminitis in the other patient. In both of the patients, cases of myocarditis were reported at about 6 to 8 weeks following treatment. The cases were mild and transient and, on cardiac MRI, were not associated with enduring clinical sequalae.

“Freeline’s proprietary AAVS3 capsid has the potential to deliver transformative treatments for patients with challenging diseases including Fabry disease...,” Pamela Foulds, MD, chief medical officer, Freeline Therapeutics, said in a statement in February.2 “It is highly encouraging to observe early signals of durability and efficacy in MARVEL-1 in Fabry disease, with sustained expression up to 2 years as of our last data reading. Advancing the study will allow further exploration of the potential of FLT190 to provide a functional cure for Fabry disease, which may eliminate the need for enzyme replacement therapy and improve patient outcomes.”

The multicenter, adaptive dose-escalation and dose-expansion clinical trial is recruiting up to 15 male patients aged 18 years or older with confirmed diagnoses classic Fabry disease.1 Participants are required to have decreased plasma α-Gal activity and an estimated glomerular filtration rate (eGFR) of at least 60mL/min/1.73m2 at the time of screening; at least one of the characteristic features of classic Fabry disease; and less than 500 mg/g Urine Protein to Creatinine Ratio (UPCR) in a spot urine sample or less than 1g/24-hours of urinary protein in a 24-hour urine analysis. Patients’ platelet counts must beat least 100x109L. Participants in part 2 of the study must additionally have elevated plasma globotriaosylsphingosine (lyso-Gb3) levels at screening. Patients who have non-classical Fabry disease or presence of AAV neutralizing antibodies or antibodies to α-GLA, Replagal, or Fabrazyme will be excluded from the study. Additional exclusion criteria relate to patient health status and treatment history.

Part 1 of the study is a dose escalation phase for patients previously treated with enzyme replacement therapy or chaperone therapy, while part 2 is a dose expansion phase for patients who have not received previous treatment.2,3 Participants are treated with a single dose of FLT190 via slow intravenous infusion. Patients in the first cohort of the dose escalation phase received a dose of 7.5x1011 vg/kg, and patients in the second cohort, which is a mid-dose cohort, will receive 1.5x1012 vg/kg. The trial may ultimately include up to 4 dose-level cohorts in total. 

The study’s primary end point is the frequency of treatment-emergent adverse events. The trial will also evaluate efficacy via measures of α-Gal A activity levels and measures of clearance of globotriaosylceramide (Gb3) and lyso-Gb3 from plasma and urine. While participants in the first cohort were recruited from Germany, Italy, Norway, and the United Kingdom, the FDA recently cleared Freeline Therapeutics to begin treating patients in the United States.1

“We believe FLT190 has the potential to be a life-changing therapy for people with Fabry disease by providing durable enzyme activity above the normal range with a one-time treatment, and we are excited to have initiated this cohort in MARVEL-1,” Foulds said in a statement regarding the initiation of dosing in the second cohort.1 “We have multiple trial sites now open across five countries with more expected to open by year-end. We look forward to reporting updated safety and efficacy data in the first half of next year.”

1. Freeline initiates dosing of second cohort in MARVEL-1 trial of FLT190 gene therapy candidate for people with fabry disease. News release. Freeline Therapeutics Holdings plc. October 4, 2022. https://www.freeline.life/investors/newsroom/freeline-initiates-dosing-of-second-cohort-in-marvel-1-trial-of-flt190-gene-therapy-candidate-for-people-with-fabry-disease/ 
2. Freeline presents on its fabry and gaucher disease AAV-based gene therapies at the 18th annual Worldsymposium. News release. Freeline Therapeutics Holdings plc. February 8, 2022. https://www.freeline.life/investors/newsroom/freeline-presents-on-its-fabry-and-gaucher-disease-aav-based-gene-therapies-at-the-18th-annual-worldsymposium/ 
3. Hughes DA, Canaan-Kühl S, Barton S, Colliis R, Sherry N. Safety and efficacy of FLT190 for the treatment of patients with Fabry disease: Results from the MARVEL-1 Phase 1/2 clinical trial. Presented at: 18th Annual WORLDSymposium. February 7-11, 2022; San Diego, California.
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