FLT190 for Fabry disease

Last updated April 16, 2024, by Margarida Maia, PhD
Fact-checked by Ana de Barros, PhD

What is FLT190 for Fabry disease?

FLT190 is an investigational gene therapy that was being developed by Freeline Therapeutics, now part of Syncona, to help ease the symptoms of Fabry disease. The company decided to pause the clinical development of FLT190 in 2023 for strategic reasons.

The gene therapy had been granted orphan drug designation in 2020 both in the U.S. and the European Union.

Therapy snapshot

How does FLT190 work in Fabry disease?

Fabry disease is caused by mutations in the GLA gene, which provides instructions for producing alpha-galactosidase A (alpha-Gal A), an enzyme that breaks down a fatty substance called globotriaosylceramide (Gb3 or GL-3) in cells.

When Gal A is faulty or missing, the fatty substance cannot be broken down and gradually builds up in cells in the body. As a result, people with Fabry disease experience a range of symptoms, particularly in the kidneys, heart, and nervous system.

FLT190 is designed to deliver a working version of the GLA gene to liver cells. The working gene is packaged aboard a proprietary delivery vehicle called adeno-associated virus serotype S3 (AAVS3), which is harmless to humans. AAVS3 directs the working gene into liver cells, where it gets unloaded from the delivery vehicle. Liver cells can then produce alpha-Gal A on their own. The enzyme is expected to be released into the bloodstream and taken up by cells in the body, where it can break down Gb3 and stop it from building up, thereby helping to ease symptoms of Fabry disease.

In preclinical studies in a mouse model of Fabry disease, where the GLA gene was missing, a single intravenous infusion of FLT190 resulted in the production of alpha-Gal A by liver cells. The enzyme stayed at consistent levels in the blood, and was taken up by cells in the body. This resulted in the clearance of inclusion bodies — aggregates or clumps — of Gb3 in the kidneys and the heart.

How was FLT190 administered in Fabry disease?

In a Phase 1/2 clinical trial, FLT190 was given as a single intravenous infusion at a dose of 7.5×10¹¹ or 1.5×10¹² vector genomes per kilogram of body weight (vg/kg). The company had anticipated testing higher doses, of 4.5×10¹² and 1.3×10¹³ vg/kg, in a planned Phase 3 clinical trial in patients previously treated with enzyme replacement therapy or chaperone therapy.

FLT190 in Fabry disease clinical trials

The open-label Phase 1/2 clinical trial MARVEL1 (NCT04040049) tested the safety and efficacy of FLT190 in men with classic Fabry disease, in which symptoms usually manifest early due to a total or near-total absence of working alpha-Gal A.

Patients who completed nine months of follow-up in MARVEL1 were given the option to enter a long-term extension (NCT04455230), where they would be monitored for an additional five years.

Two male patients were given a single intravenous infusion of FLT190 at a dose of 7.5×10¹¹ vg/kg over 1-2 hours. The first patient, a 29-year-old man, experienced a threefold increase in alpha-Gal A activity, which remained steady over the course of two years. However, alpha-Gal A activity still was too low, and the man restarted enzyme replacement therapy about 1.5 months after being given FLT190.

In the second patient, age 45 years, alpha-Gal A activity, or expression reached sustained, near-normal levels. That man remained off enzyme replacement therapy for at least six months.

These patients received corticosteroids, with or without a short course of the immunosuppressant tacrolimus, to prevent an immune response against AAVS3. The first patient, who had received only corticosteroids, had elevated liver enzymes, a sign that the liver may be damaged, which was treated with methylprednisolone and tacrolimus.

Both patients had transient elevation of troponin-T, a sign of myocarditis, or inflammation of the heart muscle, within the first two months after being given FLT190. There was no evidence of changes to heart function, however.

A third patient was given a higher dose of 1.5×10¹² vg/kg a few months before the clinical trial was terminated due to the pause in the development of FLT190. No safety or efficacy data have been reported for this patient.

Common side effects of FLT190 in Fabry disease

Side effects reported with FLT190 during clinical testing were elevated liver enzymes and mild, transient myocarditis.

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