AMT-191 for Fabry disease

Last updated Oct. 16, 2024, by Lindsey Shapiro, PhD
Fact-checked by Ana de Barros, PhD

What is AMT-191 for Fabry disease?

AMT-191 is an investigational gene therapy being developed to slow or halt disease progression in Fabry disease.

By directly addressing the underlying cause of the disease, AMT-191 is a potential one-time treatment expected to slow the progression of organ damage and provide long-term relief from Fabry symptoms with a single into-the-vein (intravenous) infusion.

The gene therapy, being developed by uniQure, has received orphan drug designation by the U.S. Food and Drug Administration (FDA), a designation meant to grant several benefits following a potential approval.

Therapy snapshot

How does AMT-191 work?

Fabry disease is caused by mutations in the GLA gene, which result in a lack of functional alpha-galactosidase A (alpha-Gal A) enzyme. This enzyme is needed to break down a fatty molecule called globotriaosylceramide (Gb3) and related molecules inside cells. Its deficiency in Fabry means that those molecules toxically accumulate and cause damage to several tissues and organs, such as the heart, kidneys, nervous system, eyes, and skin.

AMT-191 is designed to provide patients with a healthy version of the GLA gene. The therapy is packaged into a modified viral carrier called adeno-associated virus 5 (AAV5) that delivers it specifically to liver cells once it is in the body. Liver cells can then use the gene to make the alpha-Gal A needed to lower Gb3 levels and ease Fabry symptoms. The enzyme can then be taken up and used by other organs.

AAV is a commonly used viral carrier for gene therapies, as it does not cause human disease, and AAV5 in particular has been proven generally safe in clinical trials.

Preclinical studies in mice and nonhuman primates have shown that AMT-191 increases alpha-Gal A activity and normalizes Gb3 levels in key Fabry-affected organs including the liver, kidneys, heart, and brain.

How is AMT-191 administered?

In clinical trials, AMT-191 is being administered as a single infusion directly into the bloodstream. Doses currently being tested in Fabry patients include 60 trillion or 300 trillion genome copies per kilogram of body weight (gc/kg).

AMT-191 in clinical trials

The FDA cleared the first in-human trial of AMT-191 in 2023. The open-label Phase 1/2 clinical trial (NCT06270316) is now testing the safety, pharmacological properties, and exploratory efficacy of AMT-191 in up to 12 men, ages 18-50, with classic Fabry disease who have had a suboptimal clinical response after at least a year on enzyme replacement therapy (ERT).

Trial participants will receive AMT-191 at a dose of 60 trillion or 300 trillion gc/kg and be monitored for 26 months, or more than two years. During this time, safety, pharmacological properties, biomarkers, and other efficacy outcomes will be assessed.

Patients will continue regular use of their standard ERT until certain withdrawal criteria are met. The trial is expected to finish in 2027.

Common side effects of AMT-191

The first in-human clinical trial of AMT-191 was launched in 2024, and as such, the side effect profile of the investigational gene therapy is not yet known.

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