AMT-191 increases enzyme levels in 4 Fabry patients: Early trial data
Treatment with experimental gene therapy leads to discontinuation of ERT
Treatment with the experimental gene therapy AMT-191 led to increases in levels of the enzyme whose deficit causes Fabry disease for four patients in an early clinical trial. As a result, enzyme replacement therapy (ERT) was discontinued for all patients.
AMT-191 is being developed by Uniqure, which presented the findings at the International Congress of Inborn Errors of Metabolism in Kyoto, Japan.
“The early data highlight the potential of AMT-191 as a transformative one-time treatment option for people living with Fabry disease,” Walid Abi-Saab, MD, Uniqure’s chief medical officer, said in a company press release.
Phase 1/2 clinical trial of AMT-191 still recruiting at 8 US sites
Fabry disease is caused by mutations in the gene that provides instructions to make alpha-galactosidase A (alpha-Gal A), an enzyme needed to break down certain fatty molecules. Reduced activity of this enzyme in people with Fabry disease leads to fatty molecules building up to toxic levels in cells, causing damage that ultimately drives disease symptoms.
AMT-191 is a one-time gene therapy designed to deliver a gene encoding a functional version of the alpha-Gal A enzyme to the body’s cells. According to Uniqure, the goal is to achieve supraphysiological enzyme levels — levels higher than are typically seen in healthy people who don’t have Fabry disease.
The company is sponsoring a Phase 1/2 clinical trial (NCT06270316) to test AMT-191 in men with Fabry disease ages 18 to 50. The study is still recruiting participants at eight sites across the U.S.
The new data come from the first four participants in the study, all of whom received a single infusion of AMT-191 at a dose of 60 trillion genome copies per kilogram of body weight (gc/kg; one genome copy is essentially one particle of gene therapy).
Second cohort of patients enrolled
As of July, these four patients had been followed for between 12 and 45 weeks after AMT-191 treatment. All four participants showed increases in alpha-Gal A enzyme activity from 27-fold to 208-fold above average normal levels.
Before receiving AMT-191, all four patients had been receiving ERT, an approved type of Fabry treatment that works to deliver a functional version of the alpha-Gal A enzyme into the body. As of the latest follow-up, all four patients have been able to stop ERT treatment without any increase in the levels of Fabry-related fatty molecules in the blood.
“These initial findings from the first cohort are encouraging, with all patients showing robust increases in [alpha]-Gal A activity and an ability to withdraw from ERT,” Abi-Saab said.
Two serious side effects related to AMT-191 were reported: one instance of chest pain and one instance of elevated troponin, which is a marker of heart damage. There was also a case of serious leptomeningeal enhancement — an abnormality of the membrane around the brain — that was judged as potentially related to AMT-191.
These initial findings from the first cohort are encouraging, with all patients showing robust increases in [alpha]-Gal A activity and an ability to withdraw from ERT.
In addition, there was a case of markedly elevated liver enzymes, which is a sign of liver damage. Although this event was not considered serious and didn’t require hospitalization, it was judged based on the study’s protocol to be a dose-limiting toxicity — in other words, a sign that this dose of AMT-191 may be too elevated to be safely used in clinical practice.
The Phase 1/2 trial has enrolled a second cohort of three patients who will be given a lower dose of 20 trillion gc/kg. With less than three months of follow-up, no serious side effects have yet been reported in this group, according to Uniqure. The company expects to report further data from the study in 2026.
“I look forward to sharing additional data from our dose-finding study expected in the first half of 2026,” Abi-Saab said.
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