Gene therapy shows benefits in all participants in Fabry clinical trial
After 1-time dosing, patients able to stop other enzyme treatments, per data
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uniQure‘s investigational gene therapy AMT-191 markedly boosted the levels of the enzyme whose deficiency causes Fabry disease in all patients dosed thus far in a small clinical trial.
Further, each of the 11 adults with Fabry taking part in the Phase 1/2 study (NCT06270316) was able to stop enzyme replacement therapy (ERT), according to a company press release providing updates on the ongoing U.S. trial.
In February, uniQure announced it had paused the mid- and high-dose groups in the study pending further investigation into signs of symptom-free liver damage that occurred in two patients. Following a course of immunosuppressive therapy, these liver problems have since resolved, the company said.
As of the latest updates in June, “AMT-191 continued to show a manageable safety profile at all dose levels,” the release stated.
A rare, inherited condition, Fabry is caused by a deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A). Without sufficient enzyme activity, a fatty substance called globotriaosylceramide (Gb3) builds up inside cells over time, gradually damaging the kidneys, heart, and nervous system.
The standard treatment for Fabry is ERT, which involves infusions given into-the-vein, or intravenously, every other week to supply the missing enzyme. However, because the infused enzyme lasts only a short time, patients typically require lifelong administration of the therapy.
Gene therapy for Fabry would be given just once
AMT-191 is an investigational one-time gene therapy designed to deliver a working copy of the gene that carries instructions for alpha-Gal A. Its goal is to allow the body to make its own enzyme on an ongoing basis rather than relying on repeated infusions.
The Phase 1/2 clinical trial is testing AMT-191 in men with Fabry disease, ages 18 to 50, all of whom had an inadequate response to ERT. The study is being conducted at eight sites across the U.S. and may still be recruiting participants.
Early data reported in September of last year showed AMT-191 increased alpha-Gal A levels in four Fabry patients. All had discontinued ERT.
The new data come from 11 patients treated at three different dose levels and followed for periods ranging from three months to longer than 1.5 years.
These data show that AMT-191 treatment led to dose-dependent increases in alpha-Gal A activity. At the lowest dose, enzyme activity rose to between one and 16.2 times above the mean normal range. At the mid dose, activity rose to between 14.5 and 229.6 times, and at the highest dose, activity rose to between 58.7 and 143.6 times above the range.
Alongside these enzyme changes, plasma lyso-Gb3 levels, a metabolite of Gb3, remained stable after dosing across all three dose groups, regardless of whether patients had previously been on ERT. uniQure noted that all patients who received AMT-191 were able to stop their ERT.
On safety, the therapy demonstrated a manageable profile across all dose levels, the developer reported. No serious adverse events (SAEs) related to AMT-191 occurred in the low- or mid-dose groups, and no new SAEs were seen at the high dose beyond the two cases previously reported last year.
2 cases last year with serious adverse events now resolved
However, under the study protocol, additional dosing in the mid- and high-dose groups remains paused while the company further evaluates asymptomatic (symptom-free) liver enzyme elevations that occurred in two patients in the mid-dose group. These elevations were confirmed as dose-limiting toxicities, meaning they were significant enough to limit how much of the therapy could be safely given.
Both cases resolved by the end of May following a course of immunosuppressive treatment, as called for in the study protocol, the developer noted.
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