AMT-191 shows promise, but safety concerns prompt dosing pause
Part of Fabry trial paused pending investigation of liver damage at higher levels
Written by |
The experimental gene therapy AMT-191 appears to be working as intended in an early clinical trial, developer uniQure said, but the company is pausing part of the study pending further investigation into severe liver damage cases.
“While the study remains ongoing, we believe the preliminary data collected are supportive of the potential for AMT-191 as a one-time administered gene therapy for people living with Fabry disease, and we look forward to providing additional updates on the program,” Walid Abi-Saab, MD, chief medical officer of uniQure, said in a company press release.
Fabry disease is caused by mutations in the gene encoding alpha-galactosidase A (alpha-Gal A), an enzyme that breaks down certain fatty molecules. In people with Fabry, the enzyme is absent or dysfunctional, so these fatty molecules build up to toxic levels, ultimately driving Fabry disease symptoms.
AMT-191 is designed to deliver a healthy version of the gene encoding alpha-Gal A to cells, allowing the body’s cells to produce a functional version of the enzyme that can clear toxic fatty acid deposits. uniQure is sponsoring a Phase 1/2 clinical trial (NCT06270316) to test the gene therapy in a dozen men with Fabry disease, ages 18 to 50, who have had an inadequate response to enzyme replacement therapy (ERT), a standard Fabry treatment where a version of the alpha-Gal A enzyme is administered as therapy. The study may still be recruiting participants at sites in the U.S.
Data show promise
uniQure presented updated trial data at the WORLDSymposium, held Feb. 2-6 in San Diego. As of the cutoff in early January, 11 patients had received a single infusion of AMT-191 at one of three doses: 20, 40, or 60 trillion genome copies per kilogram of body weight (gc/kg). One genome copy is essentially one particle of gene therapy.
Data showed that alpha-Gal A enzyme activity increased in all treated patients. At the low dose, enzyme activity ranged from 34% of normal to more than 80 times normal levels. All patients given the medium or high dose had enzyme activity above average normal levels, with some exceeding normal levels by hundreds of times. These data indicate that the therapy is restoring enzyme activity as designed. uniQure noted that increased enzyme activity has persisted to the latest follow-up in all patients.
“These updated preliminary data reinforce our confidence in the biological activity of AMT-191, including sustained and dose-dependent increases in [alpha]-Gal A activity across all dose cohorts of the treated patients,” Abi-Saab said.
uniQure said that AMT-191 has so far shown a manageable safety profile.
However, the company noted that two patients given the medium dose (40 trillion gc/kg) experienced severe liver damage. The damage was not life-threatening and did not cause obvious symptoms, but the safety committee monitoring the trial determined that these events represent dose-limiting toxicities — meaning the dose is likely too high to be safely used as a medicine.
Serious side effects have also been reported in patients given the highest dose. No serious safety issues have been documented in patients given the lowest dose of 20 trillion gc/kg.
uniQure said it is pausing dosing of the medium and high doses pending further evaluation, per the trial’s protocol. The company said both patients in the medium-dose group who experienced liver damage have responded to treatment and are being followed by their clinicians.
