FDA clears uniQure trial of AMT-191 gene therapy in Fabry patients
US-based Phase 1/2a trial expected to begin in 1st half of 2024
UniQure says it expects that enrollment in the U.S.-based trial — which will recruit six patients in all — will begin in the first half of next year. The company sought approval of the clinical trial via an investigational new drug application (IND).
“AMT-191 has the potential to be a differentiated gene therapy for the one-time treatment of Fabry disease,” Walid Abi-Saab, MD, uniQure’s chief medical officer, said in a company press release.
“We have designed the Phase I/II study to provide dose-ranging biomarker data as rapidly and cost-effectively as possible, and we look forward to enrolling our first patient in the first half of 2024,” Abi-Saab said.
Trial expected to provide biomarker data for Fabry disease gene therapy
Fabry disease is caused by mutations in the GLA gene that encodes production of alpha-galactosidase A (Gal A), an enzyme that works to break down certain fatty molecules, namely globotriaosylceramide (Gb3), inside cells.
Consequently, not enough functional Gal A is produced, and those molecules instead build to toxic levels throughout the body, leading to organ damage.
Patients typically have been treated with enzyme replacement therapy (ERT) to provide the body with a working version of Gal A. But with ERT, patients will require regular infusions into the bloodstream for their entire lives.
Moreover, ERT is not always effective at completely eliminating Gb3 from the body’s tissues, especially the kidneys and the heart, according to uniQure.
AMT-191 is a one-time gene therapy designed to deliver a working version of the GLA gene directly to liver cells, enabling them to continuously produce their own healthy Gal A enzyme.
It is packaged into a viral carrier called adeno-associated virus 5 (AAV5), which helps the therapy be taken up by liver cells but is modified so as not to cause disease. It is the same AAV5 technology used in Hemgenix, a recently approved gene therapy for hemophilia B originally developed by uniQure.
The company previously had been developing another gene therapy candidate, known as AMT-190, as a potential Fabry disease treatment. AMT-190 had aimed to provide patients with alpha-N-acetylgalactosaminidase, or NAGA, an enzyme similar to Gal A.
In September 2020, however, uniQure selected AMT-191 instead as its lead gene therapy candidate to be advanced into IND-enabling studies. Preclinical studies comparing the gene therapies found that AMT-191 led to more robust and sustained increases in GLA activity and functional improvements, according to the company.
Additional studies in mouse models of Fabry disease and non-human primates indicated that AMT-191 boosts Gal A activity in multiple organs, including the liver, kidney, heart, and brain, in addition to normalizing Gb3 levels in main target organs.
The planned Phase 1/2a trial will be the first in-human study of AMT-191. It will enroll two groups of three Fabry disease patients each, who will be given escalating doses of the gene therapy. The goals are to evaluate the safety, tolerability, and efficacy of the treatment.
The trial will be open-label, meaning that both researchers and participants will know what treatment is being given to each patient.
Other experimental gene therapies also are in development for Fabry disease. 4D Molecular Therapeutics’ candidate, 4D-310, is designed to deliver a working version of GLA to heart cells. It recently resumed clinical testing in the U.S. after an FDA-mandated pause. Meanwhile, Sangamo Therapeutics’ ST-920, which also targets a GLA gene to the liver, is headed for Phase 3 testing. It was grant fast track status by the FDA earlier this year.