First SOD1-ALS patient dosed in trial of AMT-162 gene therapy
EPISOD1 now recruiting patients with SOD1 gene mutations at 4 US sites
The first patient has been dosed in a Phase 1/2 clinical trial of AMT-162, the one-time gene therapy in development by uniQure for treating amyotrophic lateral sclerosis (ALS) caused by mutations in the SOD1 gene, when the condition is thus known as SOD1-ALS.
The open-label EPISOD1 clinical trial (NCT06100276) is now recruiting participants at four sites in the U.S., with plans to add seven more by early next year. The trial is testing three different dose levels of AMT-162 to check its safety and tolerability, and determine whether it can slow disease progression in these patients.
“We are pleased to announce the first patient dosing of AMT-162, our investigational gene therapy for the treatment of SOD1-ALS,” Walid Abi-Saab, MD, chief medical officer of uniQure, said in a company press release.
Mutations in the SOD1 gene are found in as many as 20% of people with familial ALS, which occurs among relatives, and in as many as 2% of those with the sporadic type of the disease, where there is no known family history. The mutations result in the production of a misfolded version of the SOD1 protein that’s prone to clump up into aggregates.
Such protein clumps accumulate in motor neurons, the nerve cells that control movement in the body, causing damage. As a result, patients experience progressive muscle weakness that causes them to gradually lose the ability to move their arms and legs, and to speak, swallow, and breathe.
Phase 1/2 clinical trial testing 3 dose levels of AMT-162
Licensed from Apic Bio last year, AMT-162 uses an adeno-associated virus or AAV-based vehicle to deliver a microRNA — a short segment of genetic material — that binds to the molecule carrying the instructions to produce SOD1, sending it off for degradation. This is expected to reduce the amount of misfolded protein, thereby slowing or stopping disease progression.
The therapy is administered via a one-time injection into the spinal canal (intrathecally). In two men with SOD1-ALS who received treatment in a proof-of-concept study, the gene therapy was safe when given together with an immunosuppressant to prevent immune responses against the viral vector. In one man, it resulted in a transient reduction of SOD1 in the spinal cord and improvements in the right leg. The other man had stable disease for up to one year.
“We believe our novel AAV-based gene therapy candidate can deliver on the convenience of one-time dosing with the potential for a differentiated efficacy profile that is needed for such a [devastating] disease,” Abi-Saab said.
The EPISOD1 trial aims to enroll about 20 adults with a genetic diagnosis of SOD1-ALS. Eligible patients will be experiencing symptoms of damage to lower motor neurons, which run along the spinal cord and connect to the muscles, with or without damage to the upper motor neurons, those sending messages from the brain to the spinal cord.
The study will consist of three patient groups, each receiving a single ascending dose of AMT-162. Participants will receive a short course of immunosuppression before and after the gene therapy infusion, and will be monitored for up to five years afterward.
The main goal is to determine the gene therapy’s safety, based on the number and severity of treatment-related side effects. Secondary measures include any immune response to AMT-162, and changes in lung function, muscle strength, and blood levels of neurofilament light chain, a biomarker of nerve cell damage.
We believe our novel AAV-based gene therapy candidate can deliver on the convenience of one-time dosing with the potential for a differentiated efficacy profile that is needed for such a [devastating] disease.
The company also is running clinical trials testing gene therapy candidates for Huntington’s disease, temporal lobe epilepsy, and Fabry disease. Like EPISOD1, two of these clinical trials are based on an open-label design, whereas the study in Huntington’s is a randomized controlled trial. In an open-label trial, both participants and researchers know the treatment being given.
“The start of this trial marks the advancement of our third gene therapy program into the clinic with this trial design, continuing our goal of rapidly generating proof-of-concept data using well-established biomarkers in order to bring treatments to patients as quickly as possible,” Abi-Saab said.
AMT-162 has received both orphan drug and fast track designations from the U.S. Food and Drug Administration. Such designations provide the company with incentives to accelerate a therapy’s clinical development.
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