First Patient Dosed in Trial for uniQure’s SOD1-ALS Gene Therapy AMT-162
The phase 1/2 EPISOD1 study, which is taking place in the US, will provide participants with a short immunosuppression regimen before administration of the gene therapy.
UniQure has dosed the first patient in its phase 1/2 EPISOD1 clinical trial (NCT06100276), which is evaluating AMT-162, an investigational adeno-associated virus (AAV) vector-based gene therapy, for the treatment of amyotrophic lateral sclerosis caused by mutations in superoxide dismutase 1 (SOD1-ALS).1
AMT-162 contains a transgene coding for a microRNA (miRNA) that is intended to silence the expression of the disease-targeted gene, which codes for a misfolded SOD1 protein with neurotoxic properties. The transgene is delivered via an AAVrh10 vector. The gene therapy is administered intrathecally in a one-time dose.
The multicener, open-label EPISOD1 study, which is taking place in the United States, will provide participants with a short immunosuppression regimen before administration of the gene therapy product. Participants will be treated as part of 1 of 3 cohorts, each of which may include up to 4 patients. The study is mainly focused on safety, but will also gather efficacy data via assessment of neurofilament light chain and SOD1 protein levels. Currently, 4 of the trial’s sites are active, and UniQure intends to activate 7 more sites by the first quarter of next year. According to the clinicaltrials.gov page, which was most recently updated on October 15, 2024, EPISOD1 is currently recruiting at University of California Irvine, California Pacific Medical Center, Massachusetts General Hospital, and Columbia University Irving Medical Center.
“We are pleased to announce the first patient dosing of AMT-162, our investigational gene therapy for the treatment of SOD1-ALS, a debilitating, degenerative and fatal disease,” Walid Abi-Saab, MD, the chief medical officer of uniQure, said in a statement.1 “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. 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 devasting disease.”
In addition to AMT-162, uniQure is developing several other AAV vector-based gene therapy products for neurological indications. One of these is AMT-260, a miRNA gene therapy intended to treat temporal lobe epilepsy (TLE) that is being evaluated in a phase 1/2a clinical trial (NCT06063850).2 Notably, data from preclinical research relevant to AMT-260 were reported at the 2023 American Epilepsy Society Annual Meeting, held December 1-5, in Orlando, Florida. AMT-260 was assessed at doses that ranged from 1.2x1010 vg/hippocampus to 1.2x1012 vg/hippocampus in a mouse model for TLE (mice treated with pilocarpine) and in nonhuman primates. Notably, all doses were well tolerated preclinically and showed the potential for a good risk-benefit ratio for patients with TLE.
“TLE is the most common form of focal epilepsy characterized by recurrent seizures generated in the hippocampus [and] patients with TLE are often resistant to antiseizure medications,” first author Stephane Baudouin, PhD, the senior director and head of in vivo Pharmacology at uniQure’s French subsidiary, Corlieve Therapeutics, and colleagues wrote in the poster they presented at the conference.2 “In TLE, the [dentate granule cells] operate via aberrant ectopic expression of GluK2/GluK5 kainate type receptors, and GluK2/GluK5 was demonstrated to play a central role in the generation of seizure activity. However, the pharmacological potential of GluK2/GluK5 as a target for the treatment of TLE remained to be demonstrated.” They added that “AMT-260 includes an AAV9 vector coding for 2 microRNAs capable [of knocking down] GluK2 expression, providing a novel therapeutic option for refractory TLE patients.”
