uniQure's Mesial Temporal Lobe Epilepsy Gene Therapy AMT-260 Cleared for US Trial


In light of the IND clearance, uniQure announced its intention to carry out a phase 1/2a clinical trial, with screening of potential participants with refractory MTLE anticipated to begin in the last 3 months of 2023.

uniQure NV’s AMT-260, an investigational adeno-associated virus (AAV) vector-based miRNA gene therapy intended to treat refractory mesial temporal lobe epilepsy (MTLE), has received clearance of its investigational new drug (IND) application from the FDA.1

In light of the IND clearance, uniQure intends to carry out a phase 1/2a clinical trial, with screening of potential participants with refractory MTLE anticipated to begin in the last 3 months of this year. The first-in-human study will consist of an initial multicenter, open-label portion in which 2 cohorts of 6 patients each will be treated at 2 different dose levels and a later randomized, controlled portion that will aim to demonstrate proof-of-concept.

“The clearance of the IND for AMT-260 is an important achievement in advancing our pipeline and is our next program to enter clinical development in an area of high unmet medical need,” Walid Abi-Saab, the chief medical officer of uniQure, said in a statment.1 “There are few treatment options for patients who have refractory MTLE, and we are pleased to soon begin the clinical investigation of this 1-time administered gene therapy approach as a potential new treatment.”

AMT-260 consists of 2 engineered miRNAs, delivered locally in an AAV9 vector, that are intended to degrade GRIK2, a gene involved in production of glutamate receptor subtype GLUK2. Glutamate receptor subtype GLUK2 is a protein that may be a cause of epilepsy when atypically expressed in the hippocampus of patients with MTLE.

uniQure acquired the AMT-260 program via its acquisition of Corlieve Therapeutics in 2021.2 Corlieve Therapeutics had carried out preclinical proof-of-concept research with a disease model and with resected hippocampi from patients with TLE showing clear suppression of chronic spontaneous epileptic seizures. AMT-260's development was the result of collaborative efforts between Corlieve Therapeutics; REGENXBIO; Christophe Mulle, PhD, the CNRS Research Director of the Interdisciplinary Institute of Neurosciences at the Centre National de la Recherche Scientifique of University of Bordeaux; and Valerie Crepel, PhD, the Inserm Research Director of the Institut de Neurobiologie de la Méditerranée at Institut National de la Santé et de la Recherche Médicale of Aix-Marseille University.

“The acquisition of Corlieve provides an extraordinary opportunity to transform the lives of hundreds of thousands of patients around the world suffering from epilepsy and aligns with our vision of pursuing unmet medical needs for disorders that impact large populations and can be addressed with gene therapies directed to the central nervous system and liver,” Matt Kapusta, the chief executive officer of uniQure, said in a 2021 statement.2 “The groundbreaking work of the Corlieve team, in collaboration with Drs. Mulle and Crepel, has led to compelling preclinical results in TLE that we believe can strategically leverage uniQure’s leading position in developing and delivering gene therapies that employ miRNA silencing technology. We look forward to welcoming the Corlieve team into the uniQure family as we join forces to advance this important and potentially transformative therapy into clinical studies.”

Another advanced therapeutic, Neurona Therapeutics’ inhibitory interneuron cell therapy NRTX-1001, is also in development for the treatment of MTLE.3 NRTX-1001 is currently being evaluated in a phase 1/2 clinical trial (NCT05135091) in patients with drug-resistant unilateral MTLE. In June of this year, Neurona presented results showing seizure reductions in the first 2 patients treated in the trial at the International Society for Stem Cell Research (ISSR) 2023 Annual Meeting.

“Patient 1 has reached the 1-year post treatment end point and has achieved a [greater than] 95% overall monthly seizure reduction, including elimination of all seizure events since the seventh month post-administration of NRTX-1001,” David Blum, MD, chief medical officer, Neurona Therapeutics, said in a June 2023 statement.4 “In addition, this patient has shown improved memory performance on cognitive tests. We continue to enroll patients in the first cohort of the study and look forward to providing additional updates later this year.”

1. uniQure announces FDA clearance of investigational new drug application for AMT-260 gene therapy for refractory mesial temporal lobe epilepsy. News release. uniQure N.V. September 5, 2023. Accessed September 7, 2023. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-fda-clearance-investigational-new-drug-0
2. uniQure to acquire Corlieve Therapeutics and advance its gene therapy program to treat temporal lobe epilepsy (TLE). News release. uniQure. June 22, 2021. Accessed September 7, 2023. https://www.globenewswire.com/news-release/2021/06/22/2251226/0/en/uniQure-to-Acquire-Corlieve-Therapeutics-and-Advance-its-Gene-Therapy-Program-to-Treat-Temporal-Lobe-Epilepsy-TLE.html
3. Nicholas C. A phase I/II clinical trial of NRTX-1001 HPSC-derived inhibitory interneuron cell therapy for chronic focal epilepsy. Presented at: ISSCR 2023 Annual Meeting.
4. Neurona Therapeutics Presents One-Year Data on the First Patient Treated with NRTX-1001 Cell Therapy in an Ongoing Phase I/II Trial for Drug-resistant Focal Epilepsy. News release. Neurona Therapeutics. June 15, 2023. Accessed September 7, 2023. https://www.neuronatherapeutics.com/news/press-releases/061523/
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