AMT-130 Safe for Continued Study in Phase 1/2 Huntington Disease Study

Ricardo Dolmetsch, PhD

An independent Data Safety Monitoring Board (DSMB) found no safety issues with AMT-130 at an interim assessment and advised that the phase 1/2 study assessing the therapy for adults with early manifest Huntington disease should continue as planned, according to a statement from uniQure, the company developing the gene therapy.

The safety analysis was conducted on data from the first 10 patients enrolled in the first cohort of the dose-escalation, double-blinded, randomized phase 1/2 study. This included 6 patients treated with AMT-130 and 4 who received a sham procedure. Based on the positive assessment from the DSMB, the study will begin enrolling patients in the second cohort, which is exploring a higher dose of the therapy.

“We are very pleased with the progress of the study and with the recommendations of the DSMB. We look forward to proceeding with dose-escalation in the second cohort of patients,” Ricardo Dolmetsch, PhD, president of research and development at uniQure, said in a statement. “We remain highly focused on progressing this therapy given the significant unmet need in the Huntington disease community and are committed to initiating clinical development of AMT-130 in Europe in the second half of this year and to sharing initial imaging and biomarker data from the US clinical trial before the end of the year.”

AMT-130 consists of an AAV5 vector carrying a transgene for an artificial micro-RNA sequence designed to target and silence huntingtin (HTT) gene activity at the RNA level. The micro-RNA produced by the transgene binds to HTT mRNA, causing the protein to be cleaved and degraded and a lowering in huntingtin protein translation. In preclinical models, the treatment led to a reduction in the detrimental effects of the overproduction of the mutant protein.

In the phase 1/2 study (NCT04120493), which is a proof-of-concept study for the therapy, patients are receiving a single dose of the AMT-130, which is administered through a microcatheter directly to the caudate and striatum in the brain. The therapy is administered under general anesthesia through 2 holes drilled in the skull. The sham procedure mimics this process; however, only skin incisions will be made and there are no burr holes.

The study is planned to span 5 years, with the first 12 months representing a blinded initial core study period. After the 12-month period, patients in the study will be individually unblinded and those in the sham arm will be allowed to cross over to the treatment arm. At the time of the DSMB assessment, 2 patients had reached 9 months of follow up, 2 had 6 months of follow up, and 6 were had reached a 30-day safety assessment.

The cohort 1 dose in the study consisted of AMT-130 at 6x10^12 gene copies per subject. The cohort 2 higher dose is planned to be 6 x 10^13 gene copies per subject. The estimated full enrollment in the study is 26 participants, across both cohorts and the sham arm. The primary end point of the study is adverse events, with secondary outcome measures focused on AMT-130 persistence in the brain, cognitive and motor assessments, imaging and spectroscopy data, quality of life measures, and the analysis of several cerebral spinal fluid (CSF)-based biomarkers, such as neurofilament light chains and the level of mutant proteins. The study is enrolling exclusively in the United States.

The primary completion date for the trial is listed as December 2022; however, with the first 2 patients will reach the unblinding period within 3 months and uniQure anticipates early data before the end of 2021.

Based on the early promise for the gene therapy, the FDA granted AMT-130 a fast track designation in April 2019. This designation is meant to facilitate and expedite the development of treatments for serious conditions that fill an unmet need. The gene therapy has also received an orphan drug designation in the United States and an Orphan Medicinal Product Designation (OMPD) from the European Medicines Agency.