Translation of AMT-130 Preclinical Data to Inform the Design of the First FDA-approved Human AAV Gene Therapy Clinical Trial in Adults with Early Manifest Huntington's Disease

Objective: Describe the rationale and design of a Phase I/II clinical trial in adults to explore the safety, tolerability, and efficacy of striatally-administered recombinant adeno-associated virus serotype 5, microRNA huntingtin (rAAV5-miHTT; AMT-130) gene therapy to lower huntingtin protein (HTT) in the brains of early manifest Huntington’s disease (HD) patients. Background: AMT-130 uses a therapeutic approach that efficiently lowers HTT mRNA and HTT protein by an RNA interference mechanism that targets the toxic mutant HTT (mHTT) exon 1 and avoids off-target effects. Neuropathology, motor-function, and survival improve when mHTT is lowered by 25%–75% in the brains of transgenic HD animal models. Preclinical GLP studies show that high doses of AMT-130 are safe and well-tolerated after intra-striatal administration by convection enhanced delivery. Design/Methods: The human equivalent dose (HED) to lower mHTT was extrapolated using a regression plot based on the brain biodistribution in small and large HD transgenic models. A clinical trial was designed using preclinical data and historical patient data from the TRACK-HD study. Volumetric MRI of the putamen and caudate nuclei for each HD patient were acquired. Real-time volume of distribution (Vd) and volume of infusion (Vi) data from non-human primates were used to estimate a scale-up factor for human delivery of AMT-130 gene therapy. Results: Bioanalytical modeling indicated that the AMT-130 HED to achieve a 75% lowering of mHTT in the striatum and 50% in the frontal cortex was 6×1013 AMT-130 genome copies/brain administered in a single dose. An analysis of historical HD patient data suggested that an 18-month, double-blind, imitation-surgery (sham)-controlled clinical trial enriched for early manifest subjects with ≥44 HTT CAG repeats, was optimal to evaluate primary outcomes of safety and tolerability, and exploratory efficacy signals in mHTT, NF-L, imaging, motor, and functional measures. Conclusions: This clinical trial was approved by the FDA to enroll HD subjects in 2019 (NCT04120493). Disclosure: Dr. Reilmann holds stock and/or stock options in the George-Huntington-Institute and QuantiMedis. Dr. Reilmann has received research support from Hoffmann-La Roche, Ipsen, Novartis AG, Pfizer, Teva, uniQure, Vaccinex, and Wave Life Sciences.Dr. Ross has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with uniQure B.V.. Dr. Testa has received research support from Co-Principal Investigator: First-HD. Consultant: Lundbeck, with honoraria donated to the Medical College of Virginia Foundation. Dr. Frank has received research support from First-HD, and ARC-HD.Dr. Evers has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with uniQure BV.Dr. de Haan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with uniQure, Inc. Dr. de Haan has received research support from uniQure, Inc. Dr. Valles-sanchez has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with uniQure BV. Dr. Valles-sanchez has received research support from uniQure BV. Dr. Konstantinova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with uniQure BV. Dr. Konstantinova has received research support from uniQure BV. Dr. van Deventer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with uniQure B.V.. Dr. van Deventer holds stock and/or stock options in uniQure B.V. which sponsored research in which Dr. van Deventer was involved as an investigator. Dr. Higgins has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with uniQure B.V.