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Abstract Details

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
Movement Disorders
P5 - Poster Session 5 (8:00 AM-9:00 AM)
3-014
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. 
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.
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.
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.
This clinical trial was approved by the FDA to enroll HD subjects in 2019 (NCT04120493).
Authors/Disclosures
Ralf Reilmann, MD, FÂ鶹´«Ã½Ó³»­ (George-Huntington-Institute)
PRESENTER 		The institution of Dr. Reilmann has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Hoffmann-La Roche. The institution of Dr. Reilmann has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for uniQure. The institution of Dr. Reilmann has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for WAVE. Dr. Reilmann has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for WAVE. The institution of Dr. Reilmann has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for IOS-Press. The institution of Dr. Reilmann has received research support from European Union. Dr. Reilmann has a non-compensated relationship as a Executive Committee Member with Huntington Study Group that is relevant to Â鶹´«Ã½Ó³»­ interests or activities. Dr. Reilmann has a non-compensated relationship as a Member of Executive Committee with European Huntington Disease Network that is relevant to Â鶹´«Ã½Ó³»­ interests or activities. Dr. Reilmann has a non-compensated relationship as a Co-Chair Task Force on Huntington Disease with Movement Disorders Socitey that is relevant to Â鶹´«Ã½Ó³»­ interests or activities.
Christopher Ross, MD, PhD (JHU) Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for uniqure. Christopher Ross, MD, PhD has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Spark. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitoconix. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sage. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Annexon. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuCell. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuCell. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuBase. Christopher Ross, MD, PhD has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Huntington Study Group. Christopher Ross, MD, PhD has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Spark. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for uniQure. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mitoconix. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sage. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Annexon. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NeuCell. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NeuBase. Christopher Ross, MD, PhD has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Christopher Ross, MD, PhD has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Huntington Study Group. Christopher Ross, MD, PhD has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Mintz. Christopher Ross, MD, PhD has received intellectual property interests from a discovery or technology relating to health care. Christopher Ross, MD, PhD has a non-compensated relationship as a consultant with Huntington Study Group that is relevant to Â鶹´«Ã½Ó³»­ interests or activities.
Claudia Testa, MD, PhD (University of North Carolina at Chapel Hill) Dr. Testa has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurocrine. Dr. Testa has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for uniQure. Dr. Testa has received personal compensation in the range of $5,000-$9,999 for serving as an officer or member of the Board of Directors for Tremor Research Group.
Samuel A. Frank, MD, FÂ鶹´«Ã½Ó³»­ (Beth Israel Deaconess Medical Center/Harvard Medical School) Dr. Frank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for uniQure. Dr. Frank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. Dr. Frank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. The institution of Dr. Frank has received research support from Huntington's Disease Society of America. The institution of Dr. Frank has received research support from Roche/Genentech. The institution of Dr. Frank has received research support from CHDI Foundation. The institution of Dr. Frank has received research support from Huntington Study Group. The institution of Dr. Frank has received research support from Cerevel.
Melvin Evers No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Joseph J. Higgins, MD, FÂ鶹´«Ã½Ó³»­ (AEGRIS LLC) No disclosure on file