J05 Interim results from cohort 1 of the double-blind, dose-escalation phase I/II clinical trial of amt-130 (HD-genetrx-1) for early-stage huntington's disease (HD). (12th September 2022)

• Record Type: Journal Article
• Authors: Furr Stimming, Erin; Sung, Victor; Testa, Claudia; Kostyk, Sandra; Ross, Christopher A; Samii, Ali; Geschwind, Michael D; Hall, Deborah; Dayalu, Praveen; Lonser, Russell; Elder, Brad; Larson, Paul S; Cooper, David L; Clarkin, Marcie; Ali, Talaha M; Dolmetsch, Ricardo E
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 93(2022)Supplement 1
• Page Start: A95
• Page End: A95
• Publication Date: 2022-09-12
• Subjects: huntingtin lowering -- clinical trial -- AAV gene therapy -- safety -- biomarkers; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2022-ehdn.255
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: Huntingtin (HTT) lowering therapies hold great promise to slow or halt neurodegeneration in Huntington's disease (HD). AMT-130 is an investigational AAV5-based gene therapy that expresses an engineered microRNA to specifically bind to huntingtin exon 1, thereby lowering total HTT mRNA. Aims: We initiated a double-blinded first-in-human study to investigate AMT-130 in early-stage patients and here describe interim 12-month results from the low-dose cohort (NCT04120493 ). Methods: Inclusion criteria were DCL 3-4, TFC 9-13, ≥40 CAG repeats, and caudate/putamen volumes greater than a prespecified minimum. Participants received one-time AMT-130 administration using MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into six sites bilaterally (3/side) in the striatum, or a sham surgical procedure. Results: At baseline, ages of 10 enrolled participants in Cohort 1 ranged from 34-58 years (mean:49), historical CAG repeats from 41-44 (mean:42), CAP scores from 318-542 (mean:426), TFC from 10-13 (mean:11.9) and TMS from 7-23 (mean:13.3). At 12-months post-treatment, the most common treatment-emergent adverse event was transient post-procedural headache (70%). Two serious adverse events judged to likely be unrelated to AMT-130 were observed: an upper extremity DVT at an intravenous line site presenting 1-week post-procedure, and brief post-operative delirium; both resolved. At 12-months post-treatment, CSF NfL returned to near baseline levels following an initial increase and the mean CSF mHTT decreased 53.8% (range:44-71%) compared to baseline. Conclusions: Follow up of participants is ongoing. Cohort 1 interim data thus far supports the safety and tolerability of a one-time infusion of AMT-130 in patients with early-stage HD.