Effects of IONIS-HTTRx in Patients with Early Huntington’s Disease, Results of the First HTT-Lowering Drug Trial (CT.002)

Objective: To characterize safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-HTT Rx , an antisense oligonucleotide (ASO) designed to target huntingtin ( HTT ) mRNA, in patients with early manifest Huntington’s disease (HD). Background: HD is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the HTT gene resulting in polyglutamine expansion in the mutant huntingtin protein (mHTT) with a toxic gain-of-function disease mechanism. No disease-modifying treatments are currently available. In transgenic rodent models of HD, suppressing HTT production delays disease progression and reverses disease phenotype (Kordasiewicz et al. 2012; Stanek et al. 2013). A comprehensive drug discovery effort, including extensive preclinical testing, was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA that potently suppresses HTT production. Design/Methods: In this first-in-human, multi-center, double-blind clinical trial (NCT02519036), 46 patients were randomized (3:1) to receive four doses of IONIS-HTT Rx or placebo by monthly bolus intrathecal (IT) injection followed by a 4-month untreated period. Five ascending-dose cohorts were enrolled with independent Data Safety Monitoring Board review of safety, PK and target engagement prior to dose escalation. Results: IONIS-HTT Rx was well-tolerated at all doses tested. Adverse events were mostly mild and unrelated to study drug. There were no adverse trends in laboratory parameters. No patients prematurely discontinued from treatment. ASO was measurable in CSF and plasma, and concentrations were generally aligned with predictions from a linked PK/PD preclinical model. Significant, dose-dependent reductions in CSF mutant HTT (mHTT) were observed. Conclusions: ASO technology has the potential to provide disease-modifying benefits to patients with neurodegenerative diseases. In this Phase 1/2a trial in early stage HD patients, IONIS-HTT Rx delivered via IT injection was well tolerated with no study drug-related adverse safety signals during the treatment or follow-up periods. Significant dose-dependent reductions in CSF mHTT were observed, suggesting that IONIS-HTT Rx is a promising therapeutic for the treatment of HD. Study Supported by: Ionis Pharmaceuticals Disclosure: Dr. Tabrizi has nothing to disclose. Dr. Leavitt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche, Ionis, uniQure, Teva, Lifemax. Dr. Leavitt has received personal compensation in an editorial capacity for Editor-in-chief of the Journal of Huntington’s Disease. Dr. Leavitt has received research support from Teva, uniQure, Lifemax. Dr. Kordasiewcz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Swayze has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Norris has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Baumann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Lane has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Bennett has nothing to disclose.