Multicenter, Randomized, Double-blind, Placebo-controlled Phase 1b/2a Studies of WVE-120101 and WVE-120102 in Patients with Huntington’s Disease (P2.006)

Objective: To describe the design of the first-in-human studies of WVE-120101 and WVE-120102 for the treatment of Huntington’s Disease (HD). Background: HD is caused by expansion of a cytosine-adenine-guanine (CAG) triplet repeat in the Huntingtin ( HTT ) gene that results in production of mutant HTT (mHTT) protein. Accumulation of mHTT protein leads to progressive loss of neurons in the brain. Significant levels of wild-type HTT (wtHTT) protein are essential for neuronal development and homeostasis. Therefore, drugs that lower expression of the mHTT gene transcript, while leaving wtHTT relatively intact, are desirable. WAVE-120101 and WVE-120102 are stereopure antisense oligonucleotides (ASOs) that selectively target the mHTT gene, acting at the U variant of single nucleotide polymorphism (SNP) rs362307 (SNP1) and the U variant of SNP rs362331 (SNP2), respectively. Combined, WVE-120101 and WVE-120102 have the potential to treat over two-thirds of HD patients. Design/Methods: These are randomized, double-blind, multicenter, placebo-controlled studies in adult patients with early manifest HD who carry the targeted SNP1 or SNP2; a screening assay will be used to identify patients who have the targeted SNP on the same allele as the pathogenic CAG expansion for study eligibility. Results: The primary objective of both studies is to assess the safety and tolerability of single-ascending and multiple doses of WVE-120101 and WVE-120102 administered intrathecally (IT) by lumbar puncture. Secondary objectives include studying pharmacokinetics in plasma and CSF, the pharmacodynamic effect on mHTT levels in CSF, and clinical signs and symptoms of HD as measured by the Unified Huntington’s Disease Rating Scale (UHDRS) and other validated measures. Details of these Phase 1b/2a studies will be presented. Conclusions: These first-in-human studies will provide proof-of-concept of the safety, tolerability and pharmacodynamic effects of targeted ASO therapy in HD. Study Supported by: WAVE Life Sciences Disclosure: Dr. Hersch has received personal compensation for activities with Wave Life Sciences: Consulting Pfizer: Consulting Roche: Consulting Voyager Therapeutics: Consulting. Dr. Hersch holds stock and/or stock options in Wave Life Sciences: Laboratory Research Voyager Therapeutics: Laboratory Research. Dr. Claassen has received personal compensation for activities with Lundbeck and Teva Neuroscience. Dr. Claassen has received research support from NIH/ NINDS, Michael J Fox Foundation, Auspex, Vaccinex, CHDI, C2N/Abbvie, and Huntington Disease Society of America. Dr. Edmondson has nothing to disclose. Dr. Wild has received personal compensation for activities with Roche Pharmaceuticals, Shire Pharmaceuticals, and Wave Life Sciences. Dr. Guerciolini has received personal compensation for activities with WAVE Life Sciences as an employee. Dr. Panzara has received personal compensation for activities with Genzyme and WAVE Life Sciences as an employee.