Intrathecal Drug Delivery of Antisense Oligonucleotides in Huntington's Disease: Experience of Ionis/Roche RG6042 Development Programme and Best Practice Considerations for Real-World Use

Objective: To describe the experience with intrathecal drug delivery across two clinical studies and suggest best practice for intrathecal drug administration in Huntington’s disease (HD). Background: Intrathecal administration involves the introduction of a drug substance into the intrathecal (subarachnoid) space of the spinal column through a spinal needle inserted typically into the lower back via lumbar puncture (LP) or via a special device (e.g. a surgically implanted catheter connected to a drug reservoir). This procedure is used when drugs cannot cross the blood–brain barrier. Once injected, drugs administered via the intrathecal route are distributed within the cerebrospinal fluid from which they can access target tissues in spinal cord and brain. The method is commonly used in spinal anaesthesia, pain management and chemotherapy; but with the advent of antisense oligonucleotides (ASOs) for treatment of neurological conditions, the indications have expanded to include spinal muscular atrophy, and, as potential new indications, amyotrophic lateral sclerosis, Alzheimer’s disease and HD. Design/Methods: We use the intrathecal route to deliver RG6042 (previously HTTRx), an investigational, huntingtin mRNA-targeting ASO to patients with HD. The RG6042 clinical development programme includes the double-blind, placebo-controlled, multiple ascending dose, Phase I/IIa study (NCT02519036) in 46 patients with early manifest HD and an ongoing Phase II open-label extension (NCT03342053) where patients receive 120 mg RG6042 monthly or every other month in a 62-week treatment period (total procedures ≥400 in the programme to date). Results: We will report on the experience with intrathecal drug delivery across these two studies and present information on suggested best practices in HD. Conclusions: Considerable experience on intrathecal administration via LP has been gained in the RG6042 clinical development programme. This experience allows us to provide a forward-looking outlook on real-world considerations of implementing intrathecally delivered therapies in the clinical interface. Disclosure: Dr. Leavitt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Personal compensation as a paid scientific advisor or consultant to several pharmaceutical companies regarding the development of new therapies for Huntington’s Disease and similar disorders including: Roche, Teva, uniQure, Novartis, PTC, sRNAlytics, and . Dr. Leavitt has received personal compensation in an editorial capacity for Personal compensation to cover administrative expenses as the co-Editor-in-Chief of the Journal of Huntington’s Disease.. Dr. Leavitt has received research support from My research lab has been funded by grants from Teva Pharmaceuticals, uniQure, and Roche to perform basic research projects in mouse models of Huntington’s disease.. Dr. Wild has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann La Roche Ltd, Triplet Therapeutics, Dementia Discovery Fund, Mitoconix Bio Ltd, PTC Therapeutics and Takeda. All payments were made to UCL Consultants, a wholly owned subsidiary of University College London.. Dr. Wild has received research support from Research grant to University College London by F. Hoffmann-La Roche..Dr. Bang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche, NAACME. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Schlegel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffman La-Roche Ltd.. Dr. Schobel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SS is a full-time employee of F. Hoffmann–LaRoche.Dr. Nicotra has nothing to disclose. Dr. Landwehrmeyer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche, Lundbeck, Triplet, Takeda.. Dr. Landwehrmeyer has received personal compensation in an editorial capacity for Journal of Oxford University Press, Thieme Verlag.. Dr. Landwehrmeyer has received research support from Clinical trial compensation from F. Hoffmann-La Roche.. Dr. Tabrizi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with University College London, F Hoffman-La Roche Ltd, Takeda Pharmaceuticals, UCB Pharma SA, and Vertex Pharmaceuticals Incorporated.. Dr. Tabrizi has received research support from Takeda Pharmaceuticals..Dr. Guttman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche and Novartis. Dr. Guttman has received research support from Roche and Wave Life Sciences.