Design of the First-in-Human Study of IONIS-MAPTRx, a Tau-lowering Antisense Oligonucleotide, in Patients With Alzheimer Disease (S2.006)

Objective: To design a study to test IONIS-MAPT Rx an antisense oligonucleotide (ASO) developed to specifically, potently and safely reduce MAPT mRNA in patients with tauopathies. Background: Tau pathology is temporally and regionally related to neurodegeneration in Alzheimer disease (AD), emphasizing its role in transducing Aβ-linked neurotoxicity. Reducing Tau mRNA in all cell types will lead to reductions of any isoforms, post-translational modifications, and conformations of tau, thus potentially impacting all tauopathies. Homozygous and hemizygous knockout of endogenous tau in mice protects against Aβ insults. Treatment with ASO in a mouse model of human tauopathy leads to the reduction of the human MAPT pre-mRNA, blocking tau pathology, preventing seeding activity, reversing established tau pathology, extending survival and improving functional outcomes (DeVos et al. Science Translational Medicine, 2017). Design/Methods: ASOs were designed and screened to identify the optimal drug candidate. Toxicology studies, performed in rodents and non-human primates, established the candidate’s safety, pharmacokinetic and pharmacodynamic profiles. Results: IONIS-MAPT Rx is a second generation 2′-O-methoxyethyl chimeric ASO designed to reduce tau expression. Intrathecal administrations of IONIS-MAPT Rx in nonhuman primates showed a mean MAPT mRNA reduction of 77% in frontal cortex and 74% in hippocampus without dose-limiting side effects. These findings informed the design of the first clinical trial of this tau- lowering ASO. Ionis-MAPT Rx CS1 (NCT03186989) is a multi-center, randomized, placebo-controlled multiple-ascending dose study assessing the safety, tolerability and pharmacokinetic parameters of repeated intrathecal injections in patients with mild AD. The study endpoints, including CSF biomarker, neuroimaging, and clinical outcomes, serve both as safety measures and as exploratory measures of pharmacodynamic effects. Conclusions: IONIS-MAPT Rx is the result of a comprehensive drug discovery effort to design a well-tolerated, potent ASO with high specificity to human MAPT mRNA. This promising therapeutic approach for primary and secondary tauopathies recently initiated dosing in patients with mild AD. Disclosure: Dr. Mignon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Kordasiewcz 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. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Miller has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Cytokinetics, Biogen, Ionis. Dr. Miller has received royalty, license fees, or contractual rights payments from C2N. Dr. Miller has received research support from Biogen. Dr. Narayanan 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. Fitzsimmons 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.