Design of the First-in-Human Study of IONIS-MAPTRx, a Tau-lowering Antisense Oligonucleotide, in Patients With Alzheimer Disease (S2.006)
Citation Manager Formats
Make Comment
See Comments

Abstract
Objective: To design a study to test IONIS-MAPTRx 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-MAPTRx is a second generation 2′-O-methoxyethyl chimeric ASO designed to reduce tau expression. Intrathecal administrations of IONIS-MAPTRx 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-MAPTRx 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-MAPTRx 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.
Disputes & Debates: Rapid online correspondence
NOTE: All authors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.
- Stay timely. Submit only on articles published within the last 8 weeks.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- 200 words maximum.
- 5 references maximum. Reference 1 must be the article on which you are commenting.
- 5 authors maximum. Exception: replies can include all original authors of the article.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Related Articles
- No related articles found.