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[O2–17–02]: DISCOVERY AND EARLY CLINICAL DEVELOPMENT OF IONIS‐MAPT RX , THE FIRST TAU‐LOWERING ANTISENSE OLIGONUCLEOTIDE, IN PATIENTS WITH MILD AD
Author(s) -
Lane Roger M.,
Kordasiewicz Holly B.,
Smith Anne,
Mig Laurence,
Miller Timothy M.,
Mummery Catherine J.,
Andreasen Niels,
Narayanan Padma,
Swayze Eric,
Norris Daniel A.,
Fitzsimmons Bethany,
Bennett C Frank
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.242
Subject(s) - neurodegeneration , transgene , genetically modified mouse , neurotoxicity , messenger rna , tau protein , pharmacology , biology , drug discovery , microbiology and biotechnology , medicine , gene , disease , toxicity , alzheimer's disease , pathology , bioinformatics , genetics
were randomized 3:1 to either drug or placebo in 4-subject blocks and received a single intravenous dose of ABBV-8E12 (2.5, 7.5, 15, 25, or 50 mg/kg) or placebo. Safety and pharmacokinetics were monitored for 84 days post-dosing. Results: Thirty subjects were enrolled and randomized. At screening, the mean (SD) subject age was 69.4 years (7.4); 16 (53%) were male, and the mean (SD) PSP Rating Scale score was 35.6 (7.6). Twenty-seven subjects completed the 84-day follow-up and 1 (3.3%) subject withdrew from the study due to adverse event (AE). AEs occurred in 21 of the 30 (70%) subjects. The AEs with the highest subject incidence were dermatitis (n1⁄45) and fall (n1⁄45) (Table 1). Three serious AEs were reported (10% incidence), one in each of the 15, 25, and 50 mg/kg cohorts. Noncompartmental analysis based on the complete pharmacokinetic dataset indicates dose-proportional increases in AUC and Cmax. The estimated half-life of ABBV-8E12 is approximately 1 month. A phase 2 study evaluating ABBV-8E12 in early AD subjects is currently recruiting (NCT02880956) (Figure 1). Eligible subjects (n1⁄4400) will meet criteria for early AD and have a positive amyloid Positron Emission Tomography scan. In addition to the ongoing phase 2 study in AD subjects, a phase 2 study evaluating the 52-week efficacy and safety of ABBV-8E12 in PSP subjects (n1⁄4180) is also currently recruiting (NCT02985879). Conclusions: When administered as a single dose up to 50 mg/kg in PSP subjects, ABBV-8E12 exhibited an acceptable safety and tolerability profile to support repeat-dose testing in subjects with tauopathies.