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P1‐058: EFFECTS OF THE EPIGENETIC BET‐INHIBITOR SMALL MOLECULE APABETALONE ON COGNITION IN PATIENTS WITH DIABETES AND CARDIOVASCULAR DISEASE
Author(s) -
Cummings Jeffrey L.,
Johansson Jan O.,
Sweeney Mike,
Kulikowski Ewelina,
Wong Norman C.W.,
Halliday Christopher,
Lebioda Kenneth,
Winblad Bengt,
Zetterberg Henrik,
Kalantar-Zadeh Kam,
Nicholls Stephen J.,
Schwartz Greg G.,
Ray Kausik K.
Publication year - 2019
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.2019.06.083
Subject(s) - montreal cognitive assessment , medicine , diabetes mellitus , cognition , dementia , cognitive decline , myocardial infarction , placebo , disease , cardiology , oncology , endocrinology , psychiatry , pathology , alternative medicine
-1, 1, 2, 7, and 14. Exploratory assessments of cognition were also made. Results: After 14 days of once-daily dosing, LY3154207 plasma concentrations peaked between 2-3 hours post-dose. Steady state was achieved at Day 7. There was modest accumulation with the 15-mg dose (accumulation ratio based on AUC 1⁄4 1.34) and no accumulation at higher doses. Across all dose levels, the range of total body clearance was 24.2-34.5 L/hour and renal clearance was minimal at 0.00244 0.00362 L/hour. No serious AEs occurred. Common treatment-related AEs ( 3 occurrences, primarily at the 150-mg dose) were mild in severity and included: insomnia, dizziness, nausea, nervousness, and palpitations. Dose-related increases in mean ABPM-derived SBP, DBP, and heart rate were noted on Day 1, with peak increases generally between 4-8 hours postdose. By Day 14 (Day 7 for lower LY3154207 doses), the magnitude of these increases was lower than at Day 1 and in the range observed with placebo, suggesting accommodation of these cardiovascular effects. Conclusions: Overall, multiple once-daily doses of LY3174207 were well-tolerated with a PK profile predictable from single doses. An acute dose-dependent increase in SBP, DBP, and HR was observed upon initial administration but these effects accommodated with repeated dosing.