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[P4–578]: EXPANDING THE BRIEF ASSESSMENT OF COGNITION (BAC‐APP) FOR ASSESSMENT OF COGNITION IN AGING: INITIAL FINDINGS FROM AN ONGOING NORMATIVE STUDY
Author(s) -
Atkins Alexandra S.,
Khan Anzalee,
WelshBohmer Kathleen A.,
Plassman Brenda L.,
Randolph Christopher,
Harrison John,
Keefe Richard S.E.
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.2017.07.741
Subject(s) - cognition , verbal fluency test , psychology , recall , cognitive test , verbal learning , effects of sleep deprivation on cognitive performance , verbal memory , normative , neuropsychological assessment , audiology , neuropsychology , developmental psychology , medicine , cognitive psychology , psychiatry , philosophy , epistemology
Background:We recently reported on the First-in-human Clinical Trial to Assess Safety, Tolerability and Pharmacokinetics of ORY-2001, a dual LSD1/MAOB inhibitor. Preliminary results showed that orally administered ORY-2001 was well tolerated and did not provoke clinically significant changes in laboratory tests, vital signs, ECGs, physical findings, or adverse events in SAD cohorts from 0.2 to 4 mg nor in MAD cohorts up to 2.5 mg. The PK/PD profile of ORY-2001 revealed rapid oral absorption, a 22 h half-life , moderate systemic accumulation (mean AUC ratio<2) after 5 days of administration and dose dependent LSD1 target engagement in PBMCs with a half-life of approximately 84 h. The first laboratory signs of hematopoietic impact were observed in MAD 2.5 mg cohort, showed no significant reduction of hematopoietic parameters, yet a platelet rebound was detected during follow-up. Methods:To complete the profile of ORY-2001, a) cohort of elderly volunteers was treated at 2.5 mg and a protocol amendment was introduced to b) fully characterize the hematopoietic impact at an additional dose level of 4 mg in the MAD in healthy volunteers and c) measure ORY-2001 in CSF. In parallel, we studied d) binding of ORY-2001 to LSD1 by ex-vivo treatment of PBMCs from healthy volunteers and post-mortem brain samples from healthy individuals and AD patients. Results: a) ORY-2001 treatment at 2.5 mg in elderly volunteers was well tolerated and safe. b) Treatment with ORY-2001 at 4 mg induced transient thrombocytopenia followed by a rebound that resolved in absence of any clinical signs. No other hematopoietic parameters were affected. c) CSF and plasma levels calculated after administration of single doses of 2.5 or 4 mg of ORY-2001 demonstrated CNS exposure. d) Target engagement analysis showed that ORY-2001 binds LSD1 ex vivo in native protein extracts from human PBMCs and post-mortem human brains with similar efficiency. Conclusions: ORY-2001 was safe, well tolerated and is CNS penetrant. The Phase I study provides detailed information that allows us to model the dose response in humans and to establish a safe administration scheme for long term efficacy studies of ORY-2001 in Phase II trials in neurodegeneration and neuroinflammation.