ORY-2001: AN EPIGENETIC DRUG FOR THE TREATMENT OF COGNITION DEFECTS IN ALZHEIMER’S DISEASE AND OTHER NEURODEGENERATIVE DISORDERS

Abstract

ORY-2001 is a brain-penetrable inhibitor of LSD1 and MAO-B with excellent oral bioavailability and PK profile. LSD1 is a chromatin modulator and component of repressor complexes. MAO-B plays an important role in the catabolism of neuroactive and vasoactive amines and is responsible for dopamine degradation. ORY-2001 has excellent selectivity over other FAD containing amine oxidases, does not inhibit other chromatin modulators nor +100 targets from the CEREP diversity panel. ORY-2001 is in development for treatment of CNS disorders, including Alzheimer's and in a Phase I trial in healthy young and elderly subjects. Novel Object Recognition Tests (NORT) were performed on SAMP8 mice after 2-4 months of oral treatment and in R6/1 mice after 7 weeks of treatment. Brain LSD1 target engagement was assessed using a newly developed assay. Chronic treatment with ORY-2001 was well tolerated. 0.11 to 3.2 mg/kg completely rescued the memory deficit of SAMP8 mice. Increased stringency criteria for exploration time (> 5s cut-off) in the NORT revealed a subtle dose effect; further supported by measurements of LSD1 target engagement in the brain. Binding to LSD1 saturated at 0.32 and was 75% at 0.11 mg/kg. Importantly, 0.11 to 0.96 mg/kg ORY-2001 did not affect hematopoiesis, 3.2 mg/kg reduced PLT approximately by half; yielding a 30-40 fold therapeutic window. The MAOB inhibitor Rasagiline provides some improvement, underscoring the relevance of the LSD1i component in ORY-2001. A selective LSD1 inhibitor significantly and dose-dependently improved the NORT readouts in the SAMP8 model, however ORY-2001 showed superior performance. LSD1 inhibitors may counterbalance transcriptional imbalances provoked by REST translocation to the nucleus in Huntington disease. Treatment with 0.32, 0.96 but not 0.11 mg/kg ORY-2001 completely rescued the NORT readouts in R6/1 mice. ORY-2001 has a good safety profile and therapeutic index and stops/prevents the development of cognitive impairment assessed by NORT in the SAMP-8 mice as well as in the R6/1 model for Huntington’s disease. The therapeutic range correlates convincingly with LSD1 target engagement in the mouse brain. Mechanism of action based hypotheses have been used to select additional CNS models for evaluation of the efficacy of ORY-2001, and Phase II enabling GLP toxicology studies have been initiated.