Aging of western populations is increasing the incidence of Alzheimer’s disease (AD). The etiology of AD is still unknown. No treatment is able to prevent, halt or much less reverse the neurodegenerative process. ORY-2001 is a novel brain-penetrant LSD1/MAOB inhibitor, envisaged for treatment of CNS diseases. By reducing LSD1 activity, we aim to redress or circumvent transcriptional imbalances in the brain of the AD patient.

ORY-2001 has excellent oral bioavailability, PK and pharmacological profile and  fully reverts memory defects as measured by NORT in SAMP-8 mice, down-regulates an inflammation signature and induces genes associated with synaptic plasticity and memory. ORY-2001 has finalized a Phase I trial to assess the safety, tolerability and pharmacokinetics of ORY-2001 in 106 healthy subjects and elderly population (EUDRACT 2015-003721-33). ORY-2001 was well tolerated and the PK profile showed rapid oral absorption, relatively long half-life and approximate dose proportional exposure to ORY-2001. Brain penetration was also demonstrated by measuring ORY-2001 in CSF.  

After the successful Phase I study, this proposal aims to further explore the clinical potential of ORY-2001 in a Phase IIa PoC trial, to evaluate its safety and efficacy in patients with mild to moderate AD, with special attention to the different dimensions of the disease and its symptoms. ETHERAL is a 6-month Phase II Study, entitled A multicenter, multinational, randomized, double-blind, placebo-controlled study to evaluate the safety and tolerability of ORY-2001 in patients with mild to moderate Alzheimer's disease with 6-month blinded extension.