Vafidemstat (ORY-2001) is an oral small molecule that has been optimized for CNS indications and that acts as a covalent inhibitor of the epigenetic enzyme Lysine Specific Demethylase-1, LSD1 (KDM1A).

LSD1 plays a fundamental role in neurogenesis, neuronal differentiation and axonal navigation. LSD1 is the most abundant Lysine Demethylase in the prefontal cortex.

The mechanism of action of vafidemstat acts at two main levels: it reduces cognitive impairment and also reduces neuroinflammation, as has been reported by Oryzon scientists (1). In animal models vafidemstat not only restores memory but reduces the exacerbated aggressiveness of SAMP8 mice, a model for accelerated aging and Alzheimer’s disease (AD), to normal levels and also reduces social avoidance and enhances sociability in rodent models. Furthermore, vafidemstat exhibits fast, strong and durable efficacy in several preclinical models of multiple sclerosis (MS), where it reduces neuroinflammation, modulates glial activity, shows neuroprotection and preserves  axonal integrity.

Vafidemstat has been administered to around 250 healthy volunteers and patients across the multiple Phase I and II clinical trials completed or ongoing, and has been safe and well tolerated so far.

Oryzon has performed a Phase IIa clinical trial (REIMAGINE study) to assess vafidemstat’s effects on agitation-aggression in patients with different psychiatric disorders, in particular Autism Spectrum Disorder (ASD), Borderline Personality Disorder (BPD) and adult Attention Deficit Hyperactivity Disorder (ADHD). Positive clinical results have been reported in several international conferences throughout 2019. 

Additionally, another Phase IIa clinical trial to assess vafidemstat’s effects on aggressiveness in patients with severe or moderate AD (REIMAGINE-AD study) has also been performed, with positive clinical results reported at the AAT-AD/PD 2020 conference.

Other Phase IIa trials with vafidemstat are still ongoing in Mild to Moderate AD (ETHERAL study) and in Relapse-Remitting and Secondary Progressive MS (SATEEN study). In addition, Oryzon recently started a further Phase IIa trial in severely ill COVID-19 patients (ESCAPE study) to evaluate vafidemstat’s efficacy to prevent progression to Acute Respiratory Distress Syndrome (ARDS).