Vafidemstat
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 more than 300 subjects across the multiple Phase I and II clinical trials completed or ongoing, and has been safe and well tolerated.
Oryzon has performed a Phase IIa clinical trial (REIMAGINE study) to assess vafidemstat’s effects on agitation-aggression in patients with different psychiatric disorders: 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 in 2019-2020.
Additionally, a Phase IIa clinical trial (REIMAGINE-AD study) to assess vafidemstat’s effects on aggressiveness in patients with severe or moderate AD was also performed, with positive clinical results reported at the AD/PD 2020 and 2021 conferences.
Other finalized Phase IIa trials with vafidemstat include a trial in Mild to Moderate AD (ETHERAL study), where a significant reduction in the inflammatory biomarker YKL40 has been observed after 6 months of treatment, and a pilot, small scale trial in Relapse-Remitting and Secondary Progressive MS (SATEEN study), to be reported in 2021.
Oryzon is conducting a Phase IIb clinical trial (PORTICO study) to evaluate vafidemstat in BPD patients, and has recently obtained the approval to start a Phase IIb clinical trial (EVOLUTION study) to evaluate vafidemstat's efficacy on negative symptoms and cognition in schizophrenia patients.
In addition, vafidemstat is being explored in a Phase II trial in severely ill COVID-19 patients (ESCAPE study) to evaluate vafidemstat’s efficacy to prevent progression to Acute Respiratory Distress Syndrome (ARDS), one of the most severe complications of the viral infection.
Vafidemstat in personalized medicine in psychiatric disorders
Recent publications show that patients with schizophrenia or autistic spectrum disorder carrying specific mutations causative of these diseases may also be object of a targeted therapy with LSD1 inhibitors.
Animal models with mutations in SetD1a, a histone methyl transferase that antagonizes the histone demethylase activity of LSD1, display defects in axonal branching and synapse dynamics and in working memory (2), which is similar to what is found in human schizophrenia patients carrying deleterious mutations in the gene. Treatment with LSD1 inhibitors allows complete recovery of these schizophrenia-related symptoms in mutant SetD1a adult mice.
Along the same lines, rodents with mutations in Shank3, a gene involved in post-synaptic transmission, suffer motor coordination problems, increased repetitive behaviors and social behavior deficits. This phenotype recapitulates many symptoms displayed by Phelan-McDermid syndrome patients, a variety of autistic spectrum disorder. Treatment with LSD1 inhibitors also was reported to rescue cognition or behavior deficits in NMDA receptor or Shank3 hypofunction adult mice.
Oryzon has started pioneering precision medicine collaborations with two institutions, Columbia University in NY and La Paz Hospital in Madrid, to psychometrically characterize patients harboring mutations in the SetD1A or Shank3 genes, respectively, to evaluate the feasibility of specific clinical trials with vafidemstat in these genetically defined populations.
(1) Maes et al, PLOS ONE 15(5): e0233468. https://doi.org/10.1371/journal.pone.0233468
(2) Mukai et al, Neuron 2019 Nov 6; 104(3):471-487; doi: 10.1016/j.neuron.2019.09.014.