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 multiple levels: it reduces cognitive impairment and also reduces neuroinflammation, and also exerts neuroprotective effects (1). In animal models vafidemstat not only restores memory but also 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 400 subjects across the multiple Phase I and II clinical trials completed or ongoing, and has been safe and well tolerated.
Oryzon has performed two Phase IIa clinical trials 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) (REIMAGINE trial) and in aggressive/agitated patients with severe or moderate AD (REIMAGINE-AD trial), with positive clinical results reported in both.
Other completed 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 and 12 months of treatment, and a pilot, small scale trial in Relapse-Remitting and Secondary Progressive MS (SATEEN study), where anti-inflammatory activity has also been observed.
Vafidemstat has also been tested in a Phase II in severe Covid-19 patients (ESCAPE trial) assessing the capability of the drug to prevent ARDS, one of the most severe complications of the viral infection, where it showed significant anti-inflammatory effects in severe Covid-19 patients.
Currently vafidemstat is in two Phase IIb trials in borderline personality disorder (PORTICO trial), and in schizophrenia (EVOLUTION trial) to evaluate vafidemstat's efficacy on negative symptoms and cognition in schizophrenia patients.
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.