Vafidemstat

Vafidemstat (ORY-2001) is an oral, brain-penetrant small molecule inhibitor of the epigenetic enzyme Lysine Specific Demethylase-1 (LSD1, also known as KDM1A).

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

Through selective inhibition of LSD1, vafidemstat acts at multiple levels: it reduces cognitive impairment, reduces neuroinflammation, and exerts neuroprotective effects (1). In animal models vafidemstat improves memory, reduces aggressive behavior, reduces social avoidance and enhances sociability. 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 425 subjects across multiple completed and ongoing Phase I, Phase IIa, and Phase IIb clinical trials. Across this clinical experience, vafidemstat has been safe and well tolerated.

Oryzon has conducted two Phase IIa proof-of-concept clinical trials evaluating vafidemstat in agitation and aggression associated with psychiatric and neurogenerative disorders: the REIMAGINE study in patients with Autism Spectrum Disorder (ASD), Borderline Personality Disorder (BPD) and adult Attention Deficit Hyperactivity Disorder (ADHD), and the REIMAGINE-AD study in aggressive/agitated patients with severe or moderate Alzheimer’s disease (AD). Positive clinical results were reported in both studies, showing reductions in agitation/aggression.

Additional completed Phase IIa trials with vafidemstat include:

  • the ETHERAL and ETHERAL-US studies in mild to moderate AD, where a significant reduction in the inflammatory biomarker YKL40 was observed after 6 and 12 months of treatment.
  • the SATEEN study, a pilot, small scale trial in relapse-remitting and secondary progressive multiple sclerosis, where anti-inflammatory activity was also observed.
  • the ESCAPE study, a Phase II trial in severe Covid-19 patients , which demonstrated significant anti-inflammatory effects and evaluated the drug’s potential to prevent acute respiratory distress syndrome (ARDS), one of the most severe complications of the viral infection.

Following completion of the global, randomized, double blind Phase IIb PORTICO study in BPD, vafidemstat is advancing as a Phase III-ready asset for the treatment of agitation/aggression in BPD, with a Phase III trial in preparation (the PORTICO-2 study). In parallel, vafidemstat is being evaluated in a Phase IIb trial in negative symptoms of schizophrenia (the EVOLUTION study). A Phase II clinical trial to evaluate vafidemstat as a treatment of aggression in autistic conditions is currently in preparation.

Vafidemstat in personalized medicine in psychiatric disorders

Recent scientific evidence supports the role of LSD1 inhibition as a precision medicine approach in selected psychiatric and neurodevelopmental disorders. In particular, preclinical studies have shown that mutations in genes such as SetD1a and Shank3, which are implicated in schizophrenia and autism spectrum disorders respectively, lead to epigenetic dysregulation that can be functionally counteracted by LSD1 inhibition.

Animal models with mutations in SetD1a, a histone methyl transferase that functionally antagonizes the histone demethylase activity of LSD1, display defects in axonal branching, synapse dynamics, and working memory (2), which closely mirror the alterations found in human schizophrenia patients carrying deleterious mutations in this gene. Notably, treatment with LSD1 inhibitors in adult SetD1a mutant mice allowed full recovery of these schizophrenia-related symptoms.

Similarly, rodent models with mutations in Shank3, a gene involved in post-synaptic transmission, exhibit motor coordination problems, increased repetitive behaviors and social behavior deficits, recapitulating many symptoms displayed by Phelan-McDermid syndrome patients, a variety of autistic spectrum disorder. In these models as well as in models of NMDA receptor hypofunction, treatment with LSD1 inhibitors was reported to rescue cognition and behavior deficits in adult animals.

Building on this scientific rationale, Oryzon established pioneering precision medicine collaborations with Columbia University in New York and La Paz Hospital in Madrid, aimed at psychometrically characterizing patients harboring mutations in the SetD1A or Shank3 genes, respectively, to evaluate the feasibility of future clinical trials with vafidemstat in these genetically defined populations.

 

(1)    Maes et al, PLOS ONE 15(5): e0233468;doi: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.