Name: Vafidemstat
Synonyms: ORY-2001
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Oryzon Corporate


ORY-2001 is a dual inhibitor of the transcriptional co-regulator lysine-specific demethylase 1 (LSD1 or KDM1A) and the mitochondrial membrane protein monoamine oxidase B (MAO-B, see MedChemExpress). It is an oral, brain-permeable small molecule.

LSD1 catalyzes the removal of methyl groups from histones, contributing to the epigenetic modulation of gene expression. Alterations in epigenetic regulation of gene expression have been implicated in neuropsychiatric conditions and Alzheimer’s disease (Aug 2014 newsNov 2014 news).

LSD1 is a regulator of hematopoiesis, and LSD1 inhibitors have been mainly investigated for leukemias and other cancers (reviewed in Fang et al., 2019). The enzyme is expressed in brain, and is the most abundant histone demethylase in the frontal cortex. In mice, it promotes neural-stem cell proliferation, nervous-system development, and survival of mature neurons (reviewed in Swahari and West, 2019).

MAO-B breaks down dopamine in the brain. Another MAO-B inhibitor, rasagiline, is approved to treat Parkinson’s disease, and has shown signs of efficacy in AD (Dec 2019 conference news).

In preclinical work, the inhibitor was reported to prevent development of cognitive impairment in a mouse model of Huntington’s disease, and in the SAMP8 mouse model of age-related cognitive decline (2016 AAIC abstractMaes et al., 2020). In the SAMP8 mice, ORY-2001 reduced expression of inflammatory genes including S100A9, and modulated genes associated with neuroplasticity and behavior in SAMP8 mouse brain. Mice tolerated the compound without hematological side effects. ORY-2001 also reduced aggression and increased social behavior in SAMP8 mice. These effects were attributed to LSD1/KDM1A inhibition.


In May 2017, Oryzon presented results of Phase 1 safety testing of single- and multiple-ascending doses of ORY-2001 in 88 healthy young volunteers (May 2017 conference news). Single doses from 0.6 to 4 mg produced no serious adverse events or signals in clinical and laboratory safety measures. Five days of 2.5 mg/day caused a drop in platelet count, which rebounded after a week. A pharmacodynamic analysis revealed dose-dependent binding of the drug to LSD1 in peripheral blood mononuclear cells. In subsequent work, the drug was found to reach the brain. Safety of the 2.5 mg dose was reported in an elderly cohort (2019 AAIC abstract).

In June 2018, a Phase 2a safety trial started in mild to moderate Alzheimer’s disease. Called ETHERAL (Epigenetic Therapy in Alzheimer’s disease), it recruited 117 patients with CSF evidence of amyloid pathology at 17 sites in Spain, France, and the U.K. Participants received 0.6 or 1.2 mg or placebo daily for six months, followed by a six-month continuation when everyone received drug. The trial was not powered to detect clinical changes, but secondary endpoints included measures of cognition, agitation, apathy, depression, quality of life, and volumetric MRI. The trial evaluated eight CSF biomarkers of inflammation, synaptic integrity, and others.

In May 2019, the ETHERAL-U.S. trial began to enroll an intended 33 AD patients in four U.S. locations for an identical study. 

In April 2020, the company presented preliminary data from the European six-month treatment (Apr 2020 conference news and slides). The drug met safety goals, with treated cohorts showing no more dropouts, adverse events, or changes to hematological parameters than the placebo group. The treated group had a reduction in the inflammatory biomarker YKL40 in CSF. There was a trend toward lower neurogranin levels with treatment in the group as a whole, and a post hoc analysis of mild or moderate subgroups found treatment-related changes in neurogranin or NfL in some subsets. Neither Aβ, total tau, phospho-tau, nor S100A9 changed with treatment. There was no effect on cognition. Pharmacodynamic assessments in peripheral blood cells indicated 60 to 80 percent occupancy of LSD1, but no MOAB inhibition.  

At the same meeting, Oryzon reported that in an open-label study in 12 people with AD at a single site in Barcelona, Spain, a six-month course of 1.2 mg daily led to improvement on scales measuring agitation and aggression, as well as the total Neuropsychiatric Index and measures of caregiver burden (see 2020 AAT-ADPD poster). At meetings throughout 2019, the company had reported positive data on aggression from an open-label, similarly-sized trial in people with ADHD, borderline personality disorder, and autism spectrum disorder (Jul 2020 company press release).

A small, placebo-controlled study for multiple sclerosis is ongoing in Spain.  

For details on Ory-2001trials, see and EU Clinical Trials Register.

Last Updated: 06 Aug 2020


No Available Comments

Make a Comment

To make a comment you must login or register.


News Citations

  1. Non-Amyloid Treatments: Inflammation, Epigenetics, Regeneration
  2. Non-Aβ, Non-Tau Drugs Tweak Markers, Cognition in Alzheimer’s, Huntington’s
  3. Alzheimer’s Brains Mottled with Epigenetic Changes
  4. Epigenetic Alterations Mark Alzheimer’s Disease Genes
  5. At CTAD, Early Failures and Hints of Success, from Small Trials

Therapeutics Citations

  1. Rasagiline

Paper Citations

  1. . LSD1/KDM1A inhibitors in clinical trials: advances and prospects. J Hematol Oncol. 2019 Dec 4;12(1):129. PubMed.
  2. . Histone demethylases in neuronal differentiation, plasticity, and disease. Curr Opin Neurobiol. 2019 Dec;59:9-15. Epub 2019 Mar 14 PubMed.
  3. . Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations. PLoS One. 2020;15(5):e0233468. Epub 2020 May 29 PubMed.

External Citations

  1. 2019 AAIC abstract
  2. slides
  3. 2020 AAT-ADPD poster
  4. Jul 2020 company press release
  6. EU Clinical Trials Register
  7. MedChemExpress
  8. 2016 AAIC abstract

Further Reading


  1. . Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice. Neuron. 2019 Nov 6;104(3):471-487.e12. Epub 2019 Oct 9 PubMed.
  2. . Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation. Elife. 2013 Jun 18;2:e00633. PubMed.
  3. . KDM1 histone lysine demethylases as targets for treatments of oncological and neurodegenerative disease. Epigenomics. 2015;7(4):609-26. PubMed.
  4. . Advances in the development of histone lysine demethylase inhibitors. Curr Opin Pharmacol. 2015 Aug;23:52-60. Epub 2015 Jun 5 PubMed.