Oryzon Genomics Sa · BME:ORY
Oryzon Genomics Sa — Technical Presentation (April 2020)
26 slides from Oryzon Genomics Sa's technical presentation, Apr 3, 2020
Slide 1: Vafidemstat in Alzheimer's Disease: Initial 6-Month ETHERAL Data
SYMPOSIUM 37 - TREATING AD: ALTERNATIVES TO IMMUNOTHERAPY II VAFIDEMSTAT IN ALZHEIMER’S DISEASE: INITIAL 6-MONTH ETHERAL DATA R. Bullock1, M. Boada2, S. Ratcliffe3, E. Macsweeney4, S. Gutierrez1, J. Xaus1, M. Ropacki1, C. Buesa1 1. Oryzon Genomics SA, Clinical Department, Cornella De Llobregat, Spai
Slide 2: Conflict of Interest
Conflict of Interest Due to the exceptional situation related to COVID-19 lock-down, this presentation will be led by Dr. Michael Ropacki Michael Ropacki. MD, PhD VP of Clinical/Product Develop Dr. Ropacki is Oryzon’s Vice-president Former Director of Clinical Development, Neuroscience, of Clinica
Slide 3: Disclaimer
Disclaimer This document has been prepared by Oryzon Genomics, S.A. exclusively for use during the presentation. Oryzon Genomics, S.A. does not assume liability for this document if it is used with a purpose other than the above. The information and any opinions or statements made in this document h
Slide 4: Solid Evidence of an Epigenetics Axis in CNS Diseases
Solid Evidence of an Epigenetics Axis in CNS Diseases EPIGENETICS: Epigenetic mechanisms modify chromosome functioning, chromatin 3D conformation and control gene expression Many features of psychiatric and neurological diseases are consistent with an epigenetic dysregulation, such as: Discord
Slide 5: LSD1, an Epigenetic Chromatin Remodeling Enzyme With a Strong Role in CNS
LSD1, an Epigenetic Chromatin Remodeling Enzyme With a Strong Role in CNS Lysine specific histone demethylase 1 (LSD1), aka KDM1A, removes methyl marks at mono- and dimethyl-H3K4 (histone H3 lysine 4) and H3K9 (histone H3 lysine 9). Also has scaffolding role in various TFs Complexes LSD1 plays a
Slide 6: Vafidemstat – a Phase II Compound with Broad CNS Potential
Vafidemstat – a Phase II Compound with Broad CNS Potential Vafidemstat is a small molecule LSD1 inhibitor optimized for CNS Excellent Pharmacology. High oral bioavailability. Highly Brain Penetrant Positive results in 7 different animal models and in in-vitro models Cognition Neuroprotecti
Slide 7: An Upstream Epigenetic Mechanism with Dual Activity: Antinflammatory and Prosynaptic
An Upstream Epigenetic Mechanism with Dual Activity: Antinflammatory and Prosynaptic Vafidemstat up-regulates genes associated with Neuroplasticity & Cognition Vafidemstat reduces the expression of inflammatory genes including S100A9 and many others Prosynaptic Anti-inflammatory cervical section
Slide 8: Current human safety data
Current human safety data Vafidemstat has proven to be safe and well tolerated in several Phase I and Phase II clinical trials – over 250 volunteers & patients to-date Phase I: +100 healthy volunteers Phase I (SAD+MAD) study No hematological impact at the planned doses Multiple Phase II trials
Slide 9: Vafidemstat Efficacy in AD patients
Vafidemstat Efficacy in AD patients REIMAGINE-AD – Efficacy in AD agitation and aggression A single center, open-label, 1-arm, 24-week study to evaluate the efficacy, safety and tolerability of vafidemstat in agitation and aggression in Alzheimer’s Disease Primary Objective: Investigate the effi
Slide 10: Vafidemstat Efficacy: Reduction of AD Agitation and Aggression (REIMAGINE-AD)
Vafidemstat Efficacy: Reduction of AD Agitation and Aggression (REIMAGINE-AD) Agitation & aggression significantly decreased in moderate and severe AD patients after 6 months Statistical improvements observed across different Agitation/Aggression scales after 6 months of treatment: CGI-I CMAI
Slide 11: Vafidemstat Efficacy: Reduction of AD Agitation and Aggression (REIMAGINE-AD)
Vafidemstat Efficacy: Reduction of AD Agitation and Aggression (REIMAGINE-AD) Total NPI also significantly decreased in moderate and severe AD patients after 6 months Total NPI Total NPI was improved after 6 months of treatment NPI-total (severity x frequency) Score 40 The beneficial impact on A
Slide 12: Vafidemstat Efficacy: Reduction of AD Agitation and Aggression (REIMAGINE-AD)
Vafidemstat Efficacy: Reduction of AD Agitation and Aggression (REIMAGINE-AD) Transient observations in cognition A statistical improvement in MMSE was detected in severe and moderate AD patients by month 2, but it did not persist in the following months Two patients (Pt111 and Pt109), however,
Slide 13: ETHERAL – Epigenetic THERapy in ALzheimer's Disease
ETHERAL – Epigenetic THERapy in ALzheimer’s Disease Trial design: Double blind placebo controlled Phase IIa safety study to provide data to inform future Phase II/III studies 150 Mild to Moderate AD patients (6+6 months) 17 sites; 117 patients Primary Objective: Safety & Tolerability Spain, Fr
Slide 14: ETHERAL: Key Inclusion & Exclusion Criteria
ETHERAL: Key Inclusion & Exclusion Criteria Inclusion criteria Men and women 50-85 years of age Probable AD diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria MMS
Slide 15: ETHERAL: Demographics
ETHERAL: Demographics No differences of distribution between groups were observed in any of the demographic variables No differences of distribution between groups were observed with regard to the time from diagnosis or disease stage (mild/moderate) at baseline 0.6 mg 1.2 mg PLACEBO Total Number
Slide 16: PK/PD Results
ETHERAL: PK/PD Results Vafidemstat acts as a selective LSD1 inhibitor in humans Pharmacokinetic results correlate with previous observations (Phase I data) No MAO-B inhibition detected in the PBMCs of AD patients, as expected from Phase I data Vafidemstat acts as a selective LSD1 inhibitor in
Slide 17: ETHERAL: Safety – Drop Outs & TEAEs
ETHERAL: Safety – Drop Outs & TEAEs TEAEs and drop-outs are randomly distributed between study arms 0.6 mg 1.2 mg Placebo Total (N=38) (N=34) (N=45) (N=117) Mild 1 (2.63%) 3 (8.82%) 1 (2.22%) 5 (4.27%) Drop-outs Moderate 6 (15.79%) 2 (5.88%) 6 (13.33%) 14 (11.97%) Total 7 (18.42%) 5 (14.71%) 7 (15.5
Slide 18: ETHERAL: Safety – Adverse Events
ETHERAL: Safety – Adverse Events Vafidemstat treatment for 6 months was safe and well tolerated No differences were observed between study arms in the number of patients showing any AEs 0,6 MG 1,2 MG PLACEBO TOTAL (n=38; 32%) (n=34; 29%) (n=45; 38%) (n=117; 100%) Total patients with AEs (% of Tota
Slide 19: ETHERAL: Safety – Vital Signs, Labs & ECG
ETHERAL: Safety – Vital Signs, Labs & ECG No safety signals nor clinically relevant hematological impact observed after 6 months of treatment No differences observed between study arms in any of the vital signs, ECG variable or laboratory safety evaluations No differences observed between groups
Slide 20: CSF Biomarkers – Abeta, t-Tau, p-Tau & S100A9
ETHERAL: CSF Biomarkers – Abeta, t-Tau, p-Tau & S100A9 Vafidemstat MoA does not relate to Abeta or Tau CSF biomarkers A low Abeta ratio while higher levels of t-Tau, p-Tau are NIA- Abeta ratio Total Tau (t-Tau) S100A9 AA criteria for AD *** *** *** ** ETHERAL population aligns with NIA-AA criter
Slide 21: CSF Biomarkers – YKL40
ETHERAL: CSF Biomarkers – YKL40 Vafidemstat treatment reduces the levels of the inflammatory CSF marker YKL40 YKL40, a secreted inflammatory chitinase, has been described to be found in higher levels in AD patients No differences were observed in the distribution between treatment groups of YKL4
Slide 22: CSF Biomarkers - Neurogranin
ETHERAL: CSF Biomarkers - Neurogranin Vafidemstat treatment has a mild impact on the levels of the synaptic marker Neurogranin Neurogranin is a calmodulin-binding protein expressed primarily in the brain and considered a synaptic damage marker in neurodegenerative disorders Although no statistic
Slide 23: CSF Biomarkers - NFL
ETHERAL: CSF Biomarkers - NFL High dose vafidemstat treatment reduces the increase of NFL levels in CSF Plasma neurofilament light chain (NFL) has been proposed as a blood-based biomarker for neurodegeneration in AD CSF NFL levels increased through study visits in the 3 arms suggesting disease p
Slide 24: Preliminary Cognitive Efficacy - ADAS-Cog14
ETHERAL: Preliminary Cognitive Efficacy- ADASCog14 6 month Interim analysis did not show cognitive improvement after vafidemstat treatment No statistically significant differences were expected or observed at 6 months in the ADAS-Cog14 between treatment arms No significant progression was seen t
Slide 25: ETHERAL - Key Findings Summary
ETHERAL - Key Findings Summary ETHERAL-EU at 6 month has met the Primary Safety Endpoint Vafidemstat was safe and well-tolerated in a mild-to-moderate AD population ETHERAL has produced interesting biomarker data that require further exploration Significant reduction in the CSF levels of YKL
Slide 26: Vafidemstat: Additional Take Home Messages
Vafidemstat: Additional Take Home Messages Solid published evidence supports the role of epigenetics across several CNS disorders Key emerging role of LSD1 as a therapeutic target of interest in both psychiatric and neurodegenerative disorders Vafidemstat is a CNS optimized LSD1 inhibitor with
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