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Ab Science Sa — Advances in Alzheimer Therapy (AAT) 2016

34 slides from Ab Science Sa's conference presentation, March 2016

  1. Slide 1: Masitinib for the treatment of Alzheimer's disease: Clinical and preclinical data

    Advances in Alzheimer Therapy (AAT) March 9-12, 2016 Masitinib for the treatment of Alzheimer’s disease: Clinical and preclinical data Olivier Hermine MD, PhD Hematology Department, Necker Hospital Centre National de référence des mastocytoses, Necker Hospital INSERM U 1163 and CNRS ERL 8654 Institu

  2. Slide 2: Disclosure

    Disclosure Co-founder of AB science Scientific consultant Research grants 2

  3. Slide 3: Mast Cells and Diseases

    MAST CELLS AND DISEASES Cancer Inflammation Allergy fibrosis Alloreactivity Autoimmunité Mastocytosis Acute chronic 3

  4. Slide 4: Mastocytosis Definition

    MASTOCYTOSIS DEFINITION  Mast cell accumulation in various organs (Skin, GI tract, Liver, Bone and Bone Marrow, etc)  Myeloproliferative disorder; Aggressive vs indolent disease  Association with hematological disorders  Clinical heterogeneity (Infiltration vs Mediators release) Photos Pr Bodeme

  5. Slide 5: Identification of All Systemic Manifestations in Patients Suffering from Mastocytosis

    IDENTIFICATION OF ALL SYSTEMIC MANIFESTATIONS IN PATIENTS SUFFERING FROM MASTOCYTOSIS  From 2004, 363 mastocytosis patients and 90 controls in France were asked to rate their overall disability (OPA score) and the severity of 38 individual symptoms.  A specific questionnaire (AFIRMM V1), encompass

  6. Slide 6: Identification of All Systemic Manifestations in Patients Suffering from Mastocytosis

    IDENTIFICATION OF ALL SYSTEMIC MANIFESTATIONS IN PATIENTS SUFFERING FROM MASTOCYTOSIS PLoS ONE. 2008 May 28;3(5):e2266 6

  7. Slide 7: Identification of Psychopathological Manifestations in Mastocytosis

    IDENTIFICATION OF PSYCHOPATHOLOGICAL MANIFESTATIONS IN PATIENTS SUFFERING FROM MASTOCYTOSIS  Determine the prevalence and to describe features of depression in a large cohort of mastocytosis patients (n = 288)  Use of 17 items Hamilton Depression Scale (Ham-D17) PLoS ONE. 2011 October:6(10): e2637

  8. Slide 8: Identification of Psychopathological Manifestations in Mastocytosis

    IDENTIFICATION OF PSYCHOPATHOLOGICAL MANIFESTATIONS IN PATIENTS SUFFERING FROM MASTOCYTOSIS  64% of Patients are depressed (Hamilton Score)  Moderate 56 %  Severe 10 %  Characterisitics of the depression  Anxiety and depression o Depressed mood o Psychiatric and somatic anxiety o Impairement an

  9. Slide 9: Evaluation of Cognitive Impairment in Patients Suffering from Mastocytosis

    EVALUATION OF COGNITIVE IMPAIRMENT IN PATIENTS SUFFERING FROM MASTOCYTOSIS  Describe the prevalence and features of cognitive impairment in a large cohort of patients with this rare disease (n = 57)  Explore the relations between memory impairment and depression  Memory impairment evaluated using

  10. Slide 10: Evaluation of Cognitive Impairment in Patients Suffering from Mastocytosis

    EVALUATION OF COGNITIVE IMPAIRMENT IN PATIENTS SUFFERING FROM MASTOCYTOSIS unpaired t-test to compare depression Cognitive dysfunctions in mastocytosis scores of patients with and without cognitive impairment Memory impairment is a symptom Cognitive impaired patients are no more associated with Mast

  11. Slide 11: Mastocytosis: Brain Blood Perfusion

    MASTOCYTOSIS: BRAIN BLOOD PERFUSION Hypoperfusion of the anterior Cingulum Hyperperfusion of central grey nuclei : 11 antérieur in 10 patients with depression and patients with cognitive imapirement vs 33 mastocytosis Vs. 18 patients with Mastocytosis controls but not depressed p<0.001 p<0.001 11

  12. Slide 12: Hypothesis

    HYPOTHESIS Tryptophane - + IDO serotonin Histamine TNFa Others ASL Kynurenine Low serotonin abnormalities Acid Acid xanthurenic quinolenic Depression ? Neurotoxicity Proteases Oxidative stress apoptosis Cognition (?) 12

  13. Slide 13: Tryptophan Metabolism Is Altered in Mastocytosis

    TRYPTOPHAN METABOLISM IS ALTERED IN MASTOCYTOSIS AND CORRELATES WITH PERCEIVED STRESS AND DEPRESSION, DEMONSTRATING MAST CELLS' INVOLVEMENT IN INFLAMMATION PATHWAYS LINKED TO DEPRESSION. Georgin Laviale, Moura D et al Mol Psychiatry, 2016 13

  14. Slide 14: Mast Cell Activation Disease

    MAST CELL ACTIVATION DISEASE 14

  15. Slide 15: Simplified Pathways of Human MC Differentiation

    SIMPLIFIED PATHWAYS OF HUMAN MC DIFFERENTIATION MCC MCTC MC T Survival : IL-4 SCF Tissues NGF IL-4 IFN-g SCF SCF …... IL-4 ? CD34+ c-kit high Circulation SCF FceRI neg IL-10 CD13+ IL-6 Bone Marrow Stem Cell CD34+ 15

  16. Slide 16: Masitinib: Selective Tyrosine Kinase Inhibitor via c-Kit Inhibition

    MASITINIB: SELECTIVE TYROSINE KINASE INHIBITOR, INHIBITING MAST CELL SURVIVAL, DEGRANULATION AND MIGRATION VIA C-KIT INHIBITION SUMMARY OF INHIBITORY EFFECTS OF MASITINIB Target IC50 [nM] Kd [µM] KIT wild-type 200 0.008 FYN 240 0.14 LYN 225 0.061 PDGFR-alpha 50 0.025 PDGFR-beta 110 0.008 CSF1R 90 0.

  17. Slide 17: Masitinib Demonstrated Efficacy in Improving Handicaps Associated with Mastocytosis

    MASITINIB DEMONSTRATED EFFICACY IN IMPROVING HANDICAPS ASSOCIATED WITH MASTOCYTOSIS Phase 3 AB06006 – efficacy analysis - W8-W24 period Odd ratio Masitinib Placebo p-value (CI95) 4H75% Primary Cumulative 75% response rate on the mITT/MDF 18.7% 7.4% 0.0076* 3.63 Analysis handicaps of pruritus or flus

  18. Slide 18: Mast Cells and Diseases

    MAST CELLS AND DISEASES Cancer Inflammation Allergy fibrosis Neurological And Psychiatric Diseases Alloreactivity Autoimmunité Mastocytosis Acute chronic 18

  19. Slide 19: Brain Blood Perfusion: Similarity Mastocytosis and Alzheimer's Disease

    BRAIN BLOOD PERFUSION: SIMILARITY MASTOCYTOSIS AND ALZHEIMER’S DISEASE Representative images from a control patient (Fig. A&B), an AD patient (Fig. C), and a mastocytosis patient (Fig. D), illustrating the impaired cognitive functions. Control Patients A C Measurement of cerebral blood flow Healthy

  20. Slide 20: Brain Blood Perfusion: Similarity Mastocytosis and Alzheimer's Disease

    BRAIN BLOOD PERFUSION: SIMILARITY MASTOCYTOSIS AND ALZHEIMER’S DISEASE Representative images from mastocytosis patient comparing ASL-MRI before masitinib treatment (A) and after 6 month treatment (B) A B Preliminary evidence suggests that masitinib may be able to reverse hypoperfusion in mastocytosi

  21. Slide 21: Putative Mechanism of Action of Masitinib in Alzheimer's Disease

    PUTATIVE MECHANISM OF ACTION OF MASITINIB IN ALZHEIMER’S DISEASE Inhibition of neuroinflammator y process Glial cells Mast cells Masitinib Neuron CD47 Modulation of NMDA receptor Inhibition of tau phosphorilation B-Amyloid Substance Inhibition of FYN kinase Memory process improvement ’ Prevention of

  22. Slide 22: Animal Model (APPxPS1dE9): Cognitive Evaluation in a Curative Setting

    ANIMAL MODEL (APPXPS1DE9): COGNITIVE EVALUATION IN A CURATIVE SETTING  Masitinib was evaluated for its effect on memory deficit in AD mice (Tg) versus using the Morris Water Maze (MWM) in a curative setting (mice aged 12-14 months)  The MWM test evaluates hippocampal-dependent learning, including

  23. Slide 23: In Vivo Proof of Concept for Masitinib's Effect on Cognitive Function

    IN VIVO PROOF OF CONCEPT FOR MASITINIB’S EFFECT ON COGNITIVE FUNCTION IN AD HAS BEEN ESTABLISHED VIA A MOUSE MODEL (APPXPS1DE9) INDICATING IMPROVED SPATIAL MEMORY IN A CURATIVE SETTING T o t a l d is t a n c e t r a v e lle d V e h ( T g v s W T 1 - 5 D ) ( R O M A N E 1 - 2 ) MWM Acquisition phase

  24. Slide 24: In Vivo Proof of Concept: Spatial Strategy

    IN VIVO PROOF OF CONCEPT FOR MASITINIB’S EFFECT ON COGNITIVE FUNCTION IN AD HAS BEEN ESTABLISHED VIA A MOUSE MODEL (APPXPS1DE9) INDICATING IMPROVED SPATIAL MEMORY IN A CURATIVE SETTING MWM Spatial Strategy  Percentage of Spatial strategy (%) spatial response increased through ** training for all mi

  25. Slide 25: In Vivo Proof of Concept for Masitinib's Effect on Amyloid Load

    IN VIVO PROOF OF CONCEPT FOR MASITINIB’S EFFECT ON AMYLOID LOAD IN AD HAS BEEN ESTABLISHED VIA A MOUSE MODEL (APPXPS1DE9) INDICATING REDUCED HIPPOCAMPAL AMYLOID LOADS IN A PREVENTIVE SETTING (MICE AGED 4-6 MONTHS) Masitinib treatment decrease the amyloid charges (Congo red +) A m y lo id lo a d ( H

  26. Slide 26: Proof of Concept Clinical Study: ADCS-ADL

    PROOF OF CONCEPT CLINCAL STUDY Efficacy results in mild-to-moderate Alzheimer's disease (Phase 2 ; n=34 patients) ADAS-ADL Masitinib Placebo 12 10 Mean change from baseline 8 6 Masitinib ± standard error worsening - improvement 4 generated 2 efficacy in 0 phase 2 on -2 ADCS-ADL. -4 -6 -8 Week 0 Week

  27. Slide 27: Proof of Concept Clinical Study: ADAS-Cog

    PROOF OF CONCEPT CLINCAL STUDY Efficacy results in mild-to-moderate Alzheimer's disease (Phase 2 ; n=34 patients) ADAS-Cog Masitinib Placebo -6 worsening - improvement -4 Mean change from baseline -2 Masitinib ± standard error 0 generated efficacy in 2 phase 2 on 4 ADAS-Cog. 6 8 10 Week 0 Week 12 We

  28. Slide 28: Proof of Concept Clinical Study: MMSE

    PROOF OF CONCEPT CLINCAL STUDY Efficacy results in mild-to-moderate Alzheimer's disease (Phase 2 ; n=34 patients) MMSE Masitinib Placebo worsening - improvement 2 1 Mean change from baseline 0 Masitinib ± standard error generated -1 efficacy in -2 phase 2 on MMSE. -3 -4 -5 Week 0 Week 12 Week 24 p=0

  29. Slide 29: Ongoing Phase 3 Design

    ON GOING PHASE 3 DESIGN  Patients with mild to moderate Alzheimer’s disease Study  Blinded, placebo controlled design  24 week treatment period  675 patients Patient with  dementia of Alzheimer's type, according to DSM-IV criteria Selection  probable Alzheimer' disease according to NINCDS-ADRD

  30. Slide 30: Ongoing Phase 3 Passed Futility Test

    ON GOING PHASE 3 PASSED FUTILITY TEST  Efficacy : DSMB performed a futility analysis with efficacy data o Definition of futility test : test the inability of a clinical trial to achieve its efficacy objective o Test performed on ADCS-ADL and ADAS-Cog o Test performed after about one third of the pa

  31. Slide 31: Contact Alzheimer Study Phase 3

    CONTACT ALZHEIMER STUDY PHASE 3  ohermine@gmail.com  Denys.zaitsev@ab-science.com 31

  32. Slide 32: Psychiatric Department Saint Anne Paris R Gaillard

    U8147 Psychiatric Department Centre de référence des mastocytoses - NEM Saint Anne Paris Olivier Hermine O Chandesris Christine Bodemer R Gaillard Olivier Lortholary S Barete G Damaj D Moura Sophie Georgin Laville Department of radiology N Bodaert Inserm U891 - Marseille Patrice Dubreuil Inserm U112

  33. Slide 33: Abstracts / Neurobiology of Aging (2016) S1-S12

    Abstracts / Neurobiology of Aging 39 (2036) St-S12 Olivier Hermine. institut IMAGINE, CNRS UMR 8147, Hopital Necker, Paris, Paris. E-mail: ohermine@®gmail.com Cognitive dysfunction is a hallmark symptom of Alzheimer's disease (AD). Mastocytosis (MCO)}, a mast cell (MC) related disease, is also assoc

  34. Slide 34: Abstracts / Neurobiology of Aging (2016) S1-S13

    Abstracts / Neurobiology of Aging 39 (2016) $1-S13 cognitive impairment. Around 40% of MCO patients (pts) present with impaired cognitive functions (memory and/or attention). We performed morphological and functional MRI in pts with MCO, Arterial spin labeling (ASL) MRI revealed an abnormal pattern

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