Le point sur la recherche thérapeutique dans la maladie d ...

Le point sur la recherche thérapeutique dans la maladie d ...

Le point sur la recherche thrapeutique dans la maladie dAlzheimer Julien Delrieu (Toulouse) Le 18/09/2016 The amyloid hypothesis of Alzheimer's disease at 25 years Dennis J Selkoe, John Hardy DOI 10.15252/emmm.201606210 | Published online 29.03.2016 EMBO Molecular Medicine (2016) emmm.201606210 Active immunotherapy Passive immunotherapy Polyclonal Ig - and -secretase Inhibitors -secretase enhancers Anti-Aggregation

Hossein Samadi & David Sultzer. Solanezumab for Alzheimers disease. Expert pinion on biological therapy 2011. LES ESPOIRS DE LIMMUNOTHRAPIE Les cibles amylodes de limmunothrapie Winblad et al. Alzheimer's Research & Therapy 2014, 6:7. ANTICORPS MONOCLONAUX EN PHASE II/III Crenezumab1 Solanezumab2,3 Bapineuzumab4 BAN240157 Aducanumab8,9

Gantenerumab10,11 Sponsor Roche/ Genentech Eli Lilly Pfizer/J&J Eisai/Biogen Biogen/ Neurimmune Roche/ Genentech

Epitope Mid-domain Mid-domain N-Terminus N-Terminus N-Terminus N-Term & Mid Origine Humanis Humanis

Humanis Humanis Humain Humain Isotype IgG4 IgG1 IgG1 IgG1 IgG1

IgG1 Cible Toutes les formes de A A soluble Toutes les formes de A A protofibrillaire Oligomre et A fibrillaire Oligomre et A fibrillaire

Phase 3 en cours Phase 3 en cours Status Phase 2 en cours Phase 3 en cours termin Phase 2 en cours Adapted from Neurimmune/Biogen presentation at AD/PD 2015, Nice, FR.

1. Adolfsson O, et al. J Neurosci 2012;32:9677-9689; 2. Doody RS, et al. NEJM;2014:370:311-321; 3. Yamada K, et al. J Neurosci 2009;29:11393-11398; 4. Kerchner GA, Boxer AL. Expert Opin Biol Ther 2010;10:1121-1130; 5. Kaplow JM, et al. Alz Demen 2013;9:807808; 6. Lai R, et al. Alz Demen 2014;10:689; 7. Lannfelt L, et al. Alz Res Ther 2014;6:16 8. Hang Y, et al. Neurodegener Dis 2015;15:800; 9. Sevigny J, et al. Neurodegener Dis 2015;15:311; 10. Ostrowitzki S, et al. Arch Neurol 2012;69:198-207; 11. Bohnmann B, et al. J Alz Dis 2012;28:49-69. ANTICORPS MONOCLONAUX EN PHASE II/III Solanezumab : 1) un signal probable dans la maladie dAlzheimer au stade lger, 2) la ncessit dutiliser un biomarqueur amylode linclusion EXPEDITION 3 EN COURS Progress of Mild Alzheimer's Disease in Participants on Solanezumab Versus Placebo Rsultats de la phase III EXPEDITION-EXT Hong Liu-Seifert et al. A Novel Approach to Delayed-Start Analyses for Demonstrating Disease-Modifying Effects in Alzheimers Disease. PLOSOne 2015 Laducanumab: de la production ltude

PRIME Effet de laducanumab sur la pathologie amylode Effet sur la charge amylode 1 an Effet en fonction de la dose Jeff Sevigny et al. The antibody aducanumab reduces A plaques in Alzheimers disease. Nature 2016. Impact clinique de laducanumab Impact sur la CDR-SB Impact sur le MMSE Jeff Sevigny et al. The antibody aducanumab reduces A plaques in Alzheimers disease. Nature 2016.

Mais Jeff Sevigny et al. The antibody aducanumab reduces A plaques in Alzheimers disease. Nature 2016. Le point sur les ARIA X2 Jeff Sevigny et al. The antibody aducanumab reduces A plaques in Alzheimers disease. Nature 2016. ARIA-E: les caractristiques 92% lors des 5 premirs injections 65% des ARIA-E sont asymptomatiques 35% sont symptomatiques Le plus souvent dintensit lgre modre (78%) Gnralement transitoire, rsolutif en 4 semaines Cphales, troubles visuels, confusion, Anomalies IRM rsolutives typiquement en 4-12 semaines

Jeff Sevigny et al. The antibody aducanumab reduces A plaques in Alzheimers disease. Nature 2016. ARIAs et clearance amylode Reisa Sperling et al. Amyloid-related imaging abnormalities in patients with Alzheimers disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol 2012. Vers ltude EMERGE/ENGAGE Placebo Controlled Period (18 months) [20 doses ] Long-Term Extension (24 months)

[26 doses 6 mg/kg ] 6 mg/kg 3 mg/kg 1 mg/kg ApoE 4 + High Low 3 mg/kg 3 mg/kg

1 mg/kg 6 mg/kg 3 mg/kg 1:1 1 mg/kg 3 mg/kg Placebo Pbo 1 mg/kg 10 mg/kg 10 mg/kg

6 mg/kg 6 mg/kg ApoE 4 - 6 mg/kg 3 mg/kg 1 mg/kg High 3 mg/kg Low 10 mg/kg 1 mg/kg 6 mg/kg 1:1

Placebo Pbo WEEK R 4 16 32 48 64 6 mg/kg 3 mg/kg 1 mg/kg

3 mg/kg 1 mg/kg 80 96 112 128 144 160 176 IMMUNOTHRAPIE ACTIVE (VACCINATION) No longer at the forefront but not forgotten Selkoe 2016

Sponsor Vaccins Target Phase Population cible Enpoint principal II Nombre de patients 335

AFFITOPE AD02 CAD106 A MA lgre A II 177 MA lgre ADAS-cog ADCS-ADL Tolrance

ACC-001 A II 63 MA prodromale Imagerie amylode TEP Imagerie amylode TEP INHIBITEURS DES b-SCRTASES EN PHASE II/III

MK-8931 Studies MK-8931 cible la MA lgre modre et la MA prodromale mild-to-moderate AD prodromal AD http://www.alzforum.org/therapeutics/mk-8931 INHIBITEURS DES b-SCRTASES EN PHASE II/III AZD3293 (LY3314814) En phase I: diminution dA dans le LCR des sujets sains et MA Phase II/III: en cours Eketjll S, Janson J, Kaspersson K, Bogstedt A, Jeppsson F,

Flting J4, Haeberlein SB, Kugler AR, Alexander RC, Cebers G. J Alzheimers Dis. 2016 Feb 3;50(4):1109-23. ClinicalTrials.gov Identifier: NCT02245737 LES AUTRES VOIES THRAPEUTIQUES LES THRAPIES ANTI-TAU INHIBITION DE LAGRGATION DE LA PROTINE TAU LMTX (Methylthioninium chloride) Rsultats communiqus AAIC juillet 2016 : Essai ngatif sur le critre principal en ITT Rsultats positifs (discuts) sur le sous-groupe en monothrapie (ADAS-Cog, ADCS-ADL, IRM) IMMUNOTHRAPIE ANTI-TAU Yanamandra K, Jiang H, Mahan TE, Maloney SE, Wozniak DF, Diamond MI,

Holtzman DM. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann Clin Transl Neurol. 2015 Mar;2(3):278-88 PHASE II EN PROJET AGENTS SYMPTOMATIQUES ANTAGONISTES 5HT-6 : IDALOPIRDINE Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics. 2008 Jul;5(3):458-69. Lu AE58054 in Patients With Mild to Moderate Alzheimer's Disease Treated With an Acetylcholinesterase Inhibitor (STARBRIGHT) Study of Lu AE58054 in Patients With Mild - Moderate Alzheimer's Disease Treated With Donepezil (STARSHINE) Lu AE58054 in Patients With Mild-moderate Alzheimer's Disease Treated With Donepezil (STARBEAM)

ACTION SUR LES RECEPTEURS NMDA (INHIBITION GlyT-1) Phase II valuant 4 dose de BI 425809 versus placebo Rsultats de ltude LADDER Antagoniste des rcepteurs 5HT6 pendant 24 semaines en add-on du donepezil Sujets MA un stade dmentiel lger modr slectionnes sur des critres cliniques David Wilkinson et al. Safety and ecacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimers disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2014. VERS DE NOUVEAUX PARADIGMES TRAITER PLUS TT ou PRVENIR ?

LES ESSAIS AU STADE PRSYMPTOMATIQUE TUDE CRITRES DINCLUSION INTERVENTION DURE ENDPOINTS Anti Amyloid treatment in Asymtomatic AD Sujets normaux (CDR=0)

Amylode + Solanezumab 3 ans Score cognitif composite API-ADAD (Famille colombienne) mutation autosomique dominante PS1 Crenezumab 5 ans

Score cognitif composite API-APO Asymptomatique APOE-4 homozygote Immunothrapie active (CAD106) et BACE inhibiteur 5 ans Score cognitif composite Dominantly Inherited

Alzheimer Network Individus risque dune MA autosomique dominante Solanezumab Gantenerumab 4 ans Score cognitif composite Biomarqueurs (LCR et TEP) Tomorrow study

APOE, ge, TOMM40 AD-4833 (pioglitazone, agoniste PPAR) 5 ans Temps MCI-AD INITIATIVE EUROPENNE REGISTRE DE SUJETS A RISQUE COHORTE DE SUIVI ESSAI THRAPEUTIQUE ADAPTATIF

Coordination Franaise : Collaboration Centres Acadmiques/Partenaires Industriels CONCLUSION UN TRAITEMENT EFFICACE POUR DEMAIN ?

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