TAU PATHOLOGY REDUCTION WITH SM07883, A NOVEL, POTENT, AND SELECTIVE ORAL DYRK1A INHIBITOR - A POTENTIAL THERAPEUTIC FOR ALZHEIMER S DISEASE

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1 TAU PATHOLOGY REDUCTION WITH SM07883, A NOVEL, POTENT, AND SELECTIVE ORAL DYRK1A INHIBITOR - A POTENTIAL THERAPEUTIC FOR ALZHEIMER S DISEASE Benoît Melchior, C. Lai, K. Duong-Polk, A. Tjitro, D.C. Ince, J. Stewart, L. Dellamary, B. Hofilena, G. Mittapalli, S. KC and Y. Yazici AAT AD/PD Focus Meeting Turin March 15 th, 2018

2 X Samumed, LLC X X 2

3 Disclaimer This presentation is not intended to provide a comprehensive overview of all studies using SM SM07883 is an investigational compound; SM07883 has not been approved by the US Food and Drug Administration (FDA) or any other pharmaceutical regulatory authority, and no conclusions can or should be drawn regarding the safety or effectiveness of the product candidate. While the complete mechanism of action (MOA) for SM07883 is unknown, further investigation is being conducted. All of the MOA information is based on non-clinical data and the relationship to clinical benefit is unknown. This presentation is intended as a scientific exchange of medical information, is provided for educational purposes only, and is not intended for any promotional purpose or to offer medical advice; the information contained in this presentation is confidential and proprietary and is not available for further distribution in any form whatsoever.

4 AD pathophysiology and potential therapeutic targets Tau phosphorylation SM07883 Amyloid Precursor Protein SM07883 Tau aggregation Aβ fragments Neurofibrillary Tangles SM07883 Inflammation Amyloid Plaques SM07883 Synaptic impairment & Neurodegeneration Alzheimer s Disease Memory Loss Agitation Dementia Choi SH, et al. Nature Manassero G, et al. Aging Cell Selkoe, DJ Nat Cell Biol Heneka, MT et al., Lancet Neurol Crews L and Masliah E. Hum Mol Genet Manning G, et al. Science. 2002

5 Tau hyperphosphorylation and pathology Tau protein Hyperphosphorylated Tau Tau oligomer Oligomers spread to unaffected neurons Postsynaptic neuron Tau hyperphosphorylation Presynaptic neuron X Tau oligomerization Tau aggregation NFT SM07883 NFT staining in hippocampus of a 63 year old AD patient Tau hyperphosphorylation causes oligomerization and aggregation leading to neurofibrillary tangles (NFTs) 1 Tau oligomers are believed to spread across the synapse to unaffected neurons 2 SM07883 blocked hyperphosphorylation in rodents and inhibited downstream effects leading to NFTs and neuronal degeneration 1. Selkoe, DJ Nat Cell Biol Walsh, DM & Selkoe, DJ. Nat. Rev. Neurosci Tau Pathway figures adapted from Šimić, G. et al. Biomolecules NFT Illustration adapted from Alzheimer s Disease Research, a program of the BrightFocus Foundation.

6 Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) contributes to AD pathology DYRK1A: DYRK1A Activation Elevated expression in AD brains and in Down Syndrome patients (on chromosome 21) 1,2 Tau Phosphorylation by DYRK1A RCAN-1 Phosphorylation by DYRK1A STAT3 phosphorylation Presenilin Phosphorylation by DYRK1A APP Phosphorylation by DYRK1A Regulates phosphorylation of Tau, 1,2 APP, 3 Presenilin 4 Regulates inflammation (suppresses Th17 5, triggers T-regulatory cell differentiation 5, regulates STAT3 pathway 6 ) Tau Phosphorylation by GSK-3b and other kinases Caln Phosphatase Activity Expression of Phosphorylated Tau Pro-Inflammatory cytokines g-secretase Protease Activity b/g-secretase- Mediated Cleavage of APP Ab Primes and regulates GSK3b 7 Tau Aggregation Neuroinflammation Image adapted from Hume, C accessed 12/18/17 1. Ferrer et al., Neurobiol. Dis Ryoo, S. R. et al. J. Neurochem Branca, C. et al. Aging Cell Ryu, Y. S. et al. J. Neurochem Khor, B. et al. Elife Kurabayashi, N., et al., EMBO Rep Song, WJ. et al. J. Biol. Chem Neurofibrillary Degeneration Neuronal Death and Reduced Cognitive Functioning b-amyloidosis

7 SM07883 Drug Discovery

8 SM07883, a potent DYRK1A kinase inhibitor with a unique selectivity profile % In h ib itio n SM07883 DYRK1A kinase inhibition Kinases within 15 fold of DYRK1A IC IC 50 = 1.6 nm S M L o g C o n c. (n M ) In kinase inhibition screen assays of 414 kinases, SM07883 showed relatively specific and potent inhibition of DYRK1A 6 kinases within the 15-fold range of DYRK1A IC 50 Kinases IC 50

9 SM07883 inhibited Tau phosphorylation in vitro 3 p S ( A. U. ) p T (A.U.) DYRK1A induced Tau hyperphosphorylation in Tau/DYRK1A HEK293T cells Tau phosphorylation in a human neuroblastoma cell line (SH-SY5Y) pthr212 EC 50 = 13 nm 2 1 pser396 EC 50 = 184 nm S M L o g C o n c. (n M ) S M L o g C o n c. ( n M ) SM07883 potently inhibited DYKR1A mediated Tau hyperphosphorylation in two human cell lines

10 SM07883 Log Concentration (ng/ml) SM07883 Log Concentration (ng/ml) SM07883 is bioavailable, brain penetrant and has sustained therapeutic exposure in animals Mouse PK PO/IV administration Oral 5 mg/kg Brain Oral 5 mg/kg Plasma IV 2 mg/kg Plasma Mouse PK at 10mg/kg, PO administration Time (hr) Good bioavailability across species 35% 100% High permeability and limited efflux (Caco-2 Efflux ratio: 0.283) Brain / Plasma ratio: >3 in mice (F ub /F up =0.64); ~ 30% plasma free fraction across species; ~ 6% brain free fraction (rodent) High correlation of PK between brain, CSF and plasma; half life was consistent between plasma and brain Allometric projection >11hrs half life in human and potentially amenable to once a day dosing in human Plasma levels may be a surrogate for CNS exposure Targeted therapeutic concentration in plasma (60 ng/ml) t 1/2 ~4.25 hrs Brain Plasma CSF C max (ng/ml) Time (hr)

11 SM07883 Additional drug properties MW <400, solubility >50 mg/ml No brain or tissue accumulation over 3 months daily testing in mice Low intrinsic clearance; metabolic stability >960 min in human hepatocytes Low CYP inhibition (IC 50 >20 mm with CYP2C19 = 6.8 mm) Limited transporter inhibition (OCT2, MATE 1/2) with low potential for drugdrug interactions Limited off-target binding in panel with channels and receptors IC 50 >15 mm herg channel inhibition IC 50 of 0.6 µm

12 Animal toxicology and safety findings No cardiac abnormalities (e.g. QT prolongation, arrhythmia) were detected up to 50 mg/kg in monkey In vitro and in vivo studies demonstrated that SM07883 had low potential for genotoxicity in human No Observed Adverse Effect Level was 30x higher in AUC than the minimum efficacious dose (1.25 mg/kg/day) in mice 8x total exposure in monkeys (GI intolerance was the dose limiting factor, reversible) Suggested a broad therapeutic window for human dosing

13 Preclinical Tau efficacy studies

14 SM07883 reduced Tau hyperphosphorylation in the mouse brain P h o s p h o T a u (A T 8 / b -a c tin ) Single oral dose of SM07883 in wild type mice, followed (3 hr) by anesthesia-induced transient Tau hyperphosphorylation 1 with brain collection at 4h and western blot for ptau In d u c e d T a u h y p e rp h o s p h o ry la tio n *** SM07883 produced a dose dependent inhibition of ptau 0.5 *** *** *** *** Significant reduction of ptau after a single dose as low as 1.25 mg/kg compared to vehicle SM07883 follows free drug principle 0.0 N a ive V e h ic le m g /k g 2.5 m g /k g 5 m g /k g 1 0 m g /k g 2 5 m g /k g SM07883 Concentration Plasma (ng/ml) Brain (ng/ml) *** p<0.001 compared with vehicle 1. Bretteville et al., Scientific reports, 2012

15 Tau transgenic mouse model for preclinical efficacy JNPL3 mice carry a mutated form of human Tau from autosomal dominant Tau FTD patients In this model, Tau spreads from the brain stem and spinal cord Decreased motor coordination, no cognitive deficit Pathological Tau staining in the brain stem and spinal cord of JNPL3 mice (AT8 antibody, brown) The P301L mutation in JNPL3 mice results in Tau hyperphosphorylation at sites similar to AD brains (Thr181, Ser202/Thr205 [AT8 epitope], Thr212, Thr231, Ser396) JNPL3 mice (10 months old) treated with QD SM07883 for 14 weeks and evaluated for: Tau hyperphosphorylation Formation of Tau oligomers, aggregation, and NFTs Neuroinflammation Health and motor deficits Lewis, J. et al. Science 2001

16 L o g A T 8 In te n s ity (5 5 K D a b a n d ) / ß -a c tin L o g A T 8 b a n d in te n s ity (A.U.) SM07883 reduced Tau hyperphosphorylation in JNPL3 mice 1 0 Brainstem AT8 levels (Western Blot) 3 mg/kg 10 mg/kg * * W ild ty p e (n = 9 ) V e h ic le (n = 1 9 ) S M m g /k g q d (n = 1 9 ) 1 0 W ild ty p e (n = 1 0 ) V e h ic le (n = 1 5 ) S M m g /k g q d (n = 1 4 ) SM07883 (3 mg/kg or 10 mg/kg SM07883 QD) reduced Tau hyperphosphorylation in the brainstem at the AD pathogenic AT8 epitope (Ser202/Thr205) compared to vehicle * p<0.05 compared to vehicle

17 L o g A T 8 s ta in in g in te n s ity (A.U.) L o g A T 8 S ta in in g In te n s ity (A.U.) SM07883 prevented formation of insoluble Tau in JNPL3 mice AT8 in the sarkosyl-insoluble fraction 3 mg/kg (Western Blot) 10 mg/kg * ** W ild ty p e (n = 9 ) V e h ic le (n = 2 0 ) S M m g /k g q d (n = 1 9 ) 1 W ild ty p e (n = 1 0 ) V e h ic le (n = 1 5 ) S M m g /k g q d (n = 1 3 ) SM07883 (3 mg/kg or 10 mg/kg SM07883 QD) inhibited insoluble Tau formation in the brainstem at the AD pathogenic AT8 epitope (Ser202/Thr205) compared to vehicle (sarkosyl insoluble fraction) Only positive values plotted (eight 0 or negative values not shown 3 WT, 2 Veh, 3 SM07883) * p<0.05, ** p<0.01 compared to vehicle

18 T a u a g g re g a tio n (S ig n a l n m /S ig n a l n m x ) T a u a g g re g a tio n (S ig n a l n m /S ig n a l n m x ) SM07883 prevented Tau aggregation in JNPL3 mice Tau aggregates in the spinal cord 3 mg/kg (HTRF assay) 10 mg/kg * ** W ild ty p e (n = 9 ) V e h ic le (n = 1 9 ) S M m g /k g (n = 1 9 ) 0 W ild ty p e (n = 1 0 ) V e h ic le (n = 1 5 ) S M m g /k g (n = 1 3 ) SM07883 (3 mg/kg or 10 mg/kg SM07883 QD) inhibited Tau aggregation in the spinal cord compared to vehicle in a FRET (HTRF) based assay HTRF: Homogeneous Time Resolved Fluorescence * p<0.05, ** p<0.01 compared to vehicle

19 L o g P e rc e n t A T 8 s ta in in g / R O I SM07883 Vehicle SM07883 reduced the formation of NFTs in JNPL3 mice Brainstem NFTs (AT8 immunostaining) 3 mg/kg * W ild ty p e V e h ic le S M (n = 1 ) (n = 1 8 ) 3 m g /k g q d (n = 1 9 ) 10x magnification Computer magnified to show detail SM07883 (3 mg/kg QD shown) significantly reduced the formation of brainstem NFTs compared to vehicle * p<0.05 compared to vehicle

20 Wild Type Wild Type SM07883 SM07883 Vehicle Vehicle SM07883 reduced Tau-induced glial activation (neuroinflammation) in JNPL3 mice GFAP Staining Iba1 Staining Bulky reactive microglial cells 10x magnification Computer magnified to show detail 200 mm 200 mm SM07883 significantly reduced GFAP (astrocytes) and Iba1 (activated microglia) expression compared to vehicle in the brainstems of JNPL3 mice (representative images shown)

21 Im p ro v m e n t p o in ts (p ts o v e r 1 7 w e e k s ) SM07883 reduced functional deficits in Tau JNPL3 mice Motor Coordination (Wire Hang Test Performance) Task Improvement Score WT + vehicle 4 3 W ild ty p e (n = 1 0 ) J N P L 3 + V e h ic le (n = 1 9 ) J N P L 3 + S M m g /k g (n = 1 9 ) JNPL3 + vehicle 2 1 * JNPL3 + SM Combined score based on time in which the mice fall from the wire or reach the platform and grip score (motor coordination) SM07883 improved motor coordination in JNPL3 mice compared to Vehicle * P = compared to vehicle

22 W e ig h t (g ra m s ) W e ig h t d iffe re n c e (g ra m s ) SM07883 improved weight & reduced morbidity / mortality of JNPL3 mice 4 4 Animal Weight J N P L 3 + S M J N P L 3 + V e h ic le (3 m g /k g Q D ) 2 Weight change week 0 to 14 *** ω ω -1 W T + V e h ic le J N P L 3 + V e h ic le J N P L 3 + S M m g /k g Q D W e e k s ω = animal died -3 WT n=9, Vehicle n=20, SM07883 n=19; *** p<0.001 vs. JNPL3 + Vehicle JNPL3 mice have low body weight with incidence of morbidities and mortality SM07883 treatment significantly improved body weight and empirically improved morbidity / mortality compared to vehicle Morbidity / Mortality Vehicle SM07883 Death 2/20 0/19 Pronounced hunched back 1/18 0/19 Severe tremors 3/18 0/19 Moderate tremors 6/18 0/19 Mild tremors 0/18 2/19

23 Summary SM07883 is a potent DYRK1A inhibitor with a unique selectivity profile that reduces Tau hyperphosphorylation in mice In Tau transgenic mice daily SM07883 vs. vehicle control reduced: Tau hyperphosphorylation Formation of Tau oligomers and aggregation Formation of NFTs Glial activation SM07883 demonstrated sustained brain and CSF exposures and was stable in all species 28 day repeated dose studies in animals demonstrated acceptable tolerability and therapeutic margin SM07883 may provide therapeutic, disease modifying effects in AD IND-enabling studies are completed and a Phase 1 trial in healthy volunteers is planned

24 Thank you

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