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 DYRKA INHIBITOR - A POTENTIAL THERAPEUTIC FOR ALZHEIMER S DISEASE Benoît Melchior, Carolyn Lai, Karen Duong-Polk, Amanda Tjitro, Deniz C. Ince, Joshua Stewart, Luis Dellamary, Brian Hofilena, Gopi Mittapalli, Sunil KC and Yusuf Yazici

2 PHOTO, VIDEO AND AUDIO POLICY Photography is welcome in this presentation. Video and audio recording are prohibited.

3 Disclosures and Disclaimer CME/CE credits will not be awarded for this presentation All authors are employees and shareholders of Samumed LLC This presentation is not intended to provide a comprehensive overview of all studies using SM07883 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

4 Tau hyperphosphorylation and pathology Tau protein Hyperphosphorylated tau Tau oligomer Oligomers spread to unaffected neurons Postsynaptic neuron Tau hyperphosphorylation Presynaptic neuron X DYRKA 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) Tau oligomers are believed to spread across the synapse to unaffected neurons 2 Inhibition of DYRKA activity may reduce tau hyperphosphorylation and related inflammation thus reducing the pathogenesis of Alzheimer's Disease (AD) or other chronic tauopathies. Selkoe, DJ Nat Cell Biol Walsh, DM & Selkoe, DJ. Nat. Rev. Neurosci. 206 Tau Pathway figures adapted from Šimić, G. et al. Biomolecules. 206 NFT Illustration adapted from Alzheimer s Disease Research, a program of the BrightFocus Foundation.

5 Mechanism of action of SM07883, a potent DYRKA kinase inhibitor with a novel target profile DYRKA is a novel target found overexpressed in AD, Pick s disease and Down syndrome brains,2 Regulates phosphorylation of tau,2, APP (Aβ) 3, and presenilin 4 Primes tau for further phosphorylation (hyperphosphorylation) and regulates GSK-3β (also involved in phosphorylation of tau) 5 SM07883 inhibited DYRKA-mediated tau phosphorylation thereby preventing tau oligomerization, aggregation, and NFT formation. Ferrer, et al., Neurobiol. Dis Ryoo SR, et al. J. Neurochem Branca C et al. Aging Cell Ryu, Y. S. et al. J. Neurochem Kay LJ et al. Adv Protein Chem Struct Biol Choi SH, et al. Nature Selkoe DJ. Nat Cell Biol Khor, B. et al. Elife Choi and Chung Exp Neurobiol. 20

6 SM07883 Drug Discovery

7 SM07883, a potent DYRKA kinase inhibitor with a novel selectivity profile % In h ib itio n SM07883 DYRKA kinase inhibition Kinases within 5 fold of DYRKA IC IC 50 =.6 nm S M L o g C o n c. (n M ) In kinase inhibition screen assays of 44 kinases, SM07883 showed relatively specific and potent inhibition of DYRKA 5 additional kinases within the 5-fold range of DYRKA IC 50 Kinases IC 50

8 SM07883 inhibited tau phosphorylation in vitro 3 p S ( A. U. ) p T 2 2 (A.U.) DYRKA-induced tau hyperphosphorylation in Tau/DYRKA HEK293T cells Tau phosphorylation in a human neuroblastoma cell line (SH-SY5Y) pthr22 EC 50 = 3 nm 2 pser396 EC 50 = 84 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 tau hyperphosphorylation in two human cell lines

9 SM07883 Log Concentration (ng/ml) SM07883 Log Concentration (ng/ml) SM07883 was bioavailable and brain penetrant at therapeutic levels in mice Mouse PK PO/IV administration Mouse PK at 0mg/kg, PO administration PO 5 mg/kg Brain PO 5 mg/kg Plasma IV 2 mg/kg Plasma Time (hr) Good bioavailability across species 35% 00% 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 Plasma levels may be a surrogate for CNS exposure Allometric projection > hrs half life in human plasma and potentially amenable to once a day dosing in human 00 0 Targeted therapeutic concentration in plasma (60 ng/ml) t /2 ~4.25 hrs Brain Plasma CSF C max (ng/ml) Time (hr)

10 Animal toxicology and safety findings No Observed Adverse Effect Level was 30x higher in AUC than the minimum efficacious dose (.25 mg/kg/day) in mice 8x total exposure in monkeys (GI intolerance was the dose-limiting factor, reversible) No cardiac abnormalities (e.g. QT prolongation, arrhythmia) were detected up to 50 mg/kg in monkey herg channel inhibition IC 50 of 0.6 µm In vitro and in vivo studies demonstrated that SM07883 had low potential for genotoxicity in human Suggested a broad therapeutic window for human dosing

11 Preclinical tau efficacy studies

12 SM07883 reduced tau hyperphosphorylation in the mouse brain P h o s p h o T a u (A T 8 / -a c tin ) Single oral dose of SM07883 in wild type mice, followed (3 hr) by anesthesia-induced transient tau hyperphosphorylation with brain collection at 4h and western blot for ptau.5.0 In d u c e d ta 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.25 mg/kg compared to vehicle 0.0 N a ive V e h ic le.2 5 m g /k g 2.5 m g /k g 5 m g /k g 0 m g /k g 2 5 m g /k g SM07883 Concentration Plasma (ng/ml) Brain (ng/ml) *** p<0.00 compared with vehicle. Bretteville et al., Scientific reports, 202

13 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 is primarily present in 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 P30L mutation in JNPL3 mice results in tau hyperphosphorylation at sites similar to AD brains (Thr8, Ser202/Thr205 [AT8 epitope], Thr22, Thr23, Ser396) JNPL3 mice (0 months old) treated with QD SM07883 for 4 weeks and evaluated for: Tau hyperphosphorylation Formation of tau oligomers, aggregation, and NFTs Neuroinflammation Health and motor deficits Lewis, J. et al. Nat. Genet. 2000

14 SM07883 reduced tau hyperphosphorylation in JNPL3 mice Western blots of brainstem Ser202/Thr205 (Top) and Thr22/Ser24 (Bottom) levels SM07883 (3 mg/kg or 0 mg/kg SM07883 QD) reduced tau hyperphosphorylation at the AD pathogenic epitopes compared to vehicle Log Ser202/Thr205 Intensity (55KDa band) / ß-actin L o g T h r2 2 /S e r2 4 In te n s ity (5 5 K D a b a n d ) / ß -a c tin Log Thr22/Ser24 Intensity (A.U.) Wild type (n=9) 3 mg/kg 0 mg/kg Vehicle (n=9) * * SM mg/kg qd (n=9) L o g S e r2 0 2 /T h r2 0 5 in te n s ity (A.U.) W ild ty p e (n = 0 ) V e h ic le (n = 5 ) * * S M m g /k g q d (n = 4 ) W ild ty p e (n = 9 ) V e h ic le (n = 2 0 ) S M m g /k g (n = 9 ) Wild type (n=0) Vehicle (n=5) * p<0.05 compared to vehicle SM mg/kg qd (n=3)

15 L o g S e r2 0 2 /T h r2 0 5 S ta in in g In te n s ity (A.U.) L o g S e r2 0 2 /T h r2 0 5 S ta in in g In te n s ity (A.U.) SM07883 prevented formation of insoluble tau in JNPL3 mice Ser202/Thr205 in the sarkosyl-insoluble fraction (Western Blot) 3 mg/kg 0 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 = 9 ) W ild ty p e (n = 0 ) V e h ic le (n = 5 ) S M m g /k g q d (n = 3 ) SM07883 (3 mg/kg or 0 mg/kg SM07883 QD) inhibited insoluble tau formation in the brainstem at the AD pathogenic Ser202/Thr205 (AT8) epitope 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<0.0 compared to vehicle

16 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 0 4 ) 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 0 4 ) SM07883 prevented tau aggregation in JNPL3 mice Tau aggregation in the spinal cord 3 mg/kg (HTRF assay) 0 mg/kg * ** W ild ty p e (n = 9 ) V e h ic le (n = 9 ) S M m g /k g (n = 9 ) 0 W ild ty p e (n = 0 ) V e h ic le (n = 5 ) S M m g /k g (n = 3 ) SM07883 (3 mg/kg or 0 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<0.0 compared to vehicle

17 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 3 mg/kg * Brainstem NFTs (AT8 immunostaining) W ild ty p e V e h ic le S M (n = ) (n = 8 ) 3 m g /k g q d (n = 9 ) 0x 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

18 Wild Type Wild Type SM07883 SM07883 Vehicle Vehicle SM07883 reduced tau-induced glial activation (neuroinflammation) in JNPL3 mice GFAP Staining Iba Staining Reactive microglial cells 0x magnification Computer magnified to show detail 200 mm 200 mm SM07883 significantly reduced GFAP (astrocytes) and Iba (activated microglia) expression compared to vehicle in the brainstems of JNPL3 mice (representative images shown)

19 C h a n g e in C o m p o s ite S c o re (p ts o v e r 7 w e e k s ) SM07883 reduced functional deficits in JNPL3 mice Motor Coordination (Wire Hang Test Performance) Task Score (positive = improvement; negative = deterioration) WT + vehicle 4 3 W ild ty p e (n = 0 ) J N P L 3 + V e h ic le (n = 9 ) J N P L 3 + S M m g /k g (n = 9 ) JNPL3 + vehicle 2 * JNPL3 + SM Combined score based on time in which the mice fall from the wire or reach the platform and grip capacity and agility score,2 * P = 0.0 compared to vehicle SM07883 improved motor coordination in JNPL3 mice compared to vehicle. Morgan, D. et al. J. Alzheimer s Dis Garcia, MF. Scholar Commons USF 2003

20 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 4 *** ω ω - 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=9; *** p<0.00 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 0/9 Pronounced hunched back /8 0/9 Severe tremors 3/8 0/9 Moderate tremors 6/8 0/9 Mild tremors 0/8 2/9

21 Summary SM07883 is a potent DYRKA inhibitor with a novel selectivity profile that reduced tau hyperphosphorylation in mice In tau transgenic mice daily SM07883 compared to vehicle controls reduced: Tau hyperphosphorylation Formation of tau oligomers and aggregation Formation of NFTs Glial activation SM07883 demonstrated therapeutic brain and CSF exposures after oral administration in all species tested Potentially amenable for once daily dosing in humans IND-enabling studies completed to allow 28 day multiple dose study in humans SM07883 may provide therapeutic, disease modifying effects in AD Phase trial in healthy volunteers is planned

22 Thank you

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

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