Slide 1: OC8 - A phase 2b clinical trial of neflamapimod in dementia with Lewy bodies
OC8 - A phase 2b clinical trial of neflamapimod in dementia with Lewy bodies designed to confirm the efficacy results from phase 2a Niels D. Prins (1) Amanda Gardner (2), Hui-May Chu (3), Kelly Blackburn (2), James E. Galvin (4), John Alam (2) (1) Brain Research Center - Amsterdam (Netherlands), (2)
Slide 2: Disclosures
Disclosures * Dr. Prins is CEO and co-owner of Brain Research Center, The Netherlands. He is also a consultant to Aribio, Eli-Lilly, and Janssen and received a speaker fee from Biogen. * Dr.Alam is CEO of, Ms. Blackburn is a full-time employee of, and Ms. Gardner and Dr. Chu are consultants/contract
Slide 3: Neflamapimod Background
Neflamapimod Background anya ys NON? + Oral small molecule highly selective inhibitor of the protein kinase p38a, a major activator of the cellular stress response + In preclinical studies, reverses neurodegenerative process in basal forebrain + Safety profile well defined, with clinical safety data
Slide 4: Neflamapimod Treatment Targets Basal Forebrain Cholinergic Degeneration
Neflamapimod Treatment Targets Basal Forebrain Cholinergic Degeneration Neuroinflammation APP _at-synuclein one = | Endosomal Dysfunction, NGF Signaling Defect edit > Memory - Temporal) tenon Cholinergic Degeneration Fund cone Hippocampus _/ S#* Ovstunction Basal Forebrain | - mld Precursor Protein;
Slide 5: AscenD-LB demonstrated neflamapimod improved cognition and function in DLB
AscenD-LB demonstrated neflamapimod improved cognition and function in DLB GscenD-LB 40mg BID + 40mg TID 40mg TID iar a as are Seniy® Samat Boe Coe Sh odo 9 QD oeSiy 0m” @ (aoe comer 72 owes 0% O coon a ron) Wcrfonilon nol neon ein ™ @ gthn om @ ‘On-study (al time points) results, change from baseli
Slide 6: Objective of Presentation
Objective of Presentation Detail the major learnings from the Phase 2a AscenD-LB in DLB, as well MRI results from a prior phase 2a study in AD, that were incorporated into the final design of the ongoing Phase 2b RewinD-LB Study GscenD-LB RewinD-LB Phase 2a Exploratory Study Phase 2b study designed
Slide 7: Patient Population
Patient Population
Slide 8: AscenD-LB Inclusion Criteria Identified Robust DLB Patient Population
AscenD-LB Inclusion Criteria Identified Robust DLB Patient Population GscenD-LB Inclusion criteria: Baselinez-scoretontests + Probable DLB by 2017 consensus criteria Baseline Disease Characteristics within NTS. (dementia, with at least one core clinical acca. sabe ele nee feature of DLB) + Demonstra
Slide 9: AscenD-LB results stratified by presence of AD Co-Pathology
AscenD-LB results stratified by presence of AD Co-Pathology (by plasma ptau181 levels) + Efficacy results analyzed after stratification presence (46%) of patients in study) or absence (64%) of AD co-pathology at study entry, as assessed by prospectively defined cut-off for plasma ptau181 — Analysis
Slide 10: Patients in Phase 2a without AD Co-pathology show substantial response to neflamapimod
Patients in Phase 2a without AD Co- pathology show substantial response to neflamapimod ( ‘Overall Study Population Patients Without AD Co-pathology (Plasma ptaut8 «cutoff ie me NFMD TID, Difference! Cohen's ¢ | NFMD TID, Difference’ Cohen's d Pacebo__(95%C)__palue__efectsne_| Plcebo (osc) value _tf
Slide 11: Clinical Endpoints
Clinical Endpoints
Slide 12: Performance of Clinical Endpoints in AscenD-LB
Performance of Clinical Endpoints in AscenD-LB GscenD-LB Clinical endpoints that can detect effects on both cognitive and motor function (specifically, CDR-SB and TUG) performed better in the trial with respect to detecting improvement over placebo than endpoints that are purely focused on evaluatin
Slide 13: Clinical Trial Simulations to Estimate Statistical Power of Individual Endpoints
Clinical Trial Simulations to Estimate Statistical Power of Individual Endzelnis Sample size for RewinD-LB was evaluated by power analysis via clinical trial simulations: — Data in AscenD-LB forthe major clinical endpoints in the neflamapimod 40mg TID and placebo groupsin patients without AD co-path
Slide 14: Biomarkers
Biomarkers
Slide 15: Baseline and end-of-treatment EEGs
Baseline and end-of-treatment EEGs obtained in 29 patients (17 placebo, 6 neflamapimod 40mg BID, 6 nefiamapimod 40mg TID) — Covid'9 pandemic prevented obtaining EEGs in al patients No differences betweenneflamapimod and placeboin spectral analysis Potentially confounded by all patients receiving cho
Slide 16: CSF and Plasma Biomarkers in DLB
CSF and Plasma Biomarkers in DLB No CSF or plasma biomarkers specifichave beenreported AD biomarkers (e.g., plasma ptau) may be elevated, but generally tracks with co- pathology Recent report (right) indicated that both glial fibrillary acidic protein (GFAP) and neurofilament light chain (NL) can di
Slide 17: Neflamapimod Reduced GFAP Levels vs. Placebo in Patients without AD Co-Pathology
Neflamapimod Reduced GFAP Levels vs. : : i GscenD-LB Placebo in Patients without AD Co-Pathology Patients < ptau181 cut-off for AD Co-Pathology Overall Study Population z cad 33 33 “ Pa 33 50 . £2 Be 0f-gelee . — a3 i} —< Bais 2 2 Placebo —_Neflamapimod Placebo Neflamapimod Mean 3.7 pg/ml increase i
Slide 18: Potential Effect on Basal Forebrain Atrophy in Prior Phase 2 Study in AD
Potential Effect on Basal Forebrain Atrophy in Prior Phase 2a Study in AD ‘Neflamapimod treatment is associated with increased basal forebrain volume and functional connectivity 15 Early AD patients treatedwith neflamapimod hx) MS ‘Change in NbM volume H . poss Baseline 2 weeks: Followup treatment N
Slide 19: Summary
Slide 20: Summary
Summary With incorporation of DaTscan, 2017 diagnostic criteria successfully identified a robust DLB patient population with prominent attentional deficits — Executive function deficits less prominent in early stage DLB CDR-SB is the optimal primary endpoint for phase 2b The exclusion of patients wi
Slide 21: RewinD-LB Study Design
PARTICIPANTS —_ DLB by consensus eriteria, including abnormal DaTscan™ Ly Global CDR score of 0.5 or 1.0 i — No AD co-pathology, assessed by plasma ptaut81 INTERVENTION ~ Randomized on a blinded basis 1:1 to neflamapimod 40mg capsules (n=80) or matching placebo capsules (n=80), TID for 16 weeks, fol
Slide 22: RewinD-LB Clinical Sites
RewinD-LB Clinical Sites RewinD-LB Investigator Name site Location wvkcigbor an ass iniaaae LUanaRoserthal MO ——_JohnsHopkiesUnwersty Baltimore, MO DanlelMurman MO UniverstyotNebrascaMediaiCerter Omaha, NE Matthew Sarre MD ViginaCommenwesth Unversty Richmond VA ‘uenTolendccha Mo Huson ethos ep House