Palisade Bio, Inc. · NASDAQ:PALI
Palisade Bio — Neuralstem — MGH CTNI Europe 2018
29 slides from Palisade Bio's conference presentation, Jul 5, 2018
Slide 1: Fast-Acting Synaptic Plasticity Effects of NSI-189 at High Doses
NEURALSTEM INC “Fast-Acting Synaptic Plasticity Effects of NSI-189 at High Doses” Karl Johe, Ph.D. Chief Scientific Officer MGH CTNI Europe 2018 June 30, 2018
Slide 2: Safe Harbor
Safe Harb: Safe Harbor 9 any underlying assum performance an oe sujet e certain fat uncertantes, ana assumptone ha ae cif prede. Teteoe vt aca ess cul fer mately ang aavrsey tm Rowe etrnted fay treartioang sists novus se cia, Tone aia ond vcaians ncoe he tke anos wih he aes of cheng teaneml conten,
Slide 3: Figure if iT + diy}
Figure 1 if iT + diy} and human brain. A peat bin tennis Ernst is i Mammals PLOS Biology 13(1): 1002045. https://doi.org/10.1371/journal. ob (002045 id=: FieveeHTR AN NIVERTARY
Slide 4: Adult Neurogenesis in Humans
Number of neurons ( Adult Neurogenesis in Humans Bergmann 01, Spalding KL1, Frisén J1. HE Nonrenewing new a pores bom the tst yer 30° 40 50 60 70 ‘Age of individual (years) PMC full text: doi: 10.1101/cshperspect.a018994
Slide 5: Hippocampus
A Hippocampus = wrens 7 — Reo pee oes |: —— ki; — Nucleus | i ES bh eS Cc aan sue el I Kirk |. Erickson et al. (©2011 by Nana Seinces
Slide 6: Meta-analysis of 1728 MDD vs. 7199 Controls
my meta-analysis of 1728 MDD vs. 7199 Controls S Late onset Early onset S Recurrent First episode Lateral ventricles 0.2 04 03 02 O01 0 O01 02 Cohen's d effect size [95% Cl] 01 0 o1 Cohen's d effect size [95% Cl] Molecular Psychiatry
Slide 7: Discovery of Neurogenic Drugs
Discovery of Neurogenic Drugs Based on Human F in vitro et Dayo Vehicle Control NSI-106
Slide 8: Neurogenesis in Healthy Animals
A Neurogenesis in Healthy 12= NSH185 (98) ** pe0.01;* pc00s, +o Total number of BrdU-IR cells
Slide 9: Novelty Suppressed Feeding Model
—_ in eae Novelty Suppressed Feeding Model of a ased HI Neurogenesis and Volume (10-30mg/kg po Latency to eat (sec) SLAP E ose CANICA2 Volume Analysis
Slide 10: Synaptic Remodeling during Recovery from Ischemic Stroke
Synaptic Remodeling during Recovery from Ischemic Stroke Brain (30mg/k; 12 Weeks 12 Weeks Vehicle NSI-189 A. MAP-2 in Cerebral cortex B. MAP-2 in Hippocampus — MpBrzin Cerebral Cortex td > ¥ 2 Ss __MAP-2 in Hippocampus a i tliat, "2 ¥ rs
Slide 11: Motor Nerve Conduction Velocity in Diabetic Models
Motor Nerve Conduction Velocity in Type 1 and Type 2 Diabetic Models -30mg/kg po) 30 reconstruction of nerve structure in the mouse cornea: A delta fibers (yellow) penetrating the Bowman's layer and spreading into the sub-basal nerve plexus (red)
Slide 12: Amelioration of Cognitive Deficits in Radiation-Induced Brain Injury Model
Amelioration of Cognitive Deficits in Radiation-Induced Brain Injury Model (30mg/kg po) Spatial Cognitive Impairment Episodic Memory hae pogs Neurogenesis vag OE ee B Hippocampal Volum Spatial Memory = Object in Place Task ya0s EXSEr) Barrett et al. (2017) Radiation Research 189(4):345-353. 2018 htt
Slide 13: Phase 1b Study Publication
Cafaty far 28 dd. for 20 days A Phase 1B, Randomized, Double-Blind, Placebo-Controlled, Phosphate, i il i Depressive Disorder (MDD) Maurizio Fava, M.D., Karl Johe, Ph.D., Lev G. Gertsik, MD, 1.D., Ph.D., Gustavo Martina Flynn, David Mischoulon, M. Kinrys, M.D., and Marlene Freeman, M.D.
Slide 14: Phase 1b Study Design
Phase 1b Study Design * Double-blind, randomized b hree ascending cohorts (N=24) Cohort 1 ie =8 (6 drug, 2 placebo) fe mg QD Cohort 2 | N=8 (6 drug, 2 placebo) ig mg BID Catan sd | N=8 (6 drug, 2 placebo) (40 aps Drug Treatment: No-Drug Follow up: 35, 42, 28 days 70, 84
Slide 15: Phase 1b Clinical Outcomes
MADRS CPFQ. Phase 1b Clinical Outcomes vas 199
Slide 16: Biomarker Results
Biomarker Results qEEG Topographs of High Frequency alpha IR} Nsi-189 Placebo Post-dose Left Hippocampal Vol Study Days Left posterior temporal (15) =0.02) Left parietal regions (P3) (t=3.31, p=0.004)
Slide 17: Phase 2a Mono-Therapy of Recurrent MDD
Phase 2a Mono-Therapy of Recurrent MDD ‘Study Design Sequential Comparison Parallel Design ning period: 14-28 days tment period: 12 ments performed weekly %, 2-sided 5 (MADRS) pen label scontinue treatment) Stage 1 Stage 2 6 weeks 6 weeks
Slide 18: MDD Phase 2a Study Results
MDD Phase 2a Study Results MADRS (Primary) 025 0.9 HAMD-17 Ss fa 0.33 3 038 QIDS-SR (patient p=0.040 reported)* Yes/No. (Stage 2 only) 0.68 No 0.39 8 aa see Yes/No p=0.044 0.64 No 0.20 moe oa Yes/No 0.47 0.10 CGH Yes/Yes (2°) Trend p=0.148 0.58 Trend p=0.081 0.46 cGis Yes/Yes (2°) Trend p=0.132 0.56
Slide 19: CogScreen-MDD Test Findings vs Placebo
CogScreen-MDD Test Findings for Se v Placebo (Following 6 weeks of Treatment Simple Attention al g vs. Placebo 80mg vs. Placebo Improved response spee Improved respon: accuracy (SATACACC); Improved accuracy SATINRTI; Improved response speed
Slide 20: Effect of NSI-189 vs. Placebo on Recurrent MDD
Effect of NSI-189 ys. Placebo on Recurrent MDD Stage 2 Cohen's d Working Memory: mory** Reaction Accuracy * Reaction Speed (staget) * ntal Flexibility * PFQ* SDQ-Outlook * SDQ-Depression * sDQ* QIDS-SR* HAMD-6 Anxiety HAMD-6 Depression HAMD-17 MADRS-6 MADRS-10 <+— Improvement
Slide 21: Number of CogScreen-MDD Variables Correlating with Depression Severity
Number of CogScreen-MDD Variables (n=33) Showing Significant (p < 0.05) Correlation with Depression Severity At Baseline Visit At 12 —Week Visit MADRS 4 (11%) 4 (11%) HAMD-17 5 (14%) 6 (16%) 6 (16%) 3 (8%) CPFQ 11 (30%) 5 (14%) + For 33 variables, correlation at p<0.05.
Slide 22: Summary
Summary * NSI-189 (40/80mg) showed significant improvement in cognitive functioning following 6-weeks of treatment. * CogScreen-MDD measures of processing speed, working memory, executive functioning, and negative feedback, were found to be relatively insensitive to depression severity but were sens
Slide 23: Dose- & Time-dependent Enhancement of LTP Magnitude in vitro
Dose- & Time-dependent Enhancement of LTP Magnitude in vitro Fs oo i = 400) © Control © 10uM 3% 3uM 1M + 300 Me 100mm 3 H EPSP slope (% of baseline) m0 5 0 68 4 1% 2 2 90 35 0 Time (min) ¢ J control © Nsi-189 @5h) = NSI-189 (3.6 h) 3 H a 3 0 EPSP slope (% of baseline) & 7% 2 2 90 35 40 Time (min)
Slide 24: Restoration of LTP from Angelman Syndrome mouse in vitro
Restoration of LTP from Angelman Syndrome mouse in vitro microM) 8 > WT © AS # AS#NSI-189 fEPSP slope (% of baseline) {EPSP slope (% of baseline) 10 15 20 Time (min) ¥
Slide 25: Reversal of Motor Deficit in vivo
Reversal of Motor Defici und vivo (30me/kg ip.) Wr-Cont — @WT-NSI “=A8.comt-eASsSt Hanging time (s) 3 ———_ Dts 04-07 Deo1t ——DtT-D14 forsore 018-020 30 mgikg
Slide 26: Reversal of Cognitive Deficit from Syndrome in vivo
in vivo Reversal of Cognitive Deficit from Svndi (30mg/kg ip.) Fear conditioning test Tone test Context test 100: - WT-Vehicle * @® AS-Vehicle mm Wests: i | @® ASNSI189 0. rs se Ss ee
Slide 27: Restoration of LTP from Angelman Syndrome in vivo
Restorati f LTP from Angel S vivo (30mg/kg i.p.) TBS induced LTP # 7” © WrVehicle m 3 © AS-Vehicle g 200 & . “NSI189 3 ek $ 20 © AS.NSI189 § 150 x j 3 ra & 100 s e 3 a a o & 3 60 o & oO u é or ee ee) 40 eT Time (min) ec VIE cya nS 8
Slide 28: aL leat? ec ..D, ee age Pe
aL leat? ec ..D, ee age Pe “ 3Ome/kg ip.) Ml wrt Control NS Arc/Actin P-TrkB515/TrkB P-AktlAkt
Slide 29: Conclusion
Conclusion ¢« At 1-3 microM in the CNS, NSI-189 induces fast treatment effects by mechanisms enhancing synaptic plasticity * At 0.1-—0.3 microM in the CNS: NSI-189 induces and maintains treatment effects chronically by mechanisms enhancing is and i