Slide 1: Neuralstem Inc June 2016 Corporate Presentation
NEURALSTEM INC June 2016 Corporate Presentation MOA Insight
Slide 2: Safe Harbor Statement
NEURALSTEM, INC. Safe Harbor Statement Safe Harbor statements under the Private Securities Litigation Reform Act of 1995: This presentation contains forward4ooking statements as defined in Section 274 of the Securities Act of 1933 as amended, and section 21E of the Securities E xchange Act of 1934,
Slide 3: Key Highlights
Key Highlights * Refocused Business Strategy: — New, experienced management team — Focus on lead program: NSI-189 — Internal reorganization — Partner NSI-566 programs ¢ NSI-189: Novel Neurogenic Small Molecule targeting MDD — Compelling early clinical data — IP from 2024-2034 — Phase Il MDD Efficacy
Slide 4: Pipeline
Pipeline Compound / Indication Preclinical Phase | Phase II Phase III Status Small Molecule: Lead Asset NSI-189 US ‘ ae Results 2H17 Major Depression Disorder NSI-189 Pipeline Expansion Update 2016 NSI-189 Preclinical Studies Data 2016 Cell Therapy (outsourced funding) NSI-566 US sf i P2a Completed
Slide 5: NSI-189 Overview
NSI-189 Overview + New Chemical Entity (NCE) + Novel neurogenic MOA + Highly stable and well characterized + MDD Market Opportunity + Unsatisfied patient population* + High patient turnover rate in MDD* ¢ Strong IP position through 2024 — 2034 + Efficacy: * Compelling Phase Ib MDD randomized, double
Slide 6: NSI-189 MDD Phase Ib trial design
NSI-189 MDD Phase lb trial design NSI-189 Phase Ib double-blind, randomized, placebo-controlled, dose-escalating study assessing safety and tolerability Cohort 1 | N=8 (6 drug, 2 placebo) | 40 mg QD Cohort 2 | N=8 (6 drug, 2 placebo) | 40 mg BID Cohort 3 | N=8 (6 drug, 2 placebo) | 40 mg TID Acute t
Slide 7: Clinical Results from NSI-189 MDD Phase Ib
Clinical Results from NSI-189 MDD Phase Ib Montgomery-Asberg Depression Rating Scale (MADRS) ‘Symptoms of Depression Questionnaire (S0Q) x0 Day 28 Day 84 ae Day 28 Day 84 p=0.09 p=0.19 p=0.02 p=0.03 0.95 0=0.84 38 0.90 1.10 ‘Symptoms of Depression Questionnaire mmm Placebo 244 mimNS-189 i NS-189 1x
Slide 8: Clinical Results from NSI-189 MDD Phase Ib
Clinical Results from NSI-189 MDD Phase Ib Cognitive and Physical Functioning Questionnaire (CPFQ) Day 28 Day 84 ® 50 y y s p=0.01 p<0.01 S d=0.94 d=1.20 Boas 3 g 3 2 = 40 S s 5 we 35 § = 30 a see Placebo z mie NS-189 © 954 8 NS-189 1x per day 2 —®— NS-189 2x per day € —@— NS-189 3x per day 5 8 20 -
Slide 9: NSI-189 MDD Phase Ib: Adverse Events
NSI-189 MDD Phase Ib: Adverse Events | Side effect Pooled placebo | 40mg q.d. | 40mg b.i.d. | 40mg t.i.d. | Pooled active Pooled placebo (n=6) N(%) | (n=6) N(%) | (n=6) N(%) | (n=6) N(%) | (n=18)N(%) | (n=6) N(%) ‘Autonomic Dry mouth 0 (0%) 0 (0%) 2(33.3%) | 0 (0%) |2 (11.1%) = | Palpitation 0 (0%)
Slide 10: Biomarker Results from NSI-189 MDD Phase Ib
Biomarker Results from NSI-189 MDD Phase Ib Be Blood biomarker panel: + Blood panel analysis correlates to MADRS response rate + MDD panel was developed based on SSRIs activity profile + Rapid and persistent efficacy 10 Biomarkers: Response Partial Responder | Responder Remission + A1AT * MPO Rate <
Slide 11: Biomarker Results from NSI-189 MDD Phase Ib
Biomarker Results from NSI-189 MDD Phase Ib Quantitative EEG (qEEG) biomarker: * Increases coherence activity between prefrontal cortex and hippocampus * Two coordinating brain centers utilized for depression and cognition qEEG Topographs of High Frequency alpha (10-12 Hz): Day 28 from Baseline NSI-
Slide 12: Building the Case for MOA
Building the Case for MOA Extensive screening showed novel MOA vs. currently marketed therapies Screening: 52 neurotransmitter related receptors/ion channels/enzymes Novoscreen: Adenosine, GABA, Glutamate, Histamine, Muscarinic, Nicotinic, norepinephrine, opioid, or and serotonin receptors, Ca++, Cl
Slide 13: Pipeline Update & MOA insight
Pipeline Update & MOA insight Compound / Indication NSI-189 Small Molecule NSI-189 Angelman Syndrome (orphan) Phase | Preclinical NSI-189 LTP Enhancement NsI-189 Irradiation-induced cognition NSI-189 Diabetes-related neuropathy NSI-189 MCAO Stroke _> => — > « Upcoming preclinical data presentation i
Slide 14: Understanding LTP and Memory
Understanding LTP and Memory Be For mechanistic studies: cognition = memory LTP is a cellular biomarker of memory — repetitive, high-frequency stimulus leads to long-lasting synaptic transmission — increased LTP means enhanced memory, decreased LTP means memory deficit. LTP occurs in hippocampus (me
Slide 15: NSI-189 enhances LTP magnitude
NSI-189 enhances LTP magnitude EPSP slope (% of baseline) TBS after 2.5 h incubation TBS after 3.5 h incubation AR WHchiche — -WTNSIIE9 (rq i-WT Vehicle -#-WTNSI89 20m 250 200 150 | 100 50 so ° —z : ———1 0 10 5 0 5 10 15 2 2 3 % 4 10 5 0 5 10 15 20 2 20 35 Time (min) * Enhances short-term and long-t
Slide 16: NSI-189 restores STP & LTP from Angleman Syndrome mice
NSI-189 restores STP & LTP from Angleman Syndrome mice --AS ~<WT-vehicle ---AS-NSI189 EPSP slope (% of baseline) (0) T T T T T -lo -5 oO 5 10 15 20 25 30 35 40 Time (min) Confirmatory second model in a genetic disease By courtesy of Yan Liu, Xiaoning Bi, Michel Baudry* Western University of Health S
Slide 17: LTP-based assay for NSI-189's molecular pathway
LTP-based assay for NSI-189’s molecular pathway NSI-189 increases LTP magnitude in a time-dependent and concentration-dependent manner. — This effect is not from increased synaptic transmission. — This effect is not from increased NMDA receptor properties — This effect occurs within 1-3.5 hours of t
Slide 18: Mechanism of Action
189 Mechanism of Action: Dynamic transcriptional enhancer? Potential Molecular Pathways Potential Cellular Outcome €a> “inline nin, Din ‘KakaRaghin — c synaptic scaling b intrinsic plasticity a synaptic plasticity Gronemeyer H, Gustafsson JA, Laudet V. Principles for moduiation ofthe nuclear recepto
Slide 19: Limited epigenetic pathways
Limited epigenetic pathways Be « DNA methylation & histone acetylation/deacetylation of DNA are dynamically regulated — leads to changes in protein synthesis and strength of neuronal connectivity * mRNA regulation at pre/post-synaptic ending modulates synaptic scaling — changes neurotrophic factors,
Slide 20: NSI-189 Phase II MDD Trial
NSI-189 Phase II MDD Trial Randomized, Double-Blind, Placebo-Controlled, 2-Dose Study Milestones: - First Patient enrolled May 2016 + Phase 2 Results expected 2H17 Study Objectives + Primary: Montgomery-Asberg Depression Rating Scale (MADRS) * Secondary: SDQ, HAMD17, CGI-S, CPFQ, SFI, Cogscreen Batt
Slide 21: NSI-189 Phase II MDD Trial
NSI-189 Phase II MDD Trial Placebo-reducing, Study Design Innovative Trial Design * Experienced MDD trial sites (n=12) * Dual patient screening requirement — Secondary confirmatory screen: independent, remote MADRS diagnosis by MGH * Placebo-reducing prescreen process, re-randomization Study Design
Slide 22: Cell Therapy Program Update
Cell Therapy Program Update Cell Therapy (outsourced funding) NSI-566 US P2a Compl Amyotrophic Lateral Sclerosis ‘a Completed NSI-566 US P1 follow- Chronic Spinal Cord Injury ollow-up NSI-566 China Ischemic Stroke P1 follow-up * ALS Long-term Phase 1 / 2 follow up data will be presented at an upcomi
Slide 23: Key Highlights
Key Highlights Experienced Management Team Implementation of Reorganization Lead Candidate: NSI-189 novel neurogenic small molecule New Chemical Entity; Protected IP: 2024-2034 Near term milestones: — Phase II MDD trial; results expected 2H17 — Preclinical publications; expected 2016 — Cell therapy
Slide 24: Management
Management Richard Daly, CEO President, AstraZeneca Diabetes, US; President, BMS Diabetes, US; EVP, Takeda Pharmaceuticals; VP, Commercial Strategy, TAP Pharmaceuticals Boards: Catalyst Pharmaceuticals; Synergy Pharmaceuticals Education: MBA, Kellogg Graduate School of Management; BS, Microbiology,
Slide 25: NSI-189 Scientific Advisory Board
NSI-189 Scientific Advisory Board World Class Psychiatric, Clinical and Regulatory Experts Harvard, MGH, Executive Vice Chair, Dept. of Psychiatry PIB WEMI ENE Principal Investigator: NSI-189 Phase 2 MDD clinical trial Univ. of Pennsylvania, Chief. Division of Mood and Anxiety Die Uitte THRE Disorde
Slide 26: Intellectual Property
Intellectual Property Small Molecule 11 US & 65 World Issued and Pending Patents - 16 Neurogenic compounds (including 189), composition of matter, US (7,560,553) to 2024, Patent Extension to 2029. — Assay method for screening neurogenic compounds, US (8,293,488) and Europe to 2023 — Synthesis method