World Leader in Neural Stem Cell Science

Corporate Overview October 2014

Safe Harbor

Safe Harbor statements under the Private Securities Litigation Reform Act of 1995: This presentation contains
forward-looking statements as defined in Section 27A of the Securities Act of 1933 as amended, and section 21E
of the Securities Exchange Act of 1934, as amended. Such forward-looking statements are based upon
Neuralstem, Inc.s managements current expectations, estimates, beliefs, assumptions, and projections about
Neuralstems business and industry. Words such as anticipates, expects, intends, plans, predicts,
believes, seeks, estimates, may, will, should, would, potential, continue, and variations of these
words (or negatives of these words) or similar expressions, are intended to identify forward-looking statements.
In addition, any statements that refer to expectations, projections, or other characterizations of future events or
circumstances, including any underlying assumptions, are forward-looking statements. These forward-looking
statements are not guarantees of future performance and are subject to certain risks, uncertainties, and
assumptions that are difficult to predict. Therefore, our actual results could differ materially and adversely from
those expressed in any forward-looking statements as a result of various risk factors. These risks and
uncertainties include the risks associated with the effect of changing economic conditions, trends in the products
markets, variations in Neuralstems cash flow, market acceptance risks, technical development risks and other
risk factors detailed in Neuralstems Securities and Exchange Commission filings.
For links to SEC documents please visit the companys Web site: neuralstem.com.

Overview
Industry Firsts
Inventor of human neural stem cell technology is Karl Johe, Ph.D., Chairman and Chief
Scientific Officer, while at NIH
First FDA-approved neural stem cell therapy trials for ALS & chronic spinal cord injury
First-in-class hippocampal neurogenic small molecule drug portfolio

Platform Technology
Regionally specific, fully characterized CNS human neural stem cells, cGMP mnfr.
Two programs: 1) cell therapy direct injection, brain and spinal cord, 2) neurogenic small
molecule development screening
14 U.S. patents re-affirmed worldwide technology and product; 8 pending

Cell Therapy Lead Product: NSI-566

Unmet medical needs include ALS, spinal cord injury, stroke

FDA Phase I safety approval of cells and surgical device
Data shows signs of efficacy; definitive evidence of long-term cell survival
FDA-approved ALS Phase II; FDA-approved cSCI Phase I
World-class collaborators

Small Molecule Lead Product: NSI-189

Medical markets include depression, traumatic brain injury, Alzheimers disease, PTSD
Novel hippocampus builder initially funded by DOD program, early mover advantage
FDA-approved Phase I safety proved
Phase Ib data results show significant and large treatment effects, across all depressive and
cognitive measures, for duration of trial
Multiple Phase II trial-ready hippocampus-atrophy applications

12-Month Clinical Trial Catalysts

NSI-566/ALS
Phase II/III U.S. Trial

FDA-approved Phase II trials

concluded final surgeries July
2014
Data 6 mos. after final surgery
NIH-major funding
Increased dosing, all cervical
Orphan Status Designation
Est. 30,000 ALS patients, est.
5,600 diagnosed per year, U.S.

Phase I/II Mexico City Trial

In development
Accelerated timeline

NSI-566/Chronic
Spinal Cord Injury
Phase I U.S. Trial
FDA-approved Phase I trial
commenced surgeries
September 2014
Same cells, similar procedure
as ALS
One-year timeline goal
Est. 840K SCI patients, 10K+
new SCI injuries per year, U.S.
Phase I/II Seoul Trial
Acute SCI patients
IND expected 2014

NSI-566/Ischemic
Stroke (Neuralstem China)

NSI-189/Major

Phase I/II China Trial

World-class BaYi Brain Hospital
Same cells, injected in brain
Phase I-determine max safe
dose, up to 18 Patients,
treatments commenced
December 2013
Phase II-100 patients, efficacy
China stroke pop est: 1.75+
million

Phase II U.S. Trial

Phase Ib data results showed
clinically meaningful improvement across all depressive and
cognitive measures
Results continued for 8 weeks
post-trial, despite fact of no drug

Depressive Disorder

accumulation in patients systems

Est. 14.8 million MDD patients,

U.S.
NSI-189 proven safe in Ia
healthy volunteers and Ib MDD
patient trials; addl applications
expected to commence testing
at Phase II

Neuralstem Technology Cells Nurturing, Supporting and Rescuing

Remaining Neurons
Midbrain

Dopaminergic

Regionally specific CNS neural stem cells:

brain and spinal cord

14 U.S. patents re-affirmed worldwide,

8 pending

Spinal Cord

Cholingergic

cGMP manufacturing
Numerous cell therapy stem cell products
Fully characterized

Hippocampus

GABAergic

Expanded under defined conditions: no animal-derived

reagents, serum or feeder cells

Reproducible differentiation: constitutive behavior of cells

Physiologically relevant neurons: 50%

Single Platform Technology, Two Programs, Multiple Indications

Amyotrophic
Lateral
Sclerosis

Optic Neuritis

Lysosomal
Diseases

Major Depressive
Disorder

Traumatic Brain Injury

Spinal Cord
Injury

Alzheimers
disease

Parkinsons
disease

Alzheimers disease
and Pre-Alzheimers
Dementia

Post-Traumatic Stress
Disorder

Ischemic
Stroke

Traumatic Brain
Injury

Huntingtons
disease

Cognitive
complication due to
Diabetes

Neurodegeneration

Glioblastoma
(Brain Cancer)

Ischemic Spastic
Peripheral Nerve
Paraplegia
Injury

Cerebral
Palsy

Stroke

Anti-Aging (Nootropic)

Multiple
Sclerosis

Diabetic
Neuropathy

Ischemic
Spastic
Paraplegia

Current Human Clinical Trials

Pre-clinical Applications

NSI-566 Human Proof of Concept, Safety, and Signs of Efficacy

Successful, safe injection of neural stem cells
30 patients, 36 surgeries
Lumbar and/or cervical regions of spinal cords

Amyotrophic
Lateral
Sclerosis

No complications related to cell delivery

Ischemic
Stroke

No toxicity related to cells

Spinal Cord
Injury

Definitive evidence of long-term cell survival via DNA fingerprinting

The patients with limb-onset ALS (in Phase I) appear to have a slowing of progression

of their disease and the patients of Phase II, I can comment that theyve had a lot more
stem cells than Phase I It clearly is a very safe, safe procedure and we hope to do a
trial that proves clinical efficacy beginning in February 2015. (August 2014)

Principal Investigator: Eva L. Feldman, M.D., Ph.D.

Professor of Neurology & Director, A. Alfred Taubman Medical Research
Institute of the University of Michigan Medical School

ALS Amyotrophic Lateral Sclerosis

NSI-566 FDA Orphan Designation
No Cure
Unmet Medical Need:

Est. 30,000 Americans have disease at any given time

Est. 5,600+ people diagnosed each year in the U.S.

Est. nearly 120,000 cases diagnosed worldwide each year

(ALSA)

(ALSA)

(Intl Alliance of ALS/MND Assns.)

Progressive neurodegenerative disease

Affects nerve cells in the brain and spinal cord
Leads to complete paralysis, and eventually, death

Now this is a disease that doesn't get better. So we don't see patients
who spontaneously get better. It just doesn't happen.
Neuralstem ALS Trial Site Principal Investigator and
Emory University neurologist Dr. Jonathan Glass,
referring to pre-trial disease status

NSI-566/ALS Phase I Success: Proven Safe, Signs of Efficacy

Final Safety Cohort Shows Slowed Disease Progression or Improvement Three Years Post-Transplant

Patients 10, 11, 12 received ten lumbar and five cervical injections, of 100,000 cells each

ALSFRS-R data shows one patient with functional improvement from pre-treatment baseline, which is
maintained to present day. The other two patients are maintaining the same level of functionality as they
had at the baseline for more than three years since the NSI-566 cell therapy treatment

ALS Functional Rating Scale Revised (ALSFRS-R) monitors changes in a patient over time with ten measures including speech,
swallowing, walking and breathing, total score of 48. 0 baseline: Treatment

1
2

Neuralstem ALS Patient Story:

TED HARADA - Patient 12
Surgery #12 (lumbar) - Reversed ALS Progression

39 years old, ALS diagnosed 2009

1st treatment March 2011 lumbar (lower spinal cord)

Walking without cane; limb strength and dexterity greatly surpassed pre-treatment ability

Maintained this unheard-of degree of ALS recovery approx. one year, until
gradual decline started and continued until second treatment:

10 injections, bilateral, 100,000 cells per

4-hour procedure, therapy well-tolerated

Surgery #18 (cervical and lumbar) Completes 2.5-mile ALS Walk

2nd treatment August 2012 final trial surgery

5 injections, cervical (upper spinal cord), 100,000 cells per

6-hour procedure, therapy well-tolerated

Functional Recovery repeats: two months after treatment, Ted completes 2.5-mile
fundraising ALS walk in Atlanta still going strong past finish line

Living a normal life: walking, climbing stairs, hands stronger again, increased dexterity

10

NSI-566/ALS FDA-Approved Phase II: Increase Dosage,

Evaluate Efficacy and Safety
U.S. Phase II Concluded Final Surgeries in July 2014; Subsequent 6-Month Observation Period

Goal: maximum safe tolerated dose; evaluate efficacy for clinical proof-of-concept to advance to
Phase II/III trial

Emory announced significant NIH grant to cover majority of Phase II trial cost

Collaborators: Eva L. Feldman, M.D., Ph.D. and Jonathan D. Glass, M.D.

ALS Phase II Trials, FDA-Approved Protocol

(Commenced Sept. 2013, Surgeries Completed July 2014)

Up to 15 ambulatory patients
Accelerated dosing schedule: first 12 patients cervical injections; final 3 lumbar and cervical
200,000 - 400,000 cells per injection
10 - 40 injections, escalated dosing per cohort
One-month observation period between treating each of 5 cohorts
Multiple centers, escalated timeline
Emory University Hospital
ALS Clinic at the University of Michigan Health System
Massachusetts General Hospital
6-month observation period from last surgery to trial completion

11

Spinal Cord Injury Neuralstem Cells To Bridge the Gap

Unmet Medical Need:

Approximately 840,000 SCI patients in the U.S.

10,000+ new spinal cord injuries each year in the U.S.

85% of SCI patients who survive first 24 hours are alive ten years later

(NSCIA)
(NSCIA)
(NSCIA)

Affects nerve cells in the spinal cord

Spinal cord damage results in loss of function such as mobility, feeling

Chronic spinal cord injury (cSCI): some level of paralysis that persists for a long
duration, and is usually defined as more than one year following injury
Complete cSCI: no function below the injury; no sensation, no voluntary movement
Acute SCI: early stage of injury, having rapid onset and usually with some recovery

12

NSI-566/Chronic Spinal Cord Injury Phase I Trial Commenced

U.S. FDA-approved NSI-566/cSCI Phase I Trial Initial Surgery in September 2014

Same cells and similar procedure as ALS trials

University of California, San Diego School of Medicine launched Phase I with patient recruitment in August
2014; launched and supported by the UC San Diego Sanford Stem Cell Clinical Center

One-year Phase I completion goal; trial study period ends six months post-surgery of the last patient

Principal Investigator: Joseph Ciacci, M.D., Study Investigator: Martin Marsala, M.D., Ph.D., UC San Diego
School of Medicine
cSCI Phase I Trial, FDA-Approved Protocol
(Commenced September 2014)

Four cSCI patients

T2-T12 injuries complete thoracic, no cervical
American Spinal Injury Assn. AIS-A level impairment complete paralysis one-to-two years post-injury

All dosing completed six months from trial commencement

Primary objective: safety and toxicity of NSI-566 in chronic spinal cord injury patients
Secondary endpoints: evaluate graft survival in the transplant site by MRI; effectiveness of transient
immunosuppression. Exploratory objectives include: evaluate ability of NSI-566 transplantation to positively affect AIS level,
ISNC SCI motor and sensory index scores, bowel and bladder function, pain, UAB IMR scores, SCIM scores, evoked sensory
and motor potentials, and electromyogram (EMG)

Patients to receive physical therapy post-surgery to guide newly formed nerves to proper connections & functionality
Patients to also receive immunosuppressive therapy, which will be for three months, as tolerated

13

NSI-566/Acute SCI Trial Early Stage of Injury

Seoul, South Korea - NSI-566/Acute Spinal Cord Injury Phase I/II IND Expected 2014
Same cells and similar procedure as U.S. ALS trials
Acute SCI patients are in the early stage of injury, having rapid onset and usually with

some recovery

Single site trial expected, following Korea Food and Drug Administration (KFDA) approval of trial

South Korean exclusive option partner: CJ CheilJedang

Pharma division has 1,200 employees and $400 million USD annual revenue from a wide breadth
of products
Exclusive option agreement for cell therapy products in six South Asian countries: South Korea,
Indonesia, Malaysia, Philippines, Singapore and Vietnam

14

Ischemic Stroke
Stroke is 4th-leading cause of death in U.S.

(NSA)

Stroke is a leading cause of adult disability

(NSA)

Unmet Medical Need:

Est. 7,000,000 Americans have survived a stroke

Est. 1,750,000 people in China alone, per year, survive a stroke

87% of stroke cases are ischemic stroke

2/3+ stroke survivors have some type of disability

(NSA)

(ASA, NSA)
(NSA)

Occurs as a result of an obstruction within a blood vessel supplying blood to the brain
Affects nerve cells in the brain
Post-stroke motor deficits include paralysis in arms and legs, and can be permanent

15

NSI-566/Ischemic Stroke Rebuilding Neural Circuitry and

Promoting Repair and Recovery of Surviving Tissue
Combined Phase I/II Trial, Treatments Commenced in December 2013

Wholly owned subsidiary: Neuralstem China (Suzhou Neuralstem Biopharmaceutical

Company, Ltd.)
Collaborator: BaYi Brain Hospital, in Beijing, world-class research facilities and one of Chinas premier
neurological hospitals
Expected duration: approximately two years, combined Phase I/II study, including patient monitoring and
data collection

Trial protocol developed for FDA approval in the U.S., advanced preclinical program
One-time treatment of direct intracerebral injections of cells into the stroke area, using well-accepted
stereotactic injection procedures
Up to 118 Patients: ischemic stroke with chronic residual motor disorder, 4 to 24 months post-stroke
Phase I: safety, determine maximum safe dose
Open-label, 18 patients in six cohorts of three patients each
Each cohort receives ascending doses of NSI-566:
3-5 deposits on each of 5 tracks
40,000-80,000 cells per deposit
Phase II/III: proof-of-concept, evaluates efficacy and safety
Multi-site, randomized, controlled, single-blind study
Up to 100 stroke patients with stable paralysis for at least four months
50% receive one-time treatment, with physical therapy
50 % receive physical therapy with no surgery
Outcome measures conducted in single-blinded manner

16

NSI-566/Cognitive Testing Cranial Irradiation Model

University of California, Irvine Research

Transplantation of Human Fetal-Derived Neural Stem Cells Improves Cognitive Function Following
Cranial Irradiation
Published in scientific journal: CELL TRANSPLANTATION THE REGENERATIVE MEDICINE JOURNAL (Aug. 2013)
Reversed cognitive defect and improved cognitive function in rats that had received radiation to the brain
Animal model similar to a potential clinical intervention given to treat brain cancer patients

Novel Place Recognition Tasks: Hippocampus

17

Fear Conditioning: Amygdala

First-in-class Neurogenic Small Molecule Drugs Reversing

Hippocampal Atrophy
War Fighter of the Future DOD program, initial funding
Patented novel neurogenic compounds
100% owned for commercialization
Early mover advantage

Recruit endogenous neural stem cells to generate more

new neurons in adult brain

Small molecule discovery and development enabled by

proprietary stem cell-based screening

NSI-189 - first neurogenic small molecule product candidate:
Increases hippocampal volume - +> 20% in animal studies
Rebuilds hippocampus structurally
Enhances neurogenesis

18

Major Depressive Disorder (MDD)

Neurogenic NSI-189 - first drug candidates initial application
Challenging Medical Need:

Est. 14.8 million American adults (NIMH)

Leading Cause of Disability in U.S. for ages 15-44 (NIMH)

New Theory of How To Treat:

Brain physiology in the disease rather than brain chemistry alone

Researchers now know depressed patients have reduced hippocampal volume
NSI-189, by stimulating the generation of new neurons in the hippocampus, could potentially address the
pathology of the depression itself
Current MDD oral medications, including worldwide-widely prescribed selective serotonin reuptake
inhibitors, modulate levels of different neurotransmitters in the brain

MDD, also termed major depression: combination of symptoms interferes with ability to work,
sleep, study, eat, and enjoy once-pleasurable activities
Treating depression through neurogenesis opens up an entirely new avenue of treatment
for patients who are suffering with these diseases and need new and better treatment options.
This study represents the first demonstration of a promising new compound being developed
towards that goal and we look forward to confirming these results in the next trial. (June 2014)
Lead NSI-189 Phase Ib Study Author: Maurizio Fava, M.D, Executive Vice Chair, Department of Psychiatry,
Executive Director, Clinical Trials Network and Institute, Massachusetts General Hospital

19

Neurogenic NSI-189/MDD Phase I: Clinically Meaningful

Improvement Across All Depressive and Cognitive Measures
Phase II commencement expected in late 1Q15, larger trial to confirm strong Phase I data

Phase Ib data results showed statistical significance; clinically meaningful improvement, across all depressive
and cognitive measures, persisting throughout the study 28-day dosing and two-month follow-up period

Results continued for 8 weeks post-trial, despite the fact that there was no accumulation of the drug in the patients systems

Investigators conclude that a neurogenesis-based platform could identify promising new treatments for MDD

Proven safe in Ia healthy volunteers: 41 volunteers, escalating doses

Psychiatric clinical trial consultant: Maurizio Fava, M.D., Slater Family Professor of Psychiatry at Harvard
Medical School and Executive Vice Chair of the Department of Psychiatry at Massachusetts General Hospital

(completed October 2011),

and Ib MDD trials

FDA-Approved NSI-189/MDD Phase Ib Escalated Dosing Trial

Complete Phase Ib results presented at two psychopharmacology conferences in June 2014
Trial Completed 4Q13 (commenced June 2012):
Randomized, double-blind, placebo-controlled, multiple-dose escalating trial.
24 patients with recurrent MDD: three sets of eight patients (six treated, two placebo per set)
Escalating dose per set, daily for 28 days: 40 mg. q.d., 40 mg. b.i.d., 40 mg. t.i.d.
Two-month recovery follow-up, including MRI to monitor hippocampal volume
Secondary Phase Ib Endpoints:
Tolerability
Pharmacokinetics
Pharmacodynamic effects - hippocampal volume by MRI, BDNF/CRH/other factors in blood, urine

biomarkers, cortisol in saliva, qEEG, Montgomery-Asberg Depression Scale (MADRS), NGH Depression
Questionnaire, Columbia-Suicide Severity Rating Scale (C-SSRS)

20

Neurogenic NSI-189/MDD Phase Ib: All Depression Measures

Show Clinically Meaningful Improvement For Duration of Trial
Data Shows First-time Depression Field Findings: large and significant effect size of antidepressant activity,
which continued eight weeks after treatment stopped
Large effect was seen in all four commonly used scales employed in the study: SDQ, MADRS, CGI-I and CPFQ
Effect size is a statistical term measuring the overall effect of the treatment; a value above .80 is considered
to be a large effect
SDQ data: Combined treatment group showed statistically significant improvement (p=0.02) after 28 days of
NSI-189 treatment compared to randomized, double-blind, placebo control group. Large effect size of 0.90

Montgomery and Asberg Depression Rating Scale

Day 84

Day 28
Symptoms of Depression Questionnaire

3.8

p=0.02
d=0.90

3.6

p=0.03
d=1.10

3.4
3.2
3.0
2.8
2.6
Placebo
NS-189
NS-189 1x per day
NS-189 2x per day
NS-189 3x per day

2.4
2.2
2.0
-20

20

40

60

80

Study Day

Symptoms of Depression Questionnaire (SDQ)

100

Day 84

Day 28
30

p=0.09
d=0.95

p=0.19
d=0.84

25

20

15
Placebo
NS-189
NS-189 1x per day
NS-189 2x per day
NS-189 3x per day

10

5
0

20

40

60

80

100

Study Day

Montgomery-Asberg Depression Rating Scale (MADRS)

All: A Phase 1B, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Escalation Study Evaluating the Effects of NSI-189 Phosphate,
a Neurogenic Compound, in Patients with Major Depressive Disorder (MDD), presented June 2014, by Maurizio Fava, M.D., Karl Johe, Ph.D., Lev G. Gertsik, MD,
Larry Ereshefsky, PharmD, Bettina Hoeppner, Ph.D., Martina Flynn, David Mischoulon, M.D., Ph.D., Gustavo Kinrys, M.D., and Marlene Freeman, M.D.

21

Neurogenic NSI-189/MDD Phase Ib: All Cognitive Measures

Show Clinically Meaningful Improvement for Duration of Trial
In addition to its antidepressive effects, NSI-189 showed a significant effect size in cognitive function
improvement; cognitive improvement also continued for eight weeks after the last dose
As measured by CPFQ, the assessment scale of cognitive and functioning deficits specifically designed for
depressed patients, the NSI-189 treatment group was significantly better than the placebo group (p=0.01) at
Day 28. Large effect size of 0.94
Effect size is a statistical term measuring the overall effect of the treatment; a value above .80 is considered
to be a large effect

Clinical Global Impression Scale

Improvements

p=0.09
d=1.13

p=0.22
d=0.57

Placebo
NS-189
NS-189 1x per day
NS-189 2x per day
NS-189 3x per day

1
0

20

40

60

80

Study Day

Clinical Global Impression Improvement (CGI-I)

Day 84

Day 28

Day 84
Cognitive and Physical Functioning Questionnaire

Day 28

100

5.0

p=0.01
d=0.94

p<0.01
d=1.20

4.5

4.0

3.5

3.0
Placebo
NS-189
NS-189 1x per day
NS-189 2x per day
NS-189 3x per day

2.5

2.0
-20

20

40

60

80

100

Study Day

Cognitive and Physical Functioning Questionnaire (CPFQ)

All: A Phase 1B, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Escalation Study Evaluating the Effects of NSI-189 Phosphate,
a Neurogenic Compound, in Patients with Major Depressive Disorder (MDD), presented June 2014, by Maurizio Fava, M.D., Karl Johe, Ph.D., Lev G. Gertsik, MD,
Larry Ereshefsky, PharmD, Bettina Hoeppner, Ph.D., Martina Flynn, David Mischoulon, M.D., Ph.D., Gustavo Kinrys, M.D., and Marlene Freeman, M.D.

22

Neurogenic NSI-189/MDD Phase Ib: All Depressive and Cognitive

Measures Show Clinically Meaningful Improvement for Duration of Trial

Quantitative EEG (qEEG) measurements,

an electrophysical biomarker of depression, showed:
Significantly increased brain wave patterns in the
hippocampal region of the brain
Increased electrical coherence in the prefrontal cortical
region, which is a pro-cognitive signal

Researchers concluded that these electrophysiological

changes are consistent with the neurogenic hypothesis
of the drug mechanism, which involves long-term
structural changes in the hippocampus

EEG Analysis: High-frequency Alpha at Day 28

qEEG measurements at Day 28 showed statistical

significance between the treatment and the placebo
group in the electrical wave patterns emanating from
specific areas of the brain, namely the left posterior
temporal lobe and parietal region (p<0.02)

High-frequency alpha at Day 28: 10-12 Hz

A Phase 1B, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Escalation Study Evaluating the Effects of NSI-189 Phosphate,
a Neurogenic Compound, in Patients with Major Depressive Disorder (MDD), presented June 2014, by Maurizio Fava, M.D., Karl Johe, Ph.D., Lev G. Gertsik, MD,
Larry Ereshefsky, PharmD, Bettina Hoeppner, Ph.D., Martina Flynn, David Mischoulon, M.D., Ph.D., Gustavo Kinrys, M.D., and Marlene Freeman, M.D.

23

Neuralstem Strengths and Future Value Drivers

NSI-566:

NSI-189:

Scientific Strength,
Out In Front

Clinical Trial
Advancements

Breakthrough Year,
Novel Neurogenics

Leader: neural stem cell science

Repeated firsts in both
divisions, including FDA approval:
ALS & SCI cell therapy trials
MDD first novel neurogenic
compound
Technology platform R&D
developed at NIH

FDA-approved ALS Phase II,

completed final surgeries in July
2014, 6-mo. observation
FDA-approved cSCI Phase I
commenced surgeries at UCSD in
September 2014

Broad, sustainable, worldwide

IP protection

24

Stroke Phase I/II treatments

initiated in China in Dec. 2013
Acute SCI IND expected 2014,
for Phase I/II trial in S. Korea
ALS Phase I/II in Mexico in
development

Phase II MDD application, trial

commencement expected late
1Q15
Phase Ib MDD data results,
reported June 2014, show
clinically meaningful improvement
across all depressive and
cognitive measures for duration
of trial
Multiple Phase II trial-ready
hippocampus-atrophy applications

Appendix

25

Management
Patents: Technology and Products
Proprietary Surgical Devices: Cell Therapy
Published Papers
World-Class Clinical Partners

Management: Dedicated, Driven Team

Karl Johe, PhD, Chairman of the Board and Chief Scientific Officer

Discovered and developed human neural stem cell technology, while at NIH

Successful neural stem cell therapy is career-long goal

Early work for four years as staff scientist at the NIH Laboratory of Molecular Biology of the National
Institute of Neurological Disorders and Stroke in Bethesda (1993-1997)

Education: Post Doctoral, Molecular Genetics, University of California San Francisco; Ph.D., Biochemistry,
Albert Einstein College of Medicine: Masters and B.A., Chemistry, University of Kansas

Richard Garr, JD, President and CEO

Teamed legal and business expertise with friend Karl Johes science background to co-found Neuralstem
(1996)

Focus on the business of science for 18 years; corporate legal, regulatory and patent experience

Previous corporate and commercial law practice: Beli, Weil & Jacobs, the B&G Companies, and Circle
Management Companies

Education: J.D., Columbus School of Law, The Catholic University of America; B.A., Psychology, Drew
University

Co-founder and Director, First Star Foundation; Mid-Atlantic Chapter Co-founder, The Starlight Foundation;
Former Honorary Chairman, Brain Tumor Society

Thomas G. Hazel, PhD, Senior Vice President

Served as Neuralstems Stem Cell Discovery Program Director, 2000-2004; Senior Scientist, 1998-2000

Staff Scientist at the NIH Laboratory of Molecular Biology of the National Institute of Neurological Disorders
and Stroke in Bethesda (1996-1998); IRTA fellow (1993-1996)

Education: Ph.D., Genetics, University of Illinois College of Medicine; B.A., Biology, Kalamazoo College

26

Technology & Product U.S. Patents Issued and Reaffirmed Worldwide

27

U. S. Pat. No. 8,674,098 (March 2014)

Compositions to Effect Neuronal Growth
U. S. Pat. No. 8,460,651 (June 2013)
Methods for treating ALS with expanded spinal cord stem cells
U. S. Pat. No. 8,362,262 (January 2013)
Compositions to Effect Neuronal Growth
U. S. Pat. No. 8,293,488 (October 2012)
Method for discovering neurogenic agents
U. S. Pat. No. 8,236,299 (August 2012)
Transplantation of human neural cells for
treatment of neurodegenerative conditions
U.S. Pat. No. 8,058,434 (November 2011)
Compositions to effect neuronal growth
U.S. Pat. No. 8,030,492 (October 2011)
Compositions to effect neuronal growth
U.S. Pat. No. 7,691,629 (April 2010)
Neuralstem.com Live Map Includes Worldwide I.P.
Transplantation of human neural cells for
treatment of neurodegenerative conditions
U.S. Pat. Nos. 7,560,553 and 7,858,628 (July 2009, December 2010)
Use of fused nicotinamides to promote neurogenesis
U.S. Pat. No. 7,544,511 (June 2009)
Stable neural stem cell line methods
U.S. Pat. No. 6,284,539 (September 2001)
Method for generating dopaminergic cells derived from neural precursors
U.S. Pat. No. 6,040,180 (March 2000)
In vitro generation of differentiated neurons from cultures of mammalian multipotential CNS stem cells
U.S. Pat. No. 5,753,506 (May 1998)
Isolation propagation and directed differentiation of stem cells from embryonic and adult central nervous system of mammals
8 U.S. Patents Pending; 65 International Issued Patents; 50 International Patents Pending
Exclusive License to 3 U.S. Issued Patents; 5 International Issued Patents; 1 International Patent Pending

Exclusive Worldwide Licenses: Breakthrough Cell Therapy

Surgical Devices
Spinal Platform and Floating Cannula
Proprietary breakthrough medical devices proven safe in 18 surgeries
New standard in industry and research community for intraspinal

procedures
Designed by ALS trial neurosurgeon, Nicholas M. Boulis, M.D.,

specifically for the world's first delivery of cells directly into the
gray matter of the spinal cord
Safety of device first reported in data presented at the American Association

of Neurologists' 2011 Annual Meeting

Patent-protected:

U.S. Patent No. 8,092,495 (January 2012)

Spinal Platform and Method for Delivering a Therapeutic Agent to a Spinal Cord Target

U.S. Patent No. 7,833,217 (November 2010); U.S. Patent No. 8,708,962
(April 2014)
Floating Spinal Cannula and Method of Use

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Published Papers

Effects of NSI-189, a neurogenic compound, on quantitative electroencephalography (qEEG) in patients with major
depressive disorder (MDD) during a phase 1b randomized, double-blind, placebo controlled, multiple ascending dose
study

A Phase 1B, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Escalation Study Evaluating the Effects of
NSI-189 Phosphate, a Neurogenic Compound, in Patients with Major Depressive Disorder (MDD)

Naoki Tajiri, David M. Quach, Yuji Kaneko, Stephanie Wu, David Lee, Tina Lam, Ken L. Hayama, Thomas G. Hazel, Karl Johe, Michael C. Wu, Cesar
V. Borlongan

PLOS ONE, March 10, 2014, DOI: 10.1372/journal.pone.0091408.

Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: Phase 1 trial outcomes.

Eva L. Feldman MD, PhD, Nicholas M. Boulis MD, PhD, Junguk Hur PhD, Karl Johe PhD, Seward B. Rutkove MD, Thais Federici PhD, Meraida Polak
RN, Jane Bordeau RN, Stacey A. Sakowski PhD and Jonathan D. Glass MD

Annals of Neurology, March 2014.

Transplantation of human fetal-derived neural stem cells improves cognitive function following cranial irradiation

Acharya, M. M.; Christie, L-A.; Hazel, T. G.; Johe, K. K.; Limoli, C. L.

Cell Transplantation: The Regenerative Medicine Journal, E-Pub August 2013.

Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human
neural stem cell transplantation

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Maurizio Fava, MD, Karl Johe, PhD, Lev G. Gertsik, MD, Larry Ereshefsky PharmD, Bettina Hoeppner, PhD, Martina Flynn, David Mischoulon, MD, PhD,
Gustavo Kinrys, MD, and Marlene Freeman, MD
American Society of Clinical Psychopharmacology (formerly NCDEU), Abstract posted May 23, 2014, in advance of oral presentation at ASCP Annual
Meeting: June 17, 2014.

Behavioral and Histopathological Assessment of Adult Ischemic Rat Brains after Intracerebral Transplantation of NSI566RSC Cell Lines

Brett English, PharmD, PhD, Jack Johnstone, PhD, Karl Johe, PhD, Lev Gertsik, MD, Molly Sherman, Maurizio Fava, MD Larry Ereshefsky, PharmD
The International College of Neuropsychopharmacology (CINP), Abstract posted June 17, 2014, in advance of presentation at 29 th CINP World
Congress of Neuropsychopharmacology: June 24, 2014.

Sebastiaan van Gorp, Marjolein Leerink, Osamu Kakinohana, Oleksandr Platoshyn, Camila Santucci, Jan Galik, Elbert A. Joosten, Marian HruskaPlochan, Danielle Goldberg, Silvia Marsala, Karl Johe, Joseph D. Ciacci, Martin Marsala
Stem Cell Research and Therapy, Volume 4, Issue 5 (4.57), May 28, 2013.

Published Papers

Long-Distance Growth and Connectivity of Neural Stem Cells after Severe Spinal Cord Injury

Lumbar Intraspinal Injection of Neural Stem Cells in Patients with ALS: Results of a Phase I Trial in 12 Patients

Cizkova D, Kakinohana O, Kucharova K, Marsala S, Johe K, Hazel T, Hefferan MP, Marsala M, Institute of Neurobiology, Centrum of Excellence,
Slovak Academy of Science, Kosice, Soltesovej 4, Slovakia.
Neuroscience, 2007 Jun 29;147(2):546-60. Epub 2007 May 23.

Combined immunosuppressive agents or CD4 antibodies prolong survival of human neural stem cell grafts and improve
disease outcomes in amyotrophic lateral sclerosis transgenic mice

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Yan J, Xu L, Welsh AM, Hatfield G, Hazel T, Johe K, Koliatsos VE, Department of Pathology, Division of Neuropathology, The Johns Hopkins Medical
Institutions, Baltimore
PLoS Medicine, 2007 Feb;4(2):e39.

Functional recovery in rats with ischemic paraplegia after spinal grafting of human spinal stem cells

Xu L, Ryugo DK, Pongstaporn T, Johe K, Koliatsos VE, Department of Pathology, Division of Neuropathology, The Johns Hopkins Medical Institutions,
Baltimore
The Journal of Comparative Neurology, 2009 Jun 1;514(4):297-309.

Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord

Glass JD, Boulis NM, Johe K, Rutkove SB, Federici T, Polak M, Kelly C, Feldman, EL, Department of Neurology, Emory University School of Medicine,
Atlanta
Stem Cells, 2012 Jun;30(6):1144-51.

Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into
the segmental motor circuitry

Paul Lu, Yaozhi Wang, Lori Graham, Karla McHale, Mingyong Gao, Di Wu, John Brock, Armin Blesch, Ephron S. Rosenzweig, Leif A. Havton,
Binhai Zheng, James M. Conner, Martin Marsala, Mark H. Tuszynski
Cell, Volume 150, Issue 6, 14 September 2012, Pages 1264-1273.

Yan J, Xu L, Welsh AM, Chen D, Hazel T, Johe K, Koliatsos VE, Department of Pathology, Neuropathology Division, The Johns Hopkins University
School of Medicine, Baltimore
Stem cells (Dayton, Ohio), 2006 Aug;24(8):1976-85. Epub 2006 Apr 27.

World-Class Clinical Partners

NSI-566/ALS Trial Clinical Investigators:

Principal Investigator: Eva L. Feldman, M.D., Ph.D., Professor of Neurology & Director A. Alfred Taubman Medical Research
Inst. of the University of Michigan Medical School; President of American Neurological Assn.
Site Principal Investigator: Jonathan D. Glass, M.D., Professor of Neurology & Director Emory ALS Center, Emory University
Co-Investigator & Neurosurgeon: Nicholas M. Boulis M.D., Assist. Professor Neurosurgery, Emory University
NSI-566/ALS Trial Advisory Board:
Zachary Simmons M.D., Chairman, SMB, Professor of Neurology Penn State University Hershey Medical Center and Director Neuromuscular
Program and ALS Center
Mark Bromberg M.D., Ph.D. Professor of Neurology & Director of the Motor Neuron Disease/ALS Clinic University of Utah School of Medicine
Lucie Bruijn, Ph.D., Chief Scientist & Sr. VP of Research and Development ALS Association
Thomas Freeman M.D., Professor, Dept of Neurosurgery & Medical Director, Center for Aging and Brain Repair University of South Florida
College of Medicine
Clifton L. Gooch, M.D., Professor & Chairman Department of Neurology & Director Division of Neuromuscular Disease University of South Florida
College of Medicine
Hiroshi Mitsumoto M.D., D.Sc., Professor of Neurology Columbia University & Director of the Eleanor and Lou Gehrig MDA/ALS Research Center
and Neuromuscular Division at the Neurological Institute of New York
Paul Park M.D., Assistant Professor & Neurosurgeon University of Michigan School of Medicine
Mike Vogelbaum M.D., Ph.D., Associate Director, Brain Tumor and Neuro-Oncology Center Cleveland Clinic
NSI-566/Glioblastoma (Brain Cancer)

Principal Investigator: John Zhang, M.D., Ph.D., Professor of Neurosurgery, Loma Linda University, CA

Charles L. Limoli, Ph.D., Professor of Radiation Oncology, School of Medicine, University of California, Irvine

NSI-566/Spinal Cord Injury Lead Collaborator Martin Marsala, M.D., Ph.D., University of California, San Diego
NSI-189/Psychiatric/Small Molecule Trial Consultant Maurizio Fava, M.D., Slater Family Professor of Psychiatry at Harvard Medical

School and Executive Vice Chair of the Department of Psychiatry at Massachusetts General Hospital

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