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A Placebo-Controlled Phase I Study of

NVG-291 in Healthy Subjects,

Targeting CNS Receptor Protein Tyrosine Phosphatase Sigma (PTPσ)

Key words:

Receptor Protein Tyrosine Phosphatase sigma (PTPσ) Chondroitin Sulfate Proteoglycans (CSPGs)

Daniel Mikol, Betty Lawrence, Nana Collett, Judy Toews, Matvey Lukashev, Marc DePaul

Disclosures:

All authors are employees or consultants of NervGen

3 April 2022

1

Disclosure Statement

This document may contain "forward-looking information" and "forward-looking statements" within the meaning of applicable Canadian and United States securities legislation. Many factors could cause NervGen's actual results, level of activity, performance or achievements or future events or developments to differ materially from those expressed or implied by the forward-looking statements including factors set forth in the NervGen's filings on SEDAR which can be found onwww.SEDAR.com. Readers should not place undue reliance on forward-looking statements made within this document. Furthermore, NervGen has no intention and undertakes no obligation to update or revise any forward-looking statements except as required by applicable law.

2022

Timeline of Important Discoveries Relevant to Chondroitin Sulfate Proteoglycans (CSPGs) and PTPσ

The glial scar14

CSPG

Core Protein

Glycosaminoglycan

1985

Improved outcomes in animal models of SCI following injection of chondroitinase-ABC into

SCI lesion7

1989

1993

1997

2001

CSPGs identified in human perineuronal net (PNN) 3

CSPGs found in plaques, neurofibrillary tangles of Alzheimer's disease4

CSPGs identified in brains of patients with

Parkinson's disease, diffuse Lewy body disease, Pick's disease, progressive supranuclear palsy,

Huntington's disease5

CSPGs identified in demyelinating lesions of multiple sclerosis6

PTPσ: Receptor Protein Tyrosine Phosphatase sigma CSPGs: Chondroitin Sulfate Proteoglycans

• 1. Ramon y Cajal, Oxford UP, 1928

• 2. Snow et al., Exp. Neurol, 1990

• 3. Bertolotto et al., J Neurosci Res, 1991

• 4. DeWitt et al., Exp. Neurol., 1993

• 5. DeWitt et al., Brain Research 1994

  CSPGs of the PNN regulate criticalperiods of plasticity 8

• 6. Sobel and Ahmed, J Neuropathol Exp Neurol, 2001

PTPs identified as receptor mediating inhibitory effects of CSPGs9

Limited axonal regrowth through glial scar identified by Ramon y Cajal as clue to basis for lack of repair in spinal cord injury (SCI)1

2005

2009

PTPσ expressed by neurons, oligodendrocytes (OLG), OLG precursors, astrocytes, neural stem cells, microglia; when activated, PTPσ inhibits axonal sprouting, synaptic plasticity, OLG precursor differentiation, remyelination10,11,12

• 7. Bradbury et al., Nature, 2002

• 8. Pizzorusso et al., Science 2002

• 9. Shen et al., Science 2009

Efficacy in SCI model using NVG-291-R

(rodent analogue)13

2013

2017

Demonstration of NVG-291 in CNS of rat within 1 hour of SQ administration13

NervGen formed

• 10. Kirkham et al., BMC Neurosci, 2006

• 11. Luo et al., Nature Comm, 2018

• 12. Dyck et al., J Neuroinflamm, 2018

1st human subject receives NVG-291

2022

2021

Phase 1 study complete

TODAY

10. 11. 12.

D D D

• 13. Lang et al., Nature 2015

• 14. Tran et al., Physiol Rev, 2018

NVG-291, A Peptide Mimetic of the PTPs Wedge Domain

Reverses CSPG-Mediated Inhibition of Repair

Mimetic of the intracellular wedge domain of PTPs, which regulates its phosphatase activity

h RhoA

i Erk

i Akt

CNS Injury (upregulation of CSPGs)
Vehicle	+ NVG-291
Intracellular signaling	h RhoA i Akt i Erk	i RhoA h Akt h Erk
Biological effects	i axonal growth i remyelination i plasticity	h axonal growth h remyelination h plasticity

NVG-291:

"TAT" tag (10 amino acids)

PTPs wedge domain (25 amino acids)

• • NVG-291-R = rodent version of NVG-291 (differ by 1 amino acid)

• • In different animal models of CNS damage, NVG-291-R has demonstrated the ability to overcome the inhibitory effects of CSPGs

  • ‒ Reversing intracellular signaling changes induced by CSPGs

  • ‒ Promoting

    • ▪ Axonal Regeneration

    • ▪ Remyelination

    • ▪ Plasticity

  • ‒ Enabling functional recovery

• h activation

• i deactivation

PTPσ: Receptor Protein Tyrosine Phosphatase sigmaCSPGs: Chondroitin Sulfate Proteoglycans

NVG-291-R Improves Functional Recovery in Animal Models of CNS Damage

Spinal Cord Injury

BBB Score

9

0

1

3

6

Weeks after SCI

12

Micturition recovery

Vehicle

Rink et al., Exp Neurol 2018

Lang et al, Nature 2015

NVG-291-R

CNS Demyelination

Improvement in EAE clinical scores

EAE + Vehicle

Behaviour

+Veh daily

EAE + NVG-291-R at Onset

Behaviour

+NVG-291-R daily after clinical onset

EAE + NVG-291-R at Peak

Behaviour

+NVG-291 daily after clinical score 3

Visual recovery in optic chiasm lesion

Luo et al, Nature Communications, 2018

Visual Cliff Test

Niknam et al, Molecular and Cellular Neuroscience, 2019

Stroke

Sensorimotor Recovery

Adhesive Removal Test

Time to remove (s)

Number of Errors

Cognitive recovery

BaBrnarenes MMazaeze

15

10

5

0

Vehicle

NVG-291-R

Unpublished data provided by Dr. Agnes Luo, University of Cincinnati