Epidermolysis Bullosa InMed Pharmaceuticals Development Program

November 2015

Designing Intelligent Medicines

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Forward Looking Statements

This presentation contains forward-looking statements, including statements concerning anticipated clinical development activities, the potential benefits of product candidates and anticipated market opportunities. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These statements are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements.

These risks and uncertainties include, among others, the possibility that clinical trials will not be successful, or be completed, or confirm earlier clinical trial results, risks associated with obtaining funding from third parties, risks related to the timing and costs of clinical trials and the receipt of regulatory approvals, and the risk factors set forth in the company’s filings with the CSE. The company undertakes no obligation to update the forward-looking statements contained herein or to reflect events or circumstances occurring after the date hereof.

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Epidermolysis Bullosa – Disease Overview

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• Epidermolysis Bullosa (EB) is group of inherited connective tissue diseases that share a common manifestation of faulty protein anchors in the skin that result in extremely fragile skin that blisters or tears from friction or trauma

• Each type and sub-type of the disease is classified based on phenotype, mode of inheritance, and phenotype

• Over 300 mutations have been identified in EB in any one of the 18 genes that have been found to cause the disorder

• Currently, EB is separated into four major subtypes based on where the blisters arise in the skin:

• Epidermolysis Bullosa Simplex (EBS) – Blisters arise with the epidermis • Junctional EB (JEB) – Blisters arise within the lamina lucida • Dystrophic EB (DEB) – Blisters arise beneath the lamina densa • Kindler EB (KEB) – Blisters arise at various levels within the skin

• In addition to the inherited forms of the disease there is also an autoimmune form of the disease called epidermolysis bullosa acquisita

Epidermolysis Bullosa - Pathophysiology

• The human skin consists of two major layers: – an outermost layer called the epidermis, and

– a layer underneath called the dermis

• In individuals with healthy skin, there are protein anchors between these two layers that prevent them from moving independently from one another (shearing).

• In people born with EB, the two skin layers lack the protein anchors that hold them together, resulting in extremely fragile skin. EB is caused by mutations involving at least 18 genes encoding structural proteins within keratin intermediate filaments, focal adhesions, desmosome cell junctions, and hemidesmosome attachment complexes, which form the intraepidermal adhesion and dermoepidermal anchoring complex within the basement membrane zone (BMZ) of the skin and mucosae.

– The different categories of EB are characterized by dysfunction in different structural proteins

• As a result of the protein dysfunction, even minor mechanical friction (like rubbing or pressure) or trauma will separate the layers of the skin and form blisters and painful sores. Sufferers of EB have compared the sores with third-degree burns. Furthermore, as a complication of the chronic skin damage, people suffering from EB have an increased risk of malignancies (cancers) of the skin

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Pathophysiology and Major Categories

Major EB Type Layer of Blistering Major EB Subtypes Protein Dysfunction

EB Simplex (EBS) Epidermis Basal EBS - K5, K14 - Plectin,

⍺6β4 integrin

Suprabasal EBS - desmoplakin

Junctional EB (JEB) Lamina lucida JEB Herlitz - Laminin-332

JEB, other - Laminin-332, Type XVII collagen,

⍺6β4 integrin

Dystrophic EB (DEB) Beneath the lamina densa

Dominant DEB (DDEB) - Type IV collagen

Recessive (RDEB) - Type IV collagen

Kindler EB (KEB) Throughout the skin - - Kindlin-1

EB Acquisita Beneath the lamina densa

- - Type IV collagen

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Pathophysiology and Structural Proteins

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Adapted from Medscape - Epidermolysis Bullosa Clinical Presentation, Author: M Peter Marinkovich, MD; Chief Editor: William D James, MD

EB – Clinical Manifestations

The hallmark feature of EB is mechanical fragility. This is invariably associated with the development of blisters • In most forms of EB, the blisters (or erosions) are filled with clear colorless

exudate, or they may be hemorrhagic • The blistering and sores can be painful. In many cases, they leave scars

when they heal. • The wounds heal slowly and can become infected • Although the blisters often form on the hands and feet, it's not uncommon

for them to develop on other parts of the body as well, such as the buttocks or inner thighs, after they've been subjected to friction during activities

• Excessive sweating can make the blisters worse • In severe cases, a child can develop up to 200 blisters in a single day

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Other primary findings include: • Milia present as tiny firm white papules • Nails becoming thickened and yellowish, and sometimes

with abnormal convex curvature • Exuberant granulation tissue, defined as moist, red friable

plaques • Alopecia of the scalp • Congenital Absence of the skin (CLAS) • Albopapuloid lesions • Keratodermas

Secondary lesions include: • Atrophy

• Scaring

• Pigmentary abnormalities

• Webbing

• Contractures

Epidermolysis Bullosa – Current Therapies

Currently treatment is similar to treatment given to burn victims: • non-adherent bandages,

dressings and antiseptic washes for the blisters

• various medications for pain, itching and inflammation

• oral antibiotics for infections; preventative treatments such as aluminum chloride and botulinum toxin type A to prevent sweating

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INM-750: Development Rationale

In designing a treatment for Epidermolysis Bullosa, InMed is seeking to:

• Modify the course of the disease by restoring the anchoring function that has been lost due to dysfunctional proteins.

– InMed is focusing specifically on restoring function in patients with epidermolysis bullosa simplex (EBS), where the the defective or absent structural proteins are keratin 5 (K5) and keratin 14 (K14)

– EBS is the most common from of the disease, accounting for approximately 70% of all EB patients. Most cases of EBS (75%) are due to dominantly-acting mutations in K5 or K14

• Treat the symptoms of the disease for all patients with EB, with a specific focus on healing the blisters that form as a result of mechanical friction

– InMed’s focus on selecting cannabinoids in its final product is to expedite wound healing, skin regeneration, and to provide an anti-inflammatory effect

– Secondarily, Cannabinoids are known to be active pain modulation and , and anti-itching.

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INM-750 and Disease Modulation in EBS

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The Role of Keratin’s in Structural Integrity of the Skin

• Keratins are a family of 30 proteins. They are the most abundant structural proteins in the cytoplasm of epithelial cells, in which they form a network of 10–12 nm wide intermediate filaments (IFs)

• Keratin proteins are encoded by a large family of conserved genes, numbering ~54 in the human genome that partition to the type I and II subgroupings of IF-encoding genes. There are 28 type I (K9–K28; K31–K40) and 26 type II (K1–K8; K71–K86) genes, each coding for one polypeptide chain. Type I proteins tend to be smaller (40–64 kDa) and more acidic (pI ~4.7–6.1) than the larger (52–70 kDa) and basic-neutral (pI ~5.4–8.4) type II proteins

• Keratin polymerization obligatorily begins with formation of coiled-coil heterodimers involving one type I and one type II protein. This contributes to the structure and strength of the cytoskeleton.

• The regulation of keratin genes, individually or as pairs, depends upon the type of epithelia, stage of cellular differentiation, and context (such as disease)

• The keratinocytes in the mitotically active basal layer of the epidermis always express K5, K14 and K15. Upon commitment of the keratinocyte to differentiation, it will down-regulate K5/K14/K15 transcription and activate expression of a new set of keratin pairs that vary among stratified tissues. For example, in cornified epithelia, such as those covering skin and gingivae, the differentiating keratinocytes express K1/K10

• K6, K16 and K17 are induced, generally at the expense of other keratins, in the post-mitotic layers of interfollicular epidermis under conditions of environmental challenges (e.g., tissue injury, UV exposure, viral infection)

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Keratin Dysfunction in EBS

The Role of K5 and K14 in EBS • The vast majority of EBS cases (75%) are due to mutations affecting either K14 or K5 which are type I and II

intermediate filament (IF) genes selectively expressed in basal keratinocytes in the epidermis and related complex epithelia

• Because of the complex substructure of keratin filaments, the perturbations engendered by mutations altering the primary structure of either K5 or K14 proteins for the structure, organization and/or regulation of filaments can range from the very subtle to the very severe, thereby accounting for a substantial fraction of the broad clinical spectra typifying EBS

The Potential of Compensatory Keratin’s (Taken from Colombe et al, J Invest Dermatol. 2012 March)

• The lesser degree to which the esophagus is affected relative to epidermis in newborn K14 null mice correlates with higher levels of K15, a type I keratin related to K14, in this tissue.

• The presence of small amounts of K15 likely accounts for the markedly more severe blistering of skin, and earlier death, in K5 null relative to K14 null mice.

• A compensatory role for K15 was also proposed based on studies of individuals with EBS whose genome bear the equivalent of a K14 null mutation (Chan et al., 1994a; Jonkman et al., 1996).

• Later on, the targeted expression of K16, another type I keratin homologous to K14, in basal keratinocytes of the epidermis was shown to markedly attenuate skin blistering and prevent neonatal death in K14 null mice (Paladini and Coulombe, 1999)

These findings support the notion that highly homologous keratins are partially redundant in their structural support role in vivo, and paved the way for a search for compounds that would, upon topical application, provide therapeutic relief as a result of the selective induction of a compensatory program of gene expression

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• The most common cause of skin fragility in EBS is the dysfunction of either K5 or K14

• Evidence from the difference in keratin expression at different parts of the body suggest that there is some redundancy in the function of keratins, and that up regulation of certain keratins may be able to compensate for the loss of function from K5, or K14 – Specifically, up regulation of K15, and K16 are expected to provide

compensatory function

• InMed will thus seek to modulated the course of the disease in EBS patients by: – Down regulating the potential dysfunctional keratins, K5 and K14 – Up regulating the potential compensatory keratins, K15 and K16

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InMed’s Approach to Disease Modulation for EBS

InMed’s In vitro Testing Methodology for Keratin Expresssion

• Cell culturing – Testing in immortalized keratinocyte cell lines, cultured in medium,

and supplemented with various solutions – Cultured at 37 C, medium changed every day

• Expression of Keratins – qPCR was used to identify mRNA expression for K5, K6, K14, K15, K16

and K17 – As internal control expression of peptidyl-propyl isomerase A (PPIA),

glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and actin beta (ACTB)

– The amount of the transcript was normalized to those of a housekeeping gene using the ΔCT method

• Multiple cannabinoids were tested at 0.1 µM, 1.0 µM and 10 µM • Cells were tested in both the proliferation and differentiation stage

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Regulation of Keratins (K5, K15 & K14) by Individual Cannabinoids - Example of study results

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INM-505, and INM-506 are internal InMed codes for specific cannabinoids

Summary of Results on Keratin Regulation

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Keratins INM-509 (µM) INM-505 (µM) INM-506 C (µM) INM-513 (µM)

0.1 1.0 10 0.1 1.0 10 0.1 1.0 10 0.1 1.0 10

K5 P ⬇ - - - - ⬇ - - ⬇ - -

D - - - - - - - - ⬇ ⬇ ⬇ ⬇

K14 P ⬇ - - - - ⬇ - - ⬇ - - ⬇

D - - - - - ⬇ - - ⬇ - - ⬇

K15 P ⬇ ⬆ ⬆ ⬆ - ⬆ ⬆ ⬆ - ⬆ ⬆ ⬆

D - - ⬆ - ⬇ - - ⬇ ⬇ - - -

K16 P - - - - - ⬇ - - ⬇ ⬆ - -

D - - - - ⬇ ⬇ - - ⬇ - - -

Summary of the effects of phytocannabinoids on the expressions of K5/K14/K15/K16 at both proliferation (P) and differentiation (D) stages in human epidermal keratinocytes. Cells with the background of light green indicate the effect of phytocannabinoids we prefer to treat EBS. ↓: down-regulated; ↑: up-regulated

INM-750 and Symptom Management in EB

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The Endocannabinoid System and the Skin

Endocannabinoids and cannabinoid receptors have been implicated in multiple regulatory systems in the skin

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↓ Proliferation

Secretory

activity

Melanogenesis

↓ Inflammation

↓ Degranulation

Barrier recovery

Fibrosis

↓ Fibrosis

Non-CB1 /CB2

Fibroblasts

CB1

Mast cells

CB1

CB2

CB1

Sweat glands

Epidermis

CB1 / CB2

CB1

AEA

2-AG

↓ Pain

↓ Itch

Sensory nerves

↓ Barrier recovery

Sebaceous

glands

CB1 / CB2

CB2

Hair follicles

CB1

Lipid synthesis

Apoptosis

↓ Hair growth

Catagen

Production

Effect

Proliferation Differentiation Inflammation Apoptosis

Potential Role of Cannabinoids in Symptom Regulation of EB

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EB Hallmark Pharmacological Action of Phyto-Cannabinoids

Wound Healing and Skin Regeneration

• The CB1 receptor is known to be involved in the keratinocyte migration, and thus it is postulated that cannabinoids can aid in wound healing

Anti-inflammation • Activation of cannabinoid 2 (CB2) receptors on mast cells have an anti-inflammatory effect

• Cannabinoids can effectively attenuate contact inflammation by decreasing keratinocyte derived pro-inflammatory mediators

• Cannabinoids suppress the expression of IL6 at both the protein and mRNA level

Anti-itching • Cannabinoids receptors are expressed on skin nerve fibers and may have a role in pruritus • Topical cannabinoid agonists have been demonstrated to reduce itching

Anti-microbial • Cannabinoids have been shown to have anti-microbial effects on a variety of gram-positive, gram-negative and acid fast bacteria

Pain-Killing • Inflammation is known to increase cannabinoid 1 (CB1) receptors in afferent neurons and increase sensitivity to pain

• Cannabinoid receptors have been demonstrated to bind to the CB1 receptor and produce anti-nociceptive effects

In designing INM-750 InMed has placed priority on selecting cannabinoids that have a positive effect on wound healing and skin regeneration and that will have an anti-inflammatory effect

INM-750 and Wound Healing and Skin Regeneration

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The ECIS - Wound Healing Assay

Electric Cell-substrate Impedance Sensing (ECIS) Wounding Assay

• The ECIS Wound Healing Assay replaces the

traditional "scratch" or "scrape" assay. Instead of disrupting the cell layer mechanically with a toothpick, needle or pipette tip and following the migration of cells to "heal" the wound with a microscope, ECIS employ electric signals to both wound and monitor the healing process. ECIS electrical wounding is only directed at the small population of cells in contact with the active 250 micrometer diameter ECIS electrode, producing a well defined 250 micrometer wound that can be verified both with the ECIS measurement and with vital staining. Unlike the traditional scrape method, with the ECIS Wound the protein coating is unaffected by the current, it remains fully intact. Once ECIS electrically wounds the cells, it returns to its normal mode to immediately follow the healthy neighboring cells as they migrate inward to replace the killed cells.

• This assay was used to to test the effect of individual cannabinoids on wound healing for both an acute, and chronic wound healing

• Chronic wound healing is the most reflective model for EB treatment

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Example of skin regeneration under treatment of cannabinoids

(click on image and press play)

INM-505 and INM-517 Accelerate Wound Closure by Human Keratinocytes In Vitro (Chronic Wound Healing Process)

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T1 Confluent monolayer

Treatments Applied

20 hours

INM-505 and INM-517 are internal InMed codes for specific cannabinoids

• “Confluent monolayer” represents the closing of the skin layer on the test medium • “Norm. Resistance” is a measure of the percent coverage of the cells over the

electrode after injury

INM-750 and Wound Healing - Effect on MCP-1

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INM-505 is an internal InMed code for a specific cannabinoid

• MCP-1 attracts blood monocytes and macrophages to skin wound area and plays critical role in normal skin homeostasis and wound healing process

• MCP-1 supports traffic and activation of Langerhance Cells and Macrophages strengthening innate (anti-infectious) immunity.

• INM-505 (a specific cannabinoid) increases MCP-1 production by proliferating human skin epithelial cells (keratinocytes).

INM-750 and Inflammation

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INM-750 and Inflammation

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IL-8 • IL-8 is the most potent chemoattractant for blood Neutrophils and important mediator of angiogenesis. • Chronic IL-8 production and Neutrophil activation in the skin wound is unfavourable element of skin

pathology. INM-505 (a specific cannabinoid studied by InMed) displays highly selective inhibitory effect on IL-8 production by human keratinocytes.

IL6 • IL-6 is a pro-inflammatory cytokine, and can be stimulated by IFNɣ/TNF⍺ • Certain cannabinoids can attenuate the production of IL-6 by IFNɣ/TNF⍺

• INM-750 will include several cannabinoids as its active substance. Selection of the specific cannabinoids included in the final product is based on the following criteria (in order of priority):

1. Cannabinoids that will restore the structural integrity of the skin for EBS patients by up regulating the compensatory keratins K15, and K16, and that down regulate K14

2. Cannabinoids that stimulate wound healing and skin regeneration, with priority given to efficacy as seem in ECIS Wound Healing Assay (chronic model)

3. Cannabinoids that provide an anti-inflammatory effect

• INM-750 is being developed as a topical cream, designed to maximize penetration of the cannabinoids to the dermal layer of the skin

Transdermal delivery system is being developed in collaboration with UBS, and is a novel an proprietary system based on polymer nanotechnology

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INM-750: Product Selection