Patrizia Caldirola, Ph.D., CEO

September 2013

Novel integrin receptor antagonist

Partnering Opportunity

Disclaimer

• The information and opinions in this document have not been independently verified. No representation or warranty, express or implied, is given by Clanotech AB – nor their respective directors, partners, officers, affiliates, employees, advisers or agents - as to the accuracy or completeness of the contents of this document or that the document necessarily contains such information that would be considered desirable or necessary in order to evaluate a potential investment in Clanotech AB, and assume no responsibility for the use of or relying on the information in this document.

• The information contained in this document is submitted to parties for use solely in connection with their consideration of the transaction opportunity described herein. By its acceptance hereof, the recipient agrees that neither it nor any of its employees or advisors shall use the information for any purpose other than the evaluation of the business opportunity, nor shall it divulge the information or distribute this document to any other party, in whole or in part, at any time without the prior written consent of Clanotech AB.

• This document will not constitute or form part of any offer for sale of shares in Clanotech AB, and is not to be taken as constituting the giving of investment advice by Clanotech AB.

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CLT-28643

1. Small molecule α5β1 integrin inhibitor with unique

properties and anti-angiogenic and anti-fibrotic effects

2. Therapy for maintenance of intraocular pressure

(IOP) following glaucoma surgery

3. Opportunity for treatment and prevention of wet Age

related Macular Degeneration (wAMD)

4. Possible use in both front- and back-of-eye

indications

3

Market Potential:

Glaucoma Surgery USD 590 – 960m

wAMD USD >1.5bn

Clanotech AB in Brief

• Founded in 2006 by Prof. Yihai Cao at Karolinska Institutet and Karolinska Development 2006

• Focus on development of CLT-28643 for ophthalmology

• Privately owned. Main shareholders: Karolinska Development (S) and Rosetta Capital (UK)

• Virtual company with 1FTE (Dr Patrizia Caldirola, CEO)

• Offices on campus of Karolinska Institutet, Stockholm, Sweden

Intellectual Property

• CLT-28643 composition of matter patent filed

2009

• Expiry in 2028 with possibility for extension in

Europe, USA, Japan and other countries with

legislation for patent term extensions

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CLT-28643 at a glance

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Drug target α5β1 integrin inhibitor

Properties Anti-angiogenic, anti-fibrotic, anti-inflammatory

Class Small molecule

Target indications

supported by data

Maintain IOP after Glaucoma filtration surgery

Orphan indication but market size growing

No approved drug on the EU market, Mitomycin C in USA

Market potential US$ 590m - 960m, launch 2019.

Systemic treatment of wAMD with selective accumulation in the target organs

also treating the fellow eye

Unique drug profile in a blockbuster market

No known competitors with similar product offering

Safety GLP 28 day systemic toxicology study completed

Stage First Clinical Study scheduled for 1H 2014 in Glaucoma Surgery

IP Composition of matter patent pending, priority date 2009

Other indications Diabetic eye disease, fibrotic conditions, solid tumors

CLT-28643 Lead indications

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Glaucoma surgery (subconjunctival) wAMD (non-injectable)

• Maintain IOP by preventing failure of filtering

glaucoma surgery

• Replace Mitomycin C

• ↑ bleb survival

• ↓ other medications

• Better long term safety

• 1st line co-administration with anti-VEGF

• ↑ response rate

• ↓Fellow eye involvement

• ↓ anti-VEGF injection

• ↓ fibrosis,

• ↓ RPE-atrophy

Unmet need: prolonged effect duration,

reduced number of intravitreal injections

(Lucentis required monthly), prevent fellow eye

disease, more patients achieving 20/40

Attractive features:

• Non-injectable

• Prevention of wAMD of the fellow eye too

• complementary to current therapy Lucentis

Unmet need: Safe prevention of surgical failure.

Currently used cytotoxic drugs have

unpredictable outcome and toxicity

Attractive features:

• No satisfactory drug approved today

• Large market but with orphan drug

designation‘

• Non-cytotoxic anti-fibrotic and anti-

inflammatory drug

Scientific rationale

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α5β1-integrin

• Transmembrane receptor

– inactive (quiescent cells) and active

(pathology)

– Not required for normal cell maintenance

• Fibronectin is the natural ligand

• Expressed in vascular endothelial cells,

fibroblasts, inflammatory cells, keratinocytes

• α5β1 integrin drives endothelial cell proliferation

and angiogegensis

• High expression of α5β1 integrin in proliferating

choroidal blood vessels but not in normal

vessels

• High expression of α5β1 in fibrotic scar after

glaucoma surgery

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Motility Survival Proliferation

a5b1 plays a pivotal role in pathogenic processes connected

with angiogenesis, inflammation and fibrosis

CLT-28643 - Multiple distinct actions

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VEGF bFGF Ang

/Tie2

ANGIOGENESIS

α5β1

Fibroblast activation and migration

FIBROSIS

anti-α5β1

CLT-28643

• CLT-28643 inhibits angiogenesis, fibrosis and inflammation

• essential elements in the pathology of wAMD and failure of glaucoma

filtration surgery

• CLT-28643 acts via a distinct and complementary pathway to anti-VEGFs.

CLT-28643 – Substantial Preclinical Data

• Inhibition a5b1-integrin conformational changes

leading to inhibition of migration and adhesion of

endothelial cells

• Pronounced anti-fibrotic and anti-inflammatory

effects in lung fibrosis in vivo model

• Maintains the reduction of IOP (intraocular

pressure) in rabbit after trabeculectomy over 28

days and prolongs bleb survival compared to

vehicle

• Blocks abnormal blood vessels growth in the eye

in CNV (choroidal neovascularization), ROP

(retinopathy of prematurity) and zebra fish

models.

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1. Maintenance of IOP by preventing

failure of filtration glaucoma surgeries

2. Oral treatment of wAMD

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CLT-28643 - Key Indications

CLT-28643 in Glaucoma Surgery - Overview

– First in class - small molecule α5β1-integrin antagonist

– Favorable physico-chemical properties supporting prolonged effect

of duration

– Orphan drug opportunity, but growing market size

– Faster to market

– Limited competition

– Market potential US$ 590m - 960m, launch 2019

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Glaucoma Surgery

• Glaucoma patients (EU+US) expected to increase

to >14.7 million by 2021

• Estimated number of surgical procedures (excluding

laser procedures) in

• 2021 = 348,000

• 2025 = 402,000

• Filtering Surgery: Creates enhanced drainage of

aqueous humour from the anterior chamber to

subconjunctival space.

• High failure rate due to fibrosis

• 28 – 51% (depending on definition)

• Adjuvants used today are cytotoxic antimetabolites:

• Mitomycin C (MMC) mainly in US and EU

• 5-FU mainly in JP and Australia

• MMC approved in the US, otherwise off-label

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Glaucoma Surgery - Unmet Medical Need

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Mitomycin C assisted trabeculectomy

Maintain low IOP and ↑Bleb survival

↓Complications

CLT-28643

11

6

15

55

17

26

37

0 10 20 30 40 50 60

Wound leak

Hypotony

Shallow Ant. Chamber

Cataract after 4 years

Cataract after 1 year

Failure rate (≤18mmHg)

Failure rate (≤15mmHg)

%

Market research

• Revenues from USD$590M to USD$960M in 2025 (Procedure-based

model)

• Glaucoma surgeon KOLs indicate

• Prevention of failure of filtering glaucoma surgery is still an important

unmet medical need

• Todays treatment is not satisfactory, especially in view of failure rate and

long term safety

• CLT-28643 offers tremendous potential with its combination of efficacy

and safety

• CLT-28643 would be used in the majority of their filtering surgery cases,

both intra-operatively and post-surgically

• Payers in the US would likely cover CLT-28643 with reimbursement similar to

that for other orphan drugs.

CLT-28643 meets the efficacy and safety criteria in

the rabbit trabeculectomy study

• Maintains IOP reduction throughout the study – The IOP effect of one subconjunctival

injection lasts for 21 days

– Inhibition of collagen deposition

• Well tolerated – No signs of toxicity or prolonged

inflammation following one subconjunctival injection and eye drops QID for 28 days

– Better safety than MMC evidenced as less loss of goblet cells

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Competition – Adjuvant to Glaucoma Surgery

• Source: MedTRACK

Product Originator / Licensee Class / Mechanism of Action Stage of

Development Launch Date

Mitosol (MMC) Mobius Therapeutics DNA Polymerase

Inhibitor/Antifibrotic Marketed in US 2012

PRM151 Promedior

Amylid P component, serum

(recombinant,

human)/Antifibrotic

Phase II (EU) Discontinued

ALT-401 Altacor, Ltd. TGF-Beta Inhibitor/Antifibrotic Phase II No CT registered

JB991 Swedish Orphan Biovitrum Cyclopentenone prostaglandin

analoge/antiproliferative agent Preclinical TBD

bFGF Essex Bio-Technology Ltd. Fibroblast Growth Factor

Agnonist/Angiogensis Inducer Preclinical TBD

ACUHTR028 Opko Health

TGF-Beta Inhibitor/Antifibrotic

Preclinical TBD

P144 Digna Biotech TGF-Beta Inhibitor/Antifibrotic Preclinical TBD

ISV120 InSite Vision MMP-2 & MMP-9 Inhibitor/Anti-

inflammatory Preclinical Discontinued

Modest competition – High Unmet medical Need

CLT-28643 – In Glaucoma Surgery

Differentiating features versus other programs

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Small molecule High metabolic and chemical stability

Standardized and controllable process chemistry

Favorable physico-chemical properties supporting prolonged effect of duration

Long lasting effect of a single subconjunctival injection

Optimal balance for the wound healing process due to the anti-fibrotic

combined with anti-inflammatory and anti-angiogenic effects

Long ½ life in the eye

CLT-28643 - Glaucoma Surgery Status and Development Plan

I

M

P PI/II PIII Reg

N= 65 + 65

6 months follow up

t

o

x

Ocular Safety

Clinical supply

2013 2014 2015 2016 2017 2018 2019 2020

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CLT-28643 – Proof-of-concept (Phase I/II)

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Double blind Double masked, randomised clinical trial comparing the use of CLT-28643 with

placebo (or MMC) to maintain low IOP after first-time trabeculectomy

Race Caucasian

Treatment CLT-28643 peroperative subconjunctival injection +

(repeated injection schedule TBD after PK results)

Duration of treatment 3 months

Follow up 6 months after trabeculectomy

Primary Objectives IOP, responder analysis at 6m after trabeculectomy

Secondary Objective Local tolerance, Difference in mean IOP at 6 months, bleb morphology

Use of post operative medications for IOP

Number of Subjects TBD but estimated at 2 x 65 subjects

Number of Centres 10

#pt/site 2 pt/ month /site

1. Maintenance of IOP by preventing

failure of glaucoma filtration surgeries

2. Oral treatment of wAMD

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CLT-28643 - Key Indications

Wet Age Related Macula Degeneration (wAMD)

• Progressive disease resulting in loss of central vision

• Associated with inflammation, new vessel growth and leakage into retina and

scarring disrupting photoreceptor’s function

• wAMD is the form causing 90% loss of vision

• Prevalence 1.75 million in US (3 million in 2020)

• Risk of fellow eye involvement 12% p.a.

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wAMD - Unmet Medical Need

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Complementary MoA to anti-VEGFs

Effect on both eyes (oral)

Selectively accumulates in eye

Maintenance therapy (↓ injections)

No effect on normal retina

CLT-28643

Anti-VEGF Therapy

• Only third of treated patients recover ≥3 lines of

vision

• Fellow eye not protected

– 50% risk in 5 years

• Rapid onset but short lasting anti-leakage effect

• Monthly injections needed

– (US$1500-2000/injection)

• No effect on size of CNV membrane

• Safety concerns with chronic use

CLT-28643 – Preclinical Pharmacology

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In vivo anti-angiogenic effect was demonstrated in

multiple models of eye neovascularization • Murine models CNV and ROP models

Effect obtained with different routes of administration • Oral, subcutanous and intravitreal

Unique kinetics

• accumulation in the eye and low systemic exposure following multiple

routes of administration

CLT-28643 in wAMD - Differentiating features

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• Non-injectable treatment in development

– Simultaneous treatment of the fellow eye

– Convenient and quality of life

• Favourable kinetic after systemic administration

– High concentration & long ½-life in retina and choroid, low plasma

concentrations

• Complementary to anti-VEGF

– potential to be used in combination

• Anti-fibrotic effect in addition to anti-angiogenic effect

• α5β1 integrin not required for normal tissue maintenance

– Low potential for toxicity to normal retina

• Market penetration & Potential

• Broad and rapid uptake driven by both convenience and efficacy improvements

• Market Potential USD >1.5bn

• Product assumptions

• Oral administration

• ↓anti-VEGF to quarterly injections after initial 3x monthly injections

• Fellow eye involvement reduced

• ↑Vision compared to anti-VEGF mono treatment

• Pricing Assumptions

• Generic ranibizumab (Lucentis) likely to be available when launching CLT-28643

• Price: 50% price premium compared to savings on injections and service utilisation (i.e. cost neutral scenario)

• 2282 USD/year

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Market potential: USD >1.5bn

CLT-28643 – wAMD development plan

Clanotech is seeking an industrial partnership for the

development of CLT-28643 in wAMD

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2014 2015 2016 2017

Ph1 PIIa PhIIb

2018 2019 2020 2021 2022 2023

PhIII Reg

wAMD – Competition

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Product Target Company Phase Indication route Comments

Lucentis Anti-VEGF Genentech Launched 2006 AMD, DME IVT Market leader

EYLEA® VEGF trap Regeneron Launched (US)

2011

AMD IVT Similar to

Lucentis

Macugen Anti-VEGF EyeTech Launched 2004 AMD IVT Ousted by

Lucentis

Avastin Anti-VEGF ab NEI III

AMD, PDR (&

Cancer)

IVT Off-labelled

AGN150998 Anti-VEGF

DARPin

Allergan

Molecular

Partner

II AMD IVT Failed

LFG316 Anti-VEGF Novartis II AMD IVT -

ESBA1008 Anti-VEGF Alcon II AMD IVT -

• CLT-28643 oral as unique feature

• Complementary mechanism to any product

• Positioned as maintenance therapy to reduce frequency of IVT injections

wAMD – Competition

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Product Target Company Phase Indication route

E10030 Anti-PDGF

aptamer

Ophthotech II AMD IVT

AL39324 RTKI Alcon II AMD IVT

H1-Can1 Tissue Factor Iconic Therapeutics I/II AMD IVT

Isonep Sonepcizumab

mab sphingosine-1-

phosphate

Lpath Inc. & Pfizer II AMD IVT

ORA102 Anti-angiogenic OraBio II AMD (& Cancer) IVT

Zybrestat vascular disrupting

and antineoplastic

Oxigene II AMD IV

Pazopanib Anti-PDGR/VEGF GSK II AMD ( & Cancer) Topical

ATG3 Acetylcoline

release

CoMentis II AMD Topical

Anti-integrin with anti-angiogenic anti-inflammatory and anti-fibrotic effects

In summary – CLT-28643

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First-in- class

High unmet medical needs

Dual

commercial

potential

Novel MoA

Different routes of

administration

Subconjunctival

Oral

Back-of-the eye

Front-of-the eye

Glaucoma surgery Wet AMD

CLT-28643

1. Small molecule α5β1 integrin inhibitor with unique

properties and anti-angiogenic and anti-fibrotic effects

2. Therapy for maintenance of intraocular pressure

(IOP) following glaucoma surgery

3. Opportunity for treatment and prevention of wet Age

related Macular Degeneration (wAMD)

4. Possible use in both front- and back-of-eye

indications

32

Market Potential:

Glaucoma Surgery USD 590 – 960m

wAMD USD >1.5bn

Back UP

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α5β1 is a validated target in angiogenesis

• Knock outs correlates directly with defects in blood vessels Arjan van der Flier et al, Development 137, 2439-2449, 2010

• α5β1 integrin drives endothelial cell proliferation and angiogegensis Li, Exp. Neurology, 237: 46-54, 2012

• High expression of α5β1 integrin in proliferating choroidal blood

vessels but not in normal vessels

Umeda et al, Mol. Pharmacol 69:1829-1828, 2006

Clemmons, Nature Reviews, Drug Discovery 6:821-833, 2007

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α5β1 integrin is a target for wound healing - Rational for the use

of CLT-28643 in glaucoma surgery

Integrins are the major mediator of the interaction of fibroblast and extracellular matrix during scar formation

Thannickal et al. J. Biol. Chem. 2003, 278:12384-12389.

Roberts et al JJ biol ChemVol. 263, No. 10, Issue of April 5, pp. 4586-4592, 1988

High expression of α5β1 integrin in activated fibroblasts switching to the fibrotic state

Weston et al J Am Soc Nephrol 14: 601–610, 2003

Nesbit et al Laboratory Inv. Vol. 81, No. 9, p. 1263-1274, 2001

Norman et al Exp Nephrol 1999;7:167–177

High expression of α5β1 in fibrotic scar after glaucoma surgery

Internal Information

Integrin modulations by RGD peptides derivatives used in rabbit glaucoma filtration surgery

Avila et al. Ophthalmic Surg Lasers 1998 309-317

Avila et al. Ophthalmic Surg Lasers 2001 134-139

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wAMD Market Scenarios

• General assumptions – Generic environment; Lucentis off-patent when launching CLT-28643

– Drug cost for Lucentis at launch is assumed to be similar to today’s drugs cost for Avastin of 50 USD/injection (Patel et al., 2010)

– Medical utilization: 457 USD/injection (Patel et al., 2010)

• Base Case – Effect: CLT-28643 reduces the need with 3 anti-VEGF injections per year and improves vision

compared to Lucentis mono treatment with 60%

– Price: 50% price premium compared to cost neutral scenario

• Low Case – Effect: CLT-28643 reduces the need with 3 anti-VEGF injections per year

– Price • Cost neutral scenario, i.e. CLT-28643’s price equal to the savings from reduced drug and use of

medical resources equal to 507 USD/injection

• 3 less injections per year: CLT-28643 cost neutral priced at 1521 USD/year

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Cost Neutral Scenarios

Base Case

• Generic ranibizumab (Lucentis) likely to be available when launching CLT-28643

– Scenario 1 & 2 less likely

• Cost of ranibizumab at launch similar to today’s cost of bevacizumab (Avastin)

• Medical utilization cost at similar level as today

0 2000 4000 6000 8000

Scenario 5

Scenario 4

Base Case

Scenario 2

Scenario 1

Price per year (USD)

Cost neutral price scenarios 3 less injections per year

Lucentis drug cost Avastin drug cost

Medical Utilization drug cost

7 221

5 850

1 521

1 371

150

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