e-Therapeutics plc

The Network Pharmacology Company

May 2012

e-Therapeutics plc

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Safe harbour statement / disclaimer2

e-Therapeutics plc

e-TherapeuticsDrug discovery and development companyPlatform technology in network pharmacology (NP)Clinical pipeline of three drugsAIM-listed with market cap (14 May) ~ 54m / ~ $85mFunding until 2014 (Jan 12 cash 13.9m / ~$22m)Major investors include Invesco (47%) & Henderson (11%)

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e-Therapeutics plc

Business model 4Development Led by Steve Self (former R&D Director, Merck Generic Group)

Specialist CROs, CMOs

Take drugs to phase II data

Potential discovery collaborationsProduct licensing dealsDiscovery Network Pharmacology platform

New Oxford centre

Fuels clinical pipeline

e-Therapeutics plc

Drug DiscoveryNetwork Pharmacology Platform

e-Therapeutics plc

6Chemical Biology:

Bioactive molecules interact with more than one target protein, by: promiscuous binding multiple pleiotropies metabolite polypharmacy

Network Pharmacology principles 1Each bioactive molecule has a potentially wide protein signature or footprint in patients:

e-Therapeutics plc

7Network Pharmacology principles 2Network Biology:

Biological networks are evolved to be robust against the loss of any single protein Only well-targeted multiple interventions affect biological networks significantlyIncreasing diameter indicates reduced integrity of networkReflects number of intervention pointsHub intervention strategy based on targeting network hubs

Random intervention in the network in random order

e-Therapeutics plc

Long tail:biology is redundantPeak impact combinations of targets:major impact if these hit simultaneouslyBest single targetsomewhere down hereHigh potential of combinatorial impact8

e-Therapeutics plc

Optimising for combinatorial network impactNot nanomolar potency at a single target 1. Identify optimally synergetic multiple interventions in target cells by network analysis

2. Identify molecules that deliver these multiple interventions through their specific pattern of promiscuity and pleiotropy

3. De-risk each candidate as fully as possible by examining potential impacts on the networks of normal cells

4. Develop 9Network Pharmacology

e-Therapeutics plc

Application of the platformFirst wave of discovery (20052009)Concentrated on repositioning opportunitiesThree current clinical programmes resultedNew discovery programmeFocus on cancer and degenerative diseases of nervous systemBoth NCE and repositioning opportunities soughtPlan to generate at least one new product for clinical development by end of 2013 Complex diseases plays to strengths of NP approachMajor commercial opportunities10ETX platform enjoys patent protection

e-Therapeutics plc

Clinical PipelineThree drugs entering trials in 2012

e-Therapeutics plc

ETS2101 anticancer candidate1. Targeting strategy developed using network pharmacologyIn cancer, variability leads via selection to acquisition of survival factors - the hallmarks of cancerETX programme focused on evasion of apoptosisBegan with genes implicated in evasion of apoptosisBuilt protein networks includingproducts of these genes proteins regulating their expression 103 interactome local area networks (LANs) Used impact analysis to identify best sets of target proteins per LAN and then overall desired protein signature

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e-Therapeutics plc

ETS2101 anticancer candidate 2. Drugs to deliver strategy identifiedMatched desired signature with footprints of known molecules using chemoproteomic resourcesOne of 16 was ETS2101 = dexanabinol, a synthetic cannabinoid that had failed phase III in trauma patientsWell tolerated Distinctive footprintNMDA receptorBinding affinityCOX2Gene expression/ regulationTNFaPost-translation / secretionNF-kBPhosphorylationCDP-diacylglycerol-glycerol- 3-phosphate 3 phosphatidyltransferaseNetwork-mediatedFarnesyltranstransferaseNetwork-mediatedHistone acetyltransferaseNetwork-mediatedCDK2Network-mediatedCDK5Network-mediated

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e-Therapeutics plc

ETS2101 anticancer candidate 3. Empirical testing supported network pharmacology predictionsNP platform predicted ETS2101 would stop cancer cells evading apoptosis Preclinical testing showed broad and potent anti-cancer activityWide variety of cancer cell linesParticularly interesting results in brain cancer glioma

14Killing of four brain cancer cell lines by ETS2101

e-Therapeutics plc

ETS2101 anticancer candidate4. Clinical development about to begin Two parallel phase I trials to be conducted#1 patients with a variety of solid tumours - UK#2 patients with brain cancers (primary and metastatic) - US

Both trials will explore dosing, safety and activityTrials to start shortly (plans are approved by regulators)Initial data expected by end of 2012Final data from both studies expected 2013

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e-Therapeutics plc

ETS6103 antidepressant candidateTramadol for depressionTargeting patients who have failed SSRI therapyLow side effect burden vs tricyclic antidepressantsEncouraging data from small phase IIa trial comparing agent with tricyclic amitriptylinePhase IIb dose-ranging trial to start Q3 2012Data from phase IIb trial expected H2 2013

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e-Therapeutics plc

ETX1153a topical anti-infectiveCombination of disulfiram and miconazoleTopical therapy for MRSAInitially targeting decolonisation of infected health workersFurther in vitro work plannedFormulation work & animal tolerability studies plannedPhase I volunteer proof-of-principle study expected to start Q4 2012

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e-Therapeutics plc

ETX1153c anti-infective vs C. difficileProduct with promising preclinical data in treatment of Clostridium difficile, a cause of life-threatening infectionsHigh potency based on synergistic combination of nisin and miconazoleActivity extends to drug-resistant strains such as NAP-1Issues in formulating drug & potential for better product so not progressing immediately with clinical developmentNew preclinical programme to build on positive findings with ETX1153c and recent data on related approaches18

e-Therapeutics plc

Significant market opportunitiesETS6103DepressionETX1153aMRSA topical ** Selective serotonin reuptake inhibitors, commonly used anti-depressantsETS2101OncologyPanmure Gordon , Edison (glioblastoma only)EdisonCanaccordTarget product profileAnalyst peak sales estimates19

Selective apoptotic against multiple metastatic cancers with favourable tolerability profile$300m-$600m (a)Fast-acting efficacy with low side-effects for patients who do not respond to SSRIs**$130m (b)

Potent fast-acting efficacy against all MRSA strains, with low rate of resistance (topical)

$80m (c)

e-Therapeutics plc

OutlookBusiness funded through key milestones

e-Therapeutics plc

Solid progress212011

Business funded until 2014 Restart of discovery: new hires Preparation for trials

2012

Discovery fully active Trial starts for 3 drugs First trial data Ramp-up of BD activity

Increasing interest in NP approach

e-Therapeutics plc

Discovery~1/3 of R&D investment New wave underway

One + new drug into development by end 2013

Product licensing dealsR&D investment and returns For two financial years to Jan 201422Development~2/3 of R&D investment Three drugs into clinic in 12

Significant data in 2012/13 (1 phase II & 2 phase I results by end of 2013)Potential discovery collaborations13.9mJan 12

e-Therapeutics plc

Newsflow 2012-201323

ProgrammeNewsExpectedETS2101Start of phase I programme in cancer Q2 2012ETS6103 Start of phase IIb trial in depressionQ3 2012ETX1153a Start of phase I trial topical MRSAQ4 2012ETS2101First interim findings from phase I programmeQ4 2012ETS2101 Data from phase I solid tumour trial2013ETS2101 Data from phase I brain cancer trial2013ETX1153aData from phase I trial topical MRSA2013ETS6103 Data from phase IIb trial in depressionH2 2013DiscoveryAt least one new drug development2013

e-Therapeutics plc

e-Therapeutics summaryDrug discovery and development companyNetwork pharmacology platform plus clinical pipelinePlan to realise value through pharma partnering dealsThree drugs to enter clinic in 2012New discovery effort in oncology and CNSCash covers discovery and development needs 2014Extensive newsflow expected in 2012 and 2013

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