1. e-Therapeutics
plc
The Network Pharmacology Company
May 2012

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3. e-Therapeutics Drug discovery and development company
Platform technology in network pharmacology (NP)
Clinical pipeline of three drugs
AIM-listed with market cap (14 May) ~ £54m / ~ $85m
Funding until 2014 (Jan ‘12 cash £13.9m / ~$22m)
Major investors include Invesco (47%) & Henderson (11%) 3

4. Business model Discovery Development
Network Pharmacology platform
New Oxford centre
Fuels clinical pipeline
Development
Led by Steve Self
(former R&D Director, Merck Generic Group)
Specialist CROs, CMOs
Take drugs to phase II data
Potential discovery collaborations
Product licensing deals 4

5. Network Pharmacology Platform
Drug Discovery
Network Pharmacology Platform

6. Network Pharmacology principles 1
Chemical Biology:
Bioactive molecules interact with more than one “target” protein, by:
promiscuous binding
multiple pleiotropies
metabolite polypharmacy
Each bioactive molecule has a potentially wide protein signature or footprint in patients:
Binding
affinity
Expression/
abundance
Functional
state
Other network
mediated effects 6

7. Network Pharmacology principles 2
Network Biology:
Biological networks are evolved to be robust against the loss of any single protein
Only well-targeted multiple interventions affect biological networks significantly
Hub – intervention strategy based on targeting network hubs
Random – intervention in the network in random order
Increasing diameter indicates reduced integrity of network
Reflects number of intervention points 7

8. High potential of ‘combinatorial impact’
Peak impact combinations of targets:
major impact if these hit simultaneously
Long tail:
biology is redundant
Best single target
somewhere down here 8

9. Network Pharmacology Optimising for combinatorial network impact
Not 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 9

10. Application of the platform
ETX platform enjoys patent protection
First wave of discovery (2005—2009)
Concentrated on repositioning opportunities
Three current clinical programmes resulted
New discovery programme
Focus on cancer and degenerative diseases of nervous system
Both NCE and repositioning opportunities sought
Plan to generate at least one new product for clinical development by end of 2013
Complex diseases –
plays to strengths of NP approach
Major commercial opportunities 10

11. Three drugs entering trials in 2012
Clinical Pipeline
Three drugs entering trials in 2012

12. ETS2101 – anticancer candidate 1
ETS2101 – anticancer candidate 1. Targeting strategy developed using network pharmacology
In cancer, variability leads via selection to acquisition of survival factors - the ‘hallmarks’ of cancer
ETX programme focused on evasion of apoptosis
Began with genes implicated in evasion of apoptosis
Built protein networks including
products 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 12

13. ETS2101 – anticancer candidate 2. Drugs to deliver strategy identified
Matched desired signature with footprints of known molecules using chemoproteomic resources
One of 16 was ETS2101 = dexanabinol, a synthetic cannabinoid that had failed phase III in trauma patients
Well tolerated
Distinctive footprint
NMDA receptor Binding affinity
COX2 Gene expression/ regulation
TNFa Post-translation / secretion
NF-kB Phosphorylation
CDP-diacylglycerol-glycerol-
3-phosphate 3 phosphatidyltransferase Network-mediated
Farnesyltranstransferase Network-mediated
Histone acetyltransferase Network-mediated
CDK2 Network-mediated
CDK5 Network-mediated 13

14. ETS2101 – anticancer candidate 3
ETS2101 – anticancer candidate 3. Empirical testing supported network pharmacology predictions
NP platform predicted ETS2101 would stop cancer cells evading apoptosis
Preclinical testing showed broad and potent anti-cancer activity
Wide variety of cancer cell lines
Particularly interesting results in brain cancer glioma
Killing of four brain cancer cell lines by ETS2101 14

15. ETS2101 – anticancer candidate 4. 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 activity
Trials to start shortly (plans are approved by regulators)
Initial data expected by end of 2012
Final data from both studies expected 2013 15

16. ETS6103 – antidepressant candidate
Tramadol for depression
Targeting patients who have failed SSRI therapy
Low side effect burden vs tricyclic antidepressants
Encouraging data from small phase IIa trial comparing agent with tricyclic amitriptyline
Phase IIb dose-ranging trial to start Q3 2012
Data from phase IIb trial expected H2 2013 16

17. ETX1153a – topical anti-infective
Combination of disulfiram and miconazole
Topical therapy for MRSA
Initially targeting decolonisation of infected health workers
Further in vitro work planned
Formulation work & animal tolerability studies planned
Phase I volunteer proof-of-principle study expected to start Q4 2012 17

18. ETX1153c – anti-infective vs C. difficile
Product with promising preclinical data in treatment of Clostridium difficile, a cause of life-threatening infections
High potency based on synergistic combination of nisin and miconazole
Activity extends to drug-resistant strains such as NAP-1
Issues in formulating drug & potential for better product so not progressing immediately with clinical development
New preclinical programme to build on positive findings with ETX1153c and recent data on related approaches 18

19. Significant market opportunities
Analyst peak
sales estimates
Target product profile
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)
ETS2101
Oncology
ETS6103
Depression
ETX1153a
MRSA topical
Panmure Gordon , Edison (glioblastoma only)
Edison
Canaccord
** Selective serotonin reuptake inhibitors, commonly used anti-depressants 19

20. Business funded through key milestones
Outlook
Business funded through key milestones

21. Solid progress 2011 2012 Increasing interest in NP approach
Business funded until
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 21

22. R&D investment and returns
For two financial years to Jan 2014
£13.9m
Jan ’12
Discovery
~1/3 of R&D investment
New wave underway
One + new drug into development by end 2013
Development
~2/3 of R&D investment
Three drugs into clinic in ‘12
Significant data in 2012/ (1 phase II & 2 phase I results by end of 2013)
Potential discovery collaborations
Product licensing deals 22

23. Newsflow 2012-2013 Programme News Expected 23 ETS2101
Start of phase I programme in cancer
Q2 2012
ETS6103
Start of phase IIb trial in depression
Q3 2012
ETX1153a
Start of phase I trial – topical MRSA
Q4 2012
First interim findings from phase I programme
Data from phase I solid tumour trial
2013
Data from phase I brain cancer trial
Data from phase I trial – topical MRSA
Data from phase IIb trial in depression
H2 2013
Discovery
At least one new drug  development 23

24. e-Therapeutics – summary
Drug discovery and development company
Network pharmacology platform plus clinical pipeline
Plan to realise value through pharma partnering deals
Three drugs to enter clinic in 2012
New discovery effort in oncology and CNS
Cash covers discovery and development needs  2014
Extensive newsflow expected in 2012 and 2013 24