For more information contact: Slideshare@marcusevans.com. Roy Pettipher CRTH2 Antagonists for the Treatment of Asthma and Allergic Rhinoconjunctivitis Drug Discovery Summit Lisbon March 16-18 2015

1. Roy Pettipher
CRTH2 Antagonists for the Treatment of Asthma and Allergic
Rhinoconjunctivitis
Drug Discovery Summit Lisbon March 16-18 2015
www.atopixtherapeutics.com

2. Strategy and focus
 Innovation in allergic disease, Th2-mediated disorders
 Delivering innovative, credible, clinical trials
 Focused on clear patient stratification – eosinophilic patients
measured by blood eosinophils
 Build near-term value in Th2-driven atopic dermatitis
 Preserve upside value in eosinophilic asthma
Confidential - Page 2

3. Th2-mediated eosinophilic
disorders

4. Confidential - Page 4
The successful
re-positioning of the
anti-Th2 biologics
targeting IL-4, IL-5 and
IL-13 (cytokines
downstream of CRTH2)
have driven renewed
interest in this field
Highly attractive therapeutic markets with
unmet need

5.  Exposure to allergens leads to a
burst of prostaglandin D2 (PGD2)
 PGD2 then binds to CRTH2
receptors and drives inflammation
in a variety of diseases
 CRTH2 is a G-protein coupled
receptor target on cells in the
immune system (Th2 lymphocytes,
eosinophils, basophils)
 CRTH2 antagonists such as
OC459 block this
inflammatory response
CRTH2
PGD2
Allergen
Inflamed tissue/disease
Recruitment and release
of inflammatory mediators
(IL-4, IL-5, IL-13)
Th2 cells, eosinophils,
basophils
The target CRTH2 is central to allergic disease,
allergy and asthma
X
Confidential - Page 5

6. Involvement of CRTH2 in experimental allergic
responses
 Allergic responses reduced by genetic deficiency in
CRTH2 or pharmacological blockade:
– Accumulation of leukocytes (including lymphocytes and eosinophils)
– Tissue swelling
– Production of Th2 cytokines
– Production of mucus
– Production of IgE
– Airway hyper-responsiveness and late phase airway response
– Airway inflammation in response to ds-RNA (a model of viral
exacerbation)
– Sensitisation to allergen
– Epidermal hyperplasia and hyperkeratosis
Confidential - Page 6

7. Atopix has innovative products for allergic Th-
2 driven disease
Oral, small molecule, once-a-day, CRTH2 antagonists
OC459
 Leading position in development
 Potent and selective CRTH2 antagonist
 6 efficacy studies completed; 2 studies in progress
 Safe with excellent PK/PD relationship
 Once a day dosing (anticipated dose: 25 mg)
 Low COGS; pressed-tablet formulation
 Patents (OX55) to 2024-2027
ATX2417
 IND ready
 Highly potent (2.5nM) in whole blood and selective
 Predicted human dose 1-10mg
 Patents (OX75) to 2029
Confidential - Page 7

8. OC459: Pharmacological profile
Confidential - Page 8
Target potency and selectivity Functional activity

9. OC000459 Ligand Binding Properties
-12 -11 -10 -9 -8 -7 -6 -5 -4
0
20
40
60
80
100
120
Log OC000459 (M)
%[3
H]PGD2bound
Recombinant human CRTH2
Ki=13 nM
-12 -11 -10 -9 -8 -7 -6 -5 -4
0
20
40
60
80
100
120
log OC000459 (M)
%[3
H]PGD2bound
Th2 cell membranes
Ki=4 nM

10. Inhibition of PGD2-mediated Activation of
Th2 cells by OC000459
-11 -10 -9 -8 -7 -6
0
40
80
120
160
Cytokine production by Th2 cells
Log OC000459 (M)
IL-13levels
(%Controlresponse)
-10 -9 -8 -7 -6 -5
0
20
40
60
80
100
Chemotaxis of Th2 cells
Log OC000459 (M)
MigrationofTh2cells
(%controlresponse)
-10 -9 -8 -7 -6 -5
20
25
30
35
40
45
Promotion of apoptosis of Th2 cells
Log OC000459 (M)
AnnexinVpositivecells
(%)
IC50=28 nM
IC50=19 nM
IC50=35 nM

11. Activity of OC000459 on Eosinophil Shape Change
in Mixed Leukocytes and Human Whole Blood
PGD2 EC50 in whole blood = 4.2 nM
PGD2 concentration in asthma BAL = 3.8 nM (Liu et al 1990 Am rev Respir
Dis 142: 126-1320)
-10 -8 -6
-25
0
25
50
75
Control
3000nM OC000459
1000nM OC000459
300nM OC000459
100nM OC000459
PGD2 (log M)
Shapechange(%)
-10 -8 -6
-10
0
10
20
30
Control
3000nM OC000459
1000nM OC000459
300nM OC000459
100nM OC000459
PGD2 (log M)
Shapechange(%)
Mixed leukocytes (10%serum)
Human whole blood
pKB = 7.9
pKB = 7.5 (KB = Koff/Kon=30 nM)

12. OC000459 Inhibits Mast Cell-dependent
Activation of both Th2 cells and Eosinophils
0
100
200
300
400
500
*
Migrationof
Th2lymphocytes
0
20
40
60
80
*
Eosinophilshape
change(%)
Control
Mast cell supernatant alone
Mast cell supernatant + 1M OC000459
* p<0.01

13. Phase IIb 12 Week Asthma Study Design
Inclusion Criteria
Males and females (18-55yrs)
Asthmatics on SA-β2-agonists only (salbutamol)
Mild-moderate asthma by GINA guidelines
Non smokers
Randomisation Criteria
• Morning FEV1 of 60-85% predicted
• Reversibility of >12% after salbutamol
• >1 puff/day of salbutamol required
Secondary End Points
• Quality of Life AQLQ(S)
• ACQ
• Safety and tolerability
Primary End Point
• Improvement in FEV1
compared to placebo
Screening
Placebo
Run-in
( 3 weeks) Placebo
OC000459
Randomisation
(1-2 weeks) Placebo
Wash-out
( 2 weeks)
Follow-up
(3-5 weeks)
(12 weeks)
At least 460 patients to yield 440 evaluable
4 arms (25mg od, 200mg od, 100mg bd, placebo) with 110 patients/arm

14. 0 2 4 6 8 10 12
0
100
200
300
OC000459 Pooled n=361 Placebo n=116
Weeks of Randomised Treatment
ChangeinFEV1(mL)
p=0.024
0 2 4 6 8 10 12
-100
0
100
200
300
OC000459 Pooled n=79 Placebo n=29
Weeks of Randomised Treatment
ChangeinFEV1(mL)
p=0.011
… and first to identify a high responder Th2-high
eosinophilic phenotype in Ph 2b asthma study
Eos>250/µl
Age <50
Skin prick positive
Confidential - Page 14
All-comers
High-responder phenotype

15. Effect of blood eosinophilia on response to
OC000459
Patients with Blood Eosinophils < 250/uL
0 2 4 6 8 10 12
-100
0
100
200
300
OC000459 Pooled n=189 Placebo n=59
Weeks of Randomised Treatment
ChangeinFEV1(mL)
vs.Baseline+/-SEM
Patients with Blood Eosinophils  250/uL
0 2 4 6 8 10 12
-100
0
100
200
300
OC000459 Pooled n=165
 at endpoint =160mL; p-value=0.010
Placebo n=54
Weeks of Randomised Treatment
ChangeinFEV1(mL)

16. PK profiles of doses of OC459 used in Phase IIb
asthma study
Page 16
0 6 12 18 24
0
100
200
300
400
500
600
700
800
900
1000
1100
1200 25mg tablet OD
100mg tablet BD
200mg tablet OD
IC50
Time (h)
OC459ng/ml
IC90
All doses equally effective in asthma
Plasma levels of OC459 ≥ whole blood IC50 over 24 hour period at doses
as low as 25mg
ChangeinFEV1(ml)
0 2 4 6 8 10 12
-100
0
100
200
300
400
OC000459 Pooled
Placebo
OC000459 25mg OD
Week of treatment

17. … the eosinophilic phenotype was corroborated
in earlier Phase 2a asthma study
Confidential - Page 17
Eosinophils  250/l
0 1 2 3 4
-150
-50
50
150
250
350
Weeks of Randomised Treatment
ChangeinFEV1
(ml)
OC000459 (n=35) Placebo (n=33)
p=0.011
Eosinophils < 250/l
0 1 2 3 4
-150
-50
50
150
250
350
Weeks of Randomised Treatment
ChangeinFEV1
(ml)
Placebo (n=17) OC000459 (n=20)

18. Effect of OC000459 on respiratory tract
infections and exacerbations

19. Vienna Challenge Chamber Protocol
Page 19
Study Population, n=35 completed entire protocol
• Males
• Grass pollen allergic rhinitis sufferers on history, 18-50y
•Total nasal symptom score ≥ 6 after grass pollen challenge
•
Drug or Placebo (oral)
8 day dosing (fed)
Secondary End Points
•Total nasal symptom score on Day 2
•Safety and tolerability
Placebo controlled double-blind, randomised 2-way crossover
6hrs in challenge chamber with grass pollen challenge
Challenges on Day 2 & Day 8 of dosing
Drug or Placebo (oral)
8 day dosing (fed)
Primary End Point
Total nasal symptom
score on Day 8
2.5 week
washout

20. In addition, OC459 treats co-morbid allergic
disease
Confidential - Page 20
0
1
2
3
4
5
6
0
1
2
3
4
5
6
7
8
9
10
11
12
OC000459
PLACEBO
SCREEN
Time relative to start of challenge (h)
TotalNasalSymptomScore
0
1
2
3
4
5
6
0
1
2
3
4
5
6
OC000459
PLACEBO
SCREEN
Time relative to start of challenge (h)
Nasal symptoms Eye symptoms
P=0.003 P=0.060

21. OC459 has a clean safety profile
 Dosed in > 750 subjects; 360 patients for 3 months
 Comprehensive safety database allowing 6 month
treatment regimens and extension into younger patients
 Extensive pre-clinical toxicology e.g dog 12 months
toxicology study
 No end-organ toxicity detected in non-clinical species
Confidential - Page 21

22. Two clinical studies in progress with OC459
 Phase 2 Study of OC459 in Th2-driven atopic dermatitis
patients
– strong rationale from anti-IL-4Rα dupilumab data (blocks IL-4 and IL-
13)
– double-blind, placebo controlled
– 130 patients, with Th2-high phenotype
– run by leading European ‘key opinion leaders’
– reading out Q4 2014
 Phase 3 registration study in eosinophilic asthma in Russia,
managed by Oxagen
– OC459 or placebo in combination with montelukast
– 200 patients, with Th2-high eosinophilic phenotype
– reading out Q1 2016
– data ex Russia/CIS owned by Atopix
Confidential - Page 22

23. Summary
 Pipeline of CRTH2 antagonists
 OC459 - leading oral CRTH2 therapy in clinical trials for atopic
dermatitis
 OC459 - starting Phase 3 registration studies in Russia in allergic
asthma in Q2/2014
 ATX2417 - potent and selective back-up starting Phase 1 in
H2/2014 to maximise value of CRTH2 franchise (under discussion)
 Broad portfolio of worldwide patents
 Innovative approach to allergic disease
Confidential - Page 23