Roy Pettipher

CRTH2 Antagonists for the Treatment of Asthma and Allergic

Rhinoconjunctivitis

Drug Discovery Summit Lisbon March 16-18 2015

www.atopixtherapeutics.com

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

Th2-mediated eosinophilic

disorders

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

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

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

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

OC459: Pharmacological profile

Confidential - Page 8

Target potency and selectivity Functional activity

OC000459 Ligand Binding Properties

-12 -11 -10 -9 -8 -7 -6 -5 -40

20

40

60

80

100

120

Log OC000459 (M)

% [

3H

] P

GD

2 b

ou

nd

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]P

GD

2 b

ou

nd

Th2 cell membranes

Ki=4 nM

Inhibition of PGD2-mediated Activation of

Th2 cells by OC000459

-11 -10 -9 -8 -7 -60

40

80

120

160

Cytokine production by Th2 cells

Log OC000459 (M)

IL-1

3 le

vel

s

(% C

on

tro

l res

po

nse

)

-10 -9 -8 -7 -6 -50

20

40

60

80

100

Chemotaxis of Th2 cells

Log OC000459 (M)

Mig

ratio

n o

f T

h2

cells

(% c

on

tro

l res

po

nse

)

-10 -9 -8 -7 -6 -520

25

30

35

40

45

Promotion of apoptosis of Th2 cells

Log OC000459 (M)

An

nex

in V

po

sitiv

e ce

lls

(%)

IC50=28 nM

IC50=19 nM

IC50=35 nM

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

75Control

3000nM OC000459

1000nM OC000459

300nM OC000459

100nM OC000459

PGD2 (log M)

Sh

ap

e c

han

ge (

%)

-10 -8 -6

-10

0

10

20

30

Control

3000nM OC000459

1000nM OC000459

300nM OC000459

100nM OC000459

PGD2 (log M)

Sh

ap

e c

han

ge (

%)

Mixed leukocytes (10%serum)

Human whole blood

pKB = 7.9

pKB = 7.5 (KB = Koff/Kon=30 nM)

OC000459 Inhibits Mast Cell-dependent

Activation of both Th2 cells and Eosinophils

0

100

200

300

400

500

*

Mig

rati

on

of

Th

2 lym

ph

ocyte

s

0

20

40

60

80

*

Eo

sin

op

hil s

hap

e

ch

an

ge (

%)

Control

Mast cell supernatant alone

Mast cell supernatant + 1M OC000459

* p<0.01

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

0 2 4 6 8 10 12

0

100

200

300

OC000459 Pooled n=361 Placebo n=116

Weeks of Randomised Treatment

Ch

an

ge in

FE

V1

(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

Ch

an

ge in

FE

V1

(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

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

Ch

an

ge in

FE

V1 (

mL

)

vs.

Baseli

ne +

/- S

EM

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

Ch

an

ge in

FE

V1 (

mL

)

PK profiles of doses of OC459 used in Phase IIb

asthma study

Page 16

0 6 12 18 240

100

200

300

400

500

600

700

800

900

1000

1100

1200 25mg tablet OD

100mg tablet BD

200mg tablet OD

IC50

Time (h)

OC

459 n

g/m

l

IC90

All doses equally effective in asthma

Plasma levels of OC459 ≥ whole blood IC50 over 24 hour period at doses

as low as 25mg

Ch

an

ge

in

FE

V1

(ml)

0 2 4 6 8 10 12-100

0

100

200

300

400

OC000459 Pooled

Placebo

OC000459 25mg OD

Week of treatment

… 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

Ch

an

ge in

FE

V1

(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

Ch

an

ge in

FE

V1

(ml)

Placebo (n=17) OC000459 (n=20)

Effect of OC000459 on respiratory tract

infections and exacerbations

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

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)

To

tal N

asal S

ym

pto

m

Sco

re

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

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

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

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