Prostaglandin D2: Therapeutic Indications

World Allergy OrganisationCancun 2011

Andy Wardlaw

Disclosures

• Research grants from Glaxo Smith Kline (GSK), AstraZeneca and Pfizer

• Honorariums for advisory boards from GSK and Cephalon

Airway inflammation leads to several patho-physiological outcomes

Environmental Trigger

Allergen Infection Smoking

BRONCHIAL INFLAMMATIONEos Neuts

Airway Damage(fixed airflow obstruction

Bronchiectasis)

Variable AirflowObstruction & AHR

(Asthma Like)

Uncontrolled Falls in FEV1

(Severe Exacerbations)

Increased cough reflex(cough)

The A to E of Airway diseasePavord ID and Wardlaw AJ Clin Exp Allergy 2010;40:62-67

• A Airway hyperresponsiveness– Rapid variations in airflow obstruction

• B Bronchitis– Eosinophilic:neutrophilic:both

• C Cough

• D Damage – Bronchiectasis– fixed airflow obstruction– emphysema

• E Extrapulmonary factors– Psychological and lifestyle issues including adherence– Obesity and obstructive sleep apnoea– Dysfunctional breathing:– Treatment side effects and co-morbidities

Eosinophilic Airway Inflammation and Variable Airflow Obstruction (AHR) are Largely Independent

0.3 1 3 10 30 100

0.125

0.25

0.5

1

2

4

8

16

32

• Met

hac

hol

ine

PC

20 (m

g/m

l)

Sputum Eosinophil Count (%)Eosinophilic

Inflammation

Severe

Exacerbations

Smooth Muscle

Dysfunction

Uncontrolled,

Treatment

Unresponsive

Falls in FEV1

Variable Airflow

Obstruction/AHR

Asthma

Symptoms

PGD2

• Prostaglandin is produced (outside the brain), mainly by mast cells by the combined action of cyclooxygenase enzymes and prostaglandin D2 synthase

• 50ng per 106 mast cells• Not produced in significant amounts by basophils• Released as part of the early but not the late

response to allergen challenge

Roy Pettipher et al Nature Reviews Drug Discovery 6, 313-325 (April 2007)

Synthetic pathway for PGD2

PGD2

• Some evidence synthesis is increased in clinical asthma although concentrations in sputum and BAL are variable with inconsistent difference between asthma and healthy subjects.

• Inhalation causes bronchoconstriction and vasodilation.

• Injection into the skin causes recruitment of neutrophils and to a lesser extent eosinophils.

Mediator concentrations ng/ml sputum*p<0.05, ANOVA

Brightling et al Am J Respir Crit Care Med 2000; 162: 878-882

Cys-LT ECP Hist PGD2

Normal (10)

5.86 95 15.5 0.05

Asthma (17)

11.1* 735 * 25.1 0.09

Eosinophilic Bronchitis (8)

9.27* 604 * 168* 0.78*

No increase in PGD2 in sputum from patients with asthma

Antagonism and over-expression of PGD2

• PGD2 is primarily synthesised by COX1 and PGE2 by COX2. Non-specific COX inhibitors will inhibit both so cancelling each other out – Dahem K et al CEA 2011

• PGD2 synthase transgenic mouse had increased production of PGD2 and increased Th2 inflammation in the mouse model of asthma – Fujitana et al J Immunol 2002

PGD2 Receptors

• Three receptors:– DP1 receptor expressed on airway smooth muscle,

vascular tissue, dendritic cells and T cells.

– DP2; Chemoattractant receptor homologous molecule expressed on Th2 cells (CRTh2). Expressed on Th2 cells (also Th1 in mice), basophils and eosinophils

– TP: Thromboxane A2 receptor expressed on airway smooth muscle

• PGD2 metabolites bind to CRTh2 but not DP1

DP1 receptor

• Primary function appears to be vasodilation but may also mediate bronchodilation

• In vitro down-regulates Th1 and dendritic cell function possibly leading to increased Th2 responses.

• DP1 gene deleted mouse had reduced inflammation and AHR in the mouse model of asthma as did mice and sheep treated with a DP1 antagonist. (Shichijo et al CEA 2009)

• However DP1agonist was anti-inflammatory in allergic responses in skin in mouse and in the mouse model of asthma by modulating dendritic cell and Treg function. (Hammad et al J Exp Med 2007)

Clinical efficacy of a DP1 antagonist laropiprant

(Phillip G et al JACI 2009:124:942-8)• Rhinitis:

– 767 patients with seasonal allergic rhinitis treated with laropiprant for two weeks: no difference in nasal symptom score from placebo

• Asthma:– 100 patients with asthma randomised to

laropiprant or placebo for three weeks: no difference in asthma symptoms or FEV1

TP receptor

• Receptor for a stable metabolite of PGD2

(9alpha11betaPGF2), as well as thromboxane A2

• Mediates bronchoconstrictor activities of PGD2

• A selective antagonist of the TP receptor, GR32191 blocked PGD2 induced bronchoconstriction and had a modest effect on the early response to allergen challenge, but no effect on exercise induced asthma or clinical disease after three weeks of treatment

CRTh2 receptor• Identified in 2001 as a receptor for PGD2 expressed on

eosinophils, Th2 cells (hence its name) and basophils where it mediates activation and migration – Hirai et al J Exp Med 2001:193:255

• Gene deletion showed increased eosinophil accumulation in the mouse model of asthma with short term exposure but decreased eosinophil infiltration with chronic exposure – Chevalier et al J Immunol: 2005:175:2056. Kagawa et al Int Arch

All Imm 2011:155suppl

• Gene deletion inhibits allergic skin inflammation in mice – He et al JACI:2010:126:784. Satoh et al J Immunol

2006:177:2621

CRTh2 expression on T cells in asthma

Normal AsthmaBronchoscopy

NormalBronchoscopy

Asthman 20 24 7 12

Age** 30 (19-56) 42 (20-66) 24 (21-49) 47 (36-60)

Male 7 16 3 5

Atopy 6 17 1 4

IgE* (kU/L) 17 (7.2) 513 (190) 101 (34) 611 (202)

FEV1%Pred* 94 (9) 83 (3.9) 100 (6.3) 73 (5.8)

Pc20++ >16 1.0 (0.8) >16 0.6 (0.9)

On OCS 0 8 0 5

Mutalithas K et al Clin Exp Immunol 2010:161:34-40

CRTh2 is preferentially expressed on Th2 cells

Asthma

Healthy

CCR3, CCR4, CRTh2 and CCR8 are preferentially expressed on Th2 cells but only a minority of

Th2 cells express these receptors

IL-4 IFN

% of BAL T cells expressing CRTH2

PGD2 concentrations in BAL

Antagonists of CRTh2 in clinical development

• It has been relatively easy to make potent and effective CRTh2 antagonists and there are several in early phase clinical trials which appear safe and well tolerated

• Some are based on NSAID’s as indomethacin was found to be a selective antagonist and some based on the structure of angiotensin receptor antagonists.

• Ramatroban used for allergic rhinitis in Japan is a potent TP antagonist with moderate antagonism for CRTh2, but there is little literature on clinical efficacy

Trial of a CRTh2 inhibitor (OC000459) in moderate steroid naïve asthma

Barnes et al CEA 2012 epub

• Double blind placebo controlled with parallel group design carried out in Russia

• Moderate asthma but not taking inhaled corticosteroids

• One month treatment• Change in FEV1 was primary outcome• Modest improvement which was significant in the

per protocol, but not the full analysis population

Study design

2 4 6 8 10-100

0

100

200

300

Week

Change in FEV

1(ml)

vs. Week 3 Baseline +/

-SEM

2 4 6 8 10-100

0

100

200

300

Week

Change in FEV

1(ml)

vs. Week 3 Baseline +/

-SEM

2 4 6 8 10-5

0

5

10

15

OC000459Placebo

Week

% Change in FEV

1

vs. Week 3 Baseline +/

-SEM

2 4 6 8 10-5

0

5

10

15

OC000459Placebo

Week

% Change in FEV

1

vs. Week 3 Baseline +/

-SEM

Placebo (n=50) vs. OC000459 (n=55)OC000459 Clinic FEV1 9.2% greater than baseline at end of randomised treatment period; Treatment difference OC000459-Placebo = 7.4%; p-value = 0.037

OC000459 Clinic FEV1 214mL greater than baseline at end of randomised treatment period; Treatment difference OC000459-Placebo = 184mL

OC000459 Phase II Asthma StudyEffect on FEV1 (Per Protocol Population)

Clinically relevant improvement in FEV1

% Change in FEV1 vs. Baseline Change in FEV1 (ml) vs. Baseline

Start double blind

treatment

End double blind

treatment

End Placebo washout

Start double blind

treatment

End double blind

treatment

End Placebo washout

Effect of OC000459 on sputum eosinophilia in 28 day asthma study

0

5

10

15

OC000459

Placebo

Baseline 4 weeks Baseline 4 weeks

% Sputum eosinophilia

*

* p<0.05 versus baseline; NS vs change with placebo

Conclusions• PGD2 is a major mast cell derived mediator with several activities

relevant to allergic disease• Three receptors, DP1(vasodilation and immune modulation), TP

(bronchoconstriction) and CRTh2 (immune modulation, cell recruitment)

• Mouse models for a role for DP1 and CRTh2 are conflicting and not particularly compelling for an important role of DP1 and CRTh2 in asthma

• Human studies of antagonists of TP and DP1 have been negative• Single study in humans of CRTh2 antagonist in moderate asthma

demonstrated modest effect at best, but several antagonists in early phase development

Acknowledgements

Das Mutalithas C GuillenCaroline Day C Brightling ID Pavord F Symon

Asthma UKGSK