Prostaglandin d2 therapeutic indications world allergy organisation cancun 2011
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Prostaglandin D2: Therapeutic Indications World Allergy Organisation Cancun 2011. Andy Wardlaw. Disclosures. Research grants from Glaxo Smith Kline (GSK), AstraZeneca and Pfizer Honorariums for advisory boards from GSK and Cephalon. Environmental Trigger. AllergenInfectionSmoking. Eos.

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Prostaglandin D2: Therapeutic Indications World Allergy Organisation Cancun 2011

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Prostaglandin d2 therapeutic indications world allergy organisation cancun 2011

Prostaglandin D2: Therapeutic IndicationsWorld Allergy OrganisationCancun 2011

Andy Wardlaw


Disclosures

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

AllergenInfectionSmoking

Eos

BRONCHIAL INFLAMMATION

Neuts

Uncontrolled Falls in

FEV1

(Severe

Exacerbations)

Airway Damage

(fixed airflow obstruction

Bronchiectasis)

Variable Airflow

Obstruction & AHR

(Asthma Like)

Increased cough reflex

(cough)

Airway inflammation leads to several patho-physiological outcomes


The a to e of airway disease pavord id and wardlaw aj clin exp allergy 2010 40 62 67

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

  • AAirway hyperresponsiveness

    • Rapid variations in airflow obstruction

  • BBronchitis

    • Eosinophilic:neutrophilic:both

  • CCough

  • DDamage

    • Bronchiectasis

    • fixed airflow obstruction

    • emphysema

  • EExtrapulmonary 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

  • Methacholine PC20 (mg/ml)

Sputum Eosinophil Count (%)

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

Uncontrolled,

Treatment

Unresponsive

Falls in FEV1

Variable Airflow

Obstruction/AHR

Asthma

Symptoms

Severe

Exacerbations

Eosinophilic

Inflammation

Smooth Muscle

Dysfunction


Pgd 2

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


Prostaglandin d2 therapeutic indications world allergy organisation cancun 2011

Synthetic pathway for PGD2

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


Pgd 21

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.


Prostaglandin d2 therapeutic indications world allergy organisation cancun 2011

No increase in PGD2 in sputum from patients

with asthma

Mediator concentrations ng/ml sputum

*p<0.05, ANOVA

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


Antagonism and over expression of pgd 2

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


Pgd 2 receptors

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


Dp 1 receptor

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 dp 1 antagonist laropiprant phillip g et al jaci 2009 124 942 8

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

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

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

CRTh2 expression on T cells in asthma

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


Crth2 is preferentially expressed on th2 cells

CRTh2 is preferentially expressed on Th2 cells

Asthma

Healthy


Prostaglandin d2 therapeutic indications world allergy organisation cancun 2011

CCR3, CCR4, CRTh2 and CCR8 are preferentially

expressed on Th2 cells but only a minority of

Th2 cells express these receptors

IL-4

IFNg


Of bal t cells expressing crth2

% of BAL T cells expressing CRTH2


Pgd 2 concentrations in bal

PGD2 concentrations in BAL


Antagonists of crth2 in clinical development

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 na ve asthma barnes et al cea 2012 epub

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

Study design


Prostaglandin d2 therapeutic indications world allergy organisation cancun 2011

OC000459 Phase II Asthma Study

Effect on FEV1 (Per Protocol Population)

Start

double blind

treatment

End

double blind

treatment

End

Placebo washout

Start

double blind

treatment

End

double blind

treatment

End

Placebo washout

% Change in FEV1 vs. Baseline

Change in FEV1 (ml) vs. Baseline

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

Clinically relevant improvement in FEV1


Effect of oc000459 on sputum eosinophilia in 28 day asthma study

Effect of OC000459 on sputum eosinophilia in 28 day asthma study


Conclusions

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

Acknowledgements

Das MutalithasC Guillen

Caroline Day C Brightling

ID Pavord F Symon

Asthma UK

GSK


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