prostaglandin d2: therapeutic indications world allergy organisation cancun 2011 andy wardlaw
TRANSCRIPT
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