Download PGD2 for WAO

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
Airway inflammation leads to several pathophysiological outcomes
Environmental Trigger
Allergen
Eos
Infection
Smoking
BRONCHIAL INFLAMMATION
Airway Damage
(fixed airflow obstruction
Bronchiectasis)
Variable Airflow
Obstruction & AHR
(Asthma Like)
Neuts
Uncontrolled Falls in
FEV1
(Severe
Exacerbations)
Increased cough reflex
(cough)
The A to E of Airway disease
Pavord 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
•Methacholine PC20 (mg/ml)
Eosinophilic Airway Inflammation and Variable
Airflow Obstruction (AHR) are Largely Independent
Uncontrolled,
Treatment
Unresponsive
32
16
8
Variable Airflow
Obstruction/AHR
Falls in FEV1
4
2
1
0.5
0.25
Severe
Exacerbations
Asthma
Symptoms
Eosinophilic
Inflammation
Smooth Muscle
Dysfunction
0.125
0.3
1
3
10
30
Sputum Eosinophil Count
(%)
100
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
Synthetic pathway for PGD2
Roy Pettipher et al Nature Reviews Drug Discovery 6, 313-325 (April 2007)
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.
No increase in PGD2 in sputum from patients
with asthma
Normal
(10)
Asthma
(17)
Eosinophilic
Bronchitis (8)
Cys-LT
ECP
Hist
PGD2
5.86
95
15.5
0.05
11.1*
735 *
25.1
0.09
9.27*
604 *
168*
0.78*
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 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
24
Bronchoscopy
Normal
7
Bronchoscopy
Asthma
12
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)
>16
1.0 (0.8)
>16
0.6 (0.9)
0
8
0
5
Normal
Asthma
20
Age**
n
Pc20++
On OCS
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
IFNg
% 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
OC000459 Phase II Asthma Study
Effect on FEV1 (Per Protocol Population)
% Change in FEV1 vs. Baseline
End
double
blind
treatment
Start
double
blind
treatment
End
Placebo
washout
Change in FEV1 (ml)
vs. Week 3 Baseline +/- SEM
% Change in FEV1
vs. Week 3 Baseline +/- SEM
Start
double
blind
treatment
Change in FEV1 (ml) vs. Baseline
15
10
5
0
-5
2
4
6
8
10
End
double
blind
treatment
End
Placebo
washout
300
200
100
0
-100
2
4
Week
6
8
Week
OC000459
Placebo
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
10
Effect of OC000459 on sputum eosinophilia in 28
day asthma study
OC000459
Placebo
% Sputum eosinophilia
15
10
5
*
0
Baseline
*
4 weeks
Baseline
4 weeks
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
Caroline Day
ID Pavord
C Guillen
C Brightling
F Symon
Asthma UK
GSK