Are emerging PGD2 antagonists a promising therapy class for treating asthma?

Figures & data

Figure 1. Asthma immunology.

Figure 2. Prostaglandin D₂ biology.

Table 1. Trials of CRTH2 antagonists in asthma.

Study	Year	Population	Intervention	Main findings
OC459
Barnes et al.	2012	ICS-free, allergic asthma n = 132	OC459 vs. placebo	Small but significant improvement in quality of life (AQLQ) and nighttime symptom scores Small improvement in FEV1, significant in per protocol analysis only (+9.2% vs. +1.8% placebo; p = 0.037)
Singh et al.	2013	ICS-naive allergic asthma FEV1 > 65% n = 16	OC459 vs. placebo	Effect on response to bronchial allergen challenge Reduced late but not early asthmatic response, reduced sputum eosinophils No effect on FEV1, FeNO
Pettipher et al.	2014	ICS-free, FEV1 60–85% n = 476	OC459 vs. placebo	Small but significant improvement in FEV1, ACQ, and AQLQ Nonsignificant trend toward reduced exacerbations
BI671800
Miller et al.	2012	ICS-treated, FEV1 60–85%, ACQ ≥1.5 n = 108	BI671800 + ICS vs. placebo + ICS	No significant difference in trough FEV1 or ACQ
Sutherland et al.	2012	ICS-naive, FEV1 60–85%, ACQ ≥1.5 n = 388	BI671800 vs. ICS vs. placebo	Small but significant improvement in FEV1 and ACQ
Hall et al.	2015	FEV1 60–85%, ACQ ≥1.5 (a) ICS-free (n = 388) (b) ICS-treated (n = 243)	(a) BI671800 vs. ICS (b) BI671800 + ICS vs. montelukast + ICS vs. placebo + ICS	For (a) small significant improvement in trough FEV1, no effect on ACQ For (b) small significant improvement in trough FEV1 and ACQ vs. placebo + ICS but not vs. montelukast + ICS
QAW039
Gonem et al.	2016	ICS-treated, ACQ ≥ 1.5, sputum eosinophil  ≥ 2% n = 61	QAW039 vs. placebo	Significant reduction in sputum eosinophils, and small significant improvements in FEV1 (+0.06 L vs. −0.10L placebo; p = 0.021) and AQLQ (+0.27 vs. −0.33 placebo; p = 0.008)—but not ACQ In subgroup with uncontrolled asthma at baseline, ACQ clinically and statistically significantly lower
Erpenbeck et al.	2016	Atopic, FEV1 60–85%, ACQ ≥ 1.5 n = 170	QAW039 vs. placebo	No significant differences in FEV1 or ACQ overall (both improved if baseline FEV1 < 70%)
Bateman et al.	2016	ICS-treated (low dose), FEV1 40–80%, ACQ ≥ 1.5 n = 1058	QAW039 + ICS vs. montelukast + ICS vs. placebo + ICS	Significant reduction in trough FEV1 vs. placebo, no effect on ACQ or AQLQ
ARRY-502
Wenzel et al.	2014	ICS-free, FEV1 60–85%, ACQ ≥ 1.5 n = 184	ARRY-502 vs. placebo	Patients with elevated Th2 associated biomarkers (e.g. FeNO) had improved spirometry, measures of asthma control and quality of life (unspecified)
Discontinued (AMG853, ACT-129968, AZD1981)
Busse et al.	2013	ICS-treated (200–1000μg/d fluticasone), FEV1 50–85%, ACQ ≥ 1.5 n = 396	AMG853 + ICS vs. placebo + ICS	No significant difference in ACQ, FEV1, symptoms, exacerbations, AQLQ, serum IgE, FeNO; discontinued
Diamant et al.	2014	ICS-free, house dust mite allergy, FEV1 > 70% n = 18	Setipiprant (ACT-129968) vs. placebo	Reduced late but not early asthmatic response No effect on serum eosinophils, IgE, and FeNO
NCT01225315 (unpublished)	2012	ISC-free, FEV1 ≤ 85%, ACQ ≥ 1.5 n = 438	Setipiprant (ACT-129968) vs. placebo	Did not replicate efficacy of allergen challenge model (no details available); discontinued
NCT00758589 (unpublished)	2013	ICS-treated, FEV1 40–85% n = 368	AZD1981 + ICS vs. Placebo + ICS	Significant improvement in ACQ, FEV1 only improved for middle of three doses; post-hoc analysis showed responders were atopic
NCT01197794 (unpublished)	2013	Atopic, ICS-LABA-treated, FEV1 40–85% n = 1144	AZD1981 + ICS-LABA vs. placebo + ICS-LABA	Only patients on second lowest dose demonstrated statistically significant improvement in FEV1; discontinued

ACQ: Asthma Control Questionnaire score; FEV; forced expiratory volume; ICS: Inhaled Corticosteroids.

Table 2. Trials of biologicals in asthma.

Study	Year	Drug	n		Selected outcomes (vs placebo)
				Exacerbations	Lung function / FEV1	Quality of life
		Anti-IgE
Cochrane meta-analysis	2014	Omalizumab	25 trials	38% reduction (OR 0.55)	Not significant	AQLQ +0.31
		Anti-IL-5/-5R
Haldar et al	2009	Mepolizumab	61	43% reduction (p=0.02)	Not significant	AQLQ +0.35 (p=0.02)
Nair et al	2009	Mepolizumab	20	Reduced (p=0.002) (12 exacerbations in 11 patients on placebo vs 1 in 9)	+300mL 4 weeks after last dose Not sustained 8 weeks after last dose	Not significant
Castro et al	2011	Reslizumab	106	Not significant	+240mL (p=0.002)	Not significant
Pavord et al	2012	Mepolizumab	621	39-52% reduction (p<0.001)  (range for different doses)	Not significant	Not significant
Ortega et al	2014	Mepolizumab	576	47-53% reduction (p<0.001)  (range for iv vs sc administration)	+98-100mL (p<0.05)	SGRQ +6.4-7.0 (p<0.001)
						ACQ -0.42-0.44 (p<0.001)
Bel et al	2014	Mepolizumab	135	32% reduction (p=0.04)	Not significant	ACQ +0.52 (p=0.004)
Castro et al	2014	Benralizumab	609	Not significant (Significant for subset with serum eosinophils >0.3x10^9/L)	Not significant (Significant for subset with serum eosinophils >0.3x10^9/L)	Not significant
Castro et al	2015	Reslizumab	953	54% reduction (p<0.0001)	+110mL (p<0.0001)	AQLQ +0.23 (p<0.0001) ACQ -0.25 (p<0.0001)
		Anti-IL-13
Corren et al	2011	Lebrikizumab	219	Not significant	+110mL (p<0.02)	Not significant
Piper et al	2013	Tralokinumab	194	Not significant (relatively few events)	+200mL (p<0.041) in highest dose subset only	Not significant
Noonan et al	2013	Lebrikizumab	212	79% reduction (p<0.001)	Not significant	Not significant
De Boever et al	2014	GSK679586	198	Not significant	Not significant	Not significant
Hanania et al	2015	Lebrikizumab	463	60% reduction in periostin high group (24% reduction whole cohort) (p values not given, assume <0.05)	+9.1% (periostin-high) +2.6% (periostin-low)	Not significant
		Anti-IL-4Rα
Wenzel et al	2013	Dupilumab	104	87% reduction (p<0.001)	+250mL (p=0.0002)	ACQ -0.37 (p=0.256)
Wenzel et al	2016	Dupilumab	769	33-71% reduction (ns to p=0.0001)	+100-200mL (p=0.03 to <0.0001)If EOs≥0.3/mL, +170-260mL (p=0.0002)	AQLQ + 0.23 to +0.36 (not significant for 200mg 4wkly; otherwise p<0.02) AQQ if 2wkly dosing -0.31 to -0.35 (p<0.005); not significant if 4 wkly

Notes: FEV1 = forced expiratory volume in 1 second, minimum clinically important difference (MCID) +230mL (+10%); AQLQ = Asthma Quality Life Questionnaire, MCID ≥+0.5; ACQ = Asthma Control Questionnaire, MCID ≤-0.5; SGRQ = St George’s Respiratory Questionnaire, MCID >+4.0

Legend: green = clinically and statistically significant (p<0.05); red = not statistically significant; none = statistically but not clinically significant or equivocal for some other reason (given)