Clinical studies of the DP1 antagonist laropiprant in asthma and allergic rhinitis

Background

Prostaglandin D₂ is a proinflammatory mediator believed to be important in asthma and allergic rhinitis (AR). Allelic variants in the prostaglandin D₂ receptor type 1 (DP1) gene (PTGDR) have been suggested to be associated with asthma susceptibility.

Objectives

We sought to investigate the efficacy of the DP1 antagonist laropiprant (alone or with montelukast) in asthma and seasonal AR and explore whether sequence variations in PTGDR are associated with asthma severity.

Methods

For asthma, in a double-blind crossover study, 100 patients with persistent asthma were randomized to placebo or laropiprant, 300 mg/d for 3 weeks, followed by addition of montelukast, 10 mg/d for 2 weeks. PTGDR promoter haplotypes were categorized as high, medium, or low transcriptional efficiency. The primary efficacy end point was FEV₁. For AR, in a double-blind parallel-group study, 767 patients sensitized to a regionally prevalent fall allergen with symptomatic fall rhinitis were allocated to laropiprant, 25 mg/d or 100 mg/d; cetirizine, 10mg/d; or placebo for 2 weeks. The primary end point was the Daytime Nasal Symptoms Score.

Results

For asthma, no significant differences in FEV₁ or asthma symptoms were noted for laropiprant versus placebo or laropiprant plus montelukast vs montelukast (differences between montelukast and placebo: P ≤ .001). No clear association was seen between haplotype pair (ie, diplotype) and asthma severity. For AR, although cetirizine (vs placebo) demonstrated an improvement in the Daytime Nasal Symptoms Score (P < .001), laropiprant did not.

Conclusion

Laropiprant did not demonstrate efficacy in asthmatic patients or patients with AR. Variations in PTGDR did not appear related to baseline asthma severity or treatment response (NCT00533208; NCT00783601).

Key words: Prostaglandin D receptor gene promoter, asthma susceptibility, airway disease, montelukast

Abbreviations used: AE, Adverse experience, AR, Allergic rhinitis, CRTH2, Chemoattractant receptor-homologous molecule on T-helper type 2 cells, also known as DP2, DASS, Daytime Asthma Symptoms Score, DNSS, Daytime Nasal Symptoms Score, DP1, D prostanoid type 1 receptor, also known as PGD₂ type 1 receptor, H haplotype, High-transcriptional-efficiency haplotype, L haplotype, Low-transcriptional-efficiency haplotype, M haplotype, Medium-transcriptional-efficiency haplotype, NASS, Nighttime Asthma Symptoms Score, PEF, Peak expiratory flow, PGD₂, Prostaglandin D₂, PTGDR, Prostaglandin D receptor gene, SABA, Short-acting β-agonist