Prostaglandin D₂ receptor antagonists in allergic disorders: safety, efficacy, and future perspectives

ABSTRACT

Introduction: Prostaglandin D₂ (PGD₂) is a major cyclooxygenase mediator that is synthesized by activated human mast cells and other immune cells. The biological effects of PGD₂ are mediated by D-prostanoid (DP₁), DP₂ (CRTH2) and thromboxane prostanoid (TP) receptors that are expressed on several immune and non-immune cells involved in allergic inflammation. PGD₂ exerts various proinflammatory effects relevant to the pathophysiology of allergic disorders. Several selective, orally active, DP₂ receptor antagonists and a small number of DP₁ receptor antagonists are being developed for the treatment of allergic disorders.

Areas covered: The role of DP₂ and DP₁ receptor antagonists in the treatment of asthma and allergic rhinitis.

Expert opinion: Head-to-head studies that compare DP₁ antagonists with the standard treatment for allergic rhinitis are necessary to verify the role of these novel drugs as mono- or combination therapies. Further clinical trials are necessary to verify whether DP₂ antagonists as monotherapies or, more likely, as add-on therapies, will be effective for the treatment of different phenotypes of adult and childhood asthma. Long-term studies are necessary to evaluate the safety of targeted anti-PGD₂ treatments.

KEYWORDS:

• Asthma
• CRTH2
• DP₂
• fevipiprant
• mast cells
• prostaglandin D₂
• rhinitis
• allergic disorders

Article Highlights

• Prostaglandin D₂ (PGD₂), the major cyclooxygenase mediator produced by activated human mast cells, plays a role in allergic inflammation through the engagement of DP₁ and DP₂ (also known as CRTH2) receptors expressed on several immune and stromal cells.

• Several trials have universally found DP₁ and DP₂ antagonists to be safe and well tolerated.

• Only few DP₁ antagonists have been reported to be effective in reducing symptoms of allergic rhinitis.

• Different DP₂ antagonists have demonstrated efficacy in phase II studies in adults with asthma.

• Several phase III trials are evaluating the long-term safety and efficacy of DP₂ antagonists in adult and pediatric patients with moderate-to-severe asthma.

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Acknowledgments

The authors thank scientists from CISI Laboratory for invaluable collaborations; medical graphic artist Fabrizio Fiorbianco and the administrative staff (Dr. Roberto Bifulco and Dr. Anna Ferraro), without whom we could not function as an integrated team.

Declaration of interest

The authors have no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One referee has received consultation fees from Novartis Pharma and Teijin Pharma for the development of DP2 antagonists. Other peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was funded in part by grants from Regione Campania CISI-Lab Project, CRèME Projec, and TIMING Project.