Avacopan in Eosinophilic Disorders
Critical Clarification
There appears to be confusion in the question: Avacopan is a C5a receptor antagonist used for ANCA-associated vasculitis, NOT a prostaglandin D2 receptor 2 (DP2/CRTH2) antagonist. The evidence provided discusses DP2/CRTH2 antagonists for eosinophilic disorders, which are an entirely different drug class. I will address DP2/CRTH2 antagonists as they relate to eosinophilic conditions based on the available evidence.
Role of DP2/CRTH2 Antagonists in Eosinophilic Disorders
Current Evidence Summary
DP2/CRTH2 antagonists have shown only modest effectiveness in eosinophilic airway disease and are NOT currently recommended for routine use in eosinophilic disorders. 1
Mechanism and Rationale
Prostaglandin D2 (PGD2) acts through DP2 receptors (also called CRTH2) located on Th2 cells, innate lymphoid type 2 cells (ILC2), and eosinophils, interlinking adaptive and innate immune pathways in type 2 disorders 1
PGD2 is a key mediator in allergic rhinitis, chronic rhinosinusitis, and asthma, making DP2 receptors an attractive theoretical target 1
Animal studies demonstrate that DP2 receptor activation induces robust eosinophilic pulmonary infiltration, with selective DP2 agonists producing marked airway eosinophilia within 2-12 hours 2, 3
Clinical Trial Results in Asthma
The evidence shows disappointing clinical outcomes despite biological plausibility:
Initial proof-of-concept studies showed only modest protection against allergen-mediated airway responses in both upper and lower respiratory tracts 1
When given as monotherapy or added to standard controllers for 4-12 weeks in mild-to-moderate asthma, CRTH2 antagonists demonstrated similarly modest effectiveness on symptom scores, disease control, lung function, and inflammatory markers 1
Overall therapeutic effectiveness was comparable to antihistamines and leukotriene receptor antagonists (LTRAs), with some studies showing improved effectiveness only in selected patient populations 1
In moderate-to-severe asthma uncontrolled by corticosteroids, a dual DP/CRTH2 antagonist (AMG853) failed to show clinical effectiveness after 12 weeks 1
Fevipiprant (another CRTH2 antagonist) reduced airway eosinophils and improved clinical parameters in moderate-severe asthma patients with sputum eosinophilia when added to corticosteroids for 12 weeks 1
A phase 2b trial with GB001 (DP2 antagonist) in moderate-to-severe eosinophilic asthma did not significantly reduce asthma worsening, though reductions favoring GB001 were observed; the 60 mg dose was associated with elevated liver aminotransferases and increased adverse events leading to discontinuation 4
Eosinophilic Esophagitis and Gastrointestinal Disease
Montelukast (leukotriene antagonist, not a DP2 antagonist but related pathway) and antihistamines are NOT recommended for eosinophilic esophagitis management 1
Montelukast at 20 mg/day showed only 40% remission in treatment group versus 23.8% in controls after 26 weeks (OR 0.48,95% CI 0.10-2.16, p=0.33) 1, 5
These agents may have a role only in concomitant atopic disease, not for primary eosinophilic disorder treatment 1, 5
Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)
No published data exist on CRTH2 antagonists in CRSwNP, though their mechanism suggests potential clinical utility in type 2 disease 1
- Future studies combining CRTH2 antagonists with LTRAs or biologicals on top of corticosteroids are needed to provide evidence 1
Clinical Recommendation Algorithm
Do NOT Use DP2/CRTH2 Antagonists as First-Line Therapy
For eosinophilic disorders, prioritize established therapies:
Eosinophilic esophagitis: Use PPIs twice daily for 8-12 weeks, followed by topical corticosteroids if inadequate response 1, 6
Eosinophilic enteritis: Use systemic corticosteroids as first-line therapy 5
Eosinophilic asthma: Use inhaled corticosteroids as foundation therapy; consider biologics (dupilumab, mepolizumab, benralizumab) for severe disease 1
Consider DP2/CRTH2 Antagonists Only In:
- Research settings or clinical trials 1
- Patients with moderate-severe eosinophilic asthma with documented sputum eosinophilia who have failed standard therapies and are not candidates for biologics 1
Critical Pitfalls to Avoid
- Do not confuse avacopan (C5a antagonist) with DP2/CRTH2 antagonists - they are completely different drug classes for different diseases
- Do not use DP2 antagonists as monotherapy - they have shown insufficient efficacy 1
- Monitor liver function if using higher doses - GB001 60 mg was associated with hepatotoxicity 4
- Do not expect dramatic clinical improvement - even when biological effects (eosinophil reduction) are observed, symptom improvement may be modest 1, 4