Mast cell inhibitor R112 is well tolerated and affects prostaglandin D₂ but not other mediators, symptoms, or nasal volumes in a nasal challenge model of allergic rhinitis

Abstract

Understanding of the role played by mast cells in allergic rhinitis (AR) has led to the development of novel therapies. The aim of this study was to determine the safety and tolerability of R112, an inhibitor of the tyrosine kinase Syk, in an allergen challenge model of AR. We also examined the effects of R112 on symptoms, mediator release, and nasal airway volumes. This double-blinded, randomized, placebo-controlled, crossover trial enrolled 20 out-of-season volunteers with AR. One intranasal dose of R112 or vehicle was administered and followed by an allergen challenge. In addition to safety monitoring, symptoms; changes in histamine, tryptase, and prostaglandin D2 (PGD2) content of nasal secretions; and acoustic rhinometry were determined over a 15-minute period. R112 was well tolerated. Adverse events were similar between treatments. Five minutes after allergen instillation, PGD2 was decreased when subjects received R112 compared with vehicle (93.4 +/- 23.0 pg/mL versus 171.6 +/- 23.0 pg/mL; p = 0.03), and this correlated with rhinorrhea (p = 0.05). However, at 10 minutes, changes in PGD2, tryptase, and histamine were not significant (46.8 +/- 9.2 pg/mL versus 68.6 +/- 9.2 pg/mL, p = 0.1; 9.5 +/- 2.7 ng/mL versus 16.6 +/- 2.9 ng/mL, p = 0.09; and 1.5 +/- 1.6 ng/mL versus 3.5 +/- 1.6 ng/mL, p = 0.4). No differences were found in symptoms or in acoustic rhinometry between treatment groups. Single-dose R112 appears safe and significantly reduces PGD2 but not histamine or tryptase release in response to allergen challenge in subjects with AR.

Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk

“…17,40,41 Syk inhibitors are also being evaluated for use in nasal sprays for the treatment of symptoms of seasonal allergic rhinitis. [42][43][44] In this respect curcumin has similar potential for topical therapy of various allergic diseases, including allergic rhinitis, especially in view of its low toxicity in human subjects. Curcumin is a potent inhibitor of antigen-stimulated degranulation and cytokine secretion in mast cells and of mast cell-mediated PCA in mice.…”

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

“…A Syk tyrosine kinase inhibitor, R112, which disrupts mast cell IgE-FceRI signaling has displayed promising results in recent clinical trials and may represent a new class of allergy therapeutics [149,150]. MAPKs are also well-recognized mediators of mast cell activation, survival, differentiation and cytokine production.…”

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…To avoid side effects, topical formulations have been developed. A nasal spray formulation of R112 was weakly effective in patients with seasonal allergic rhinitis exposed to outdoor allergens (Meltzer et al, 2005) and transiently decreased the concentration of PGD 2 in nasal lavage after nasal allergen challenge but had no effect on either histamine or mast cell tryptase (Guyer et al, 2006). A novel Syk inhibitor suitable for inhalation, LAS189386 [1-{2-[(1S,4S)-2,5-diazabicyclo [2.2.1]hept-2-yl]pyridin-4-yl}-N-pyrazin-2-yl-1H-indazol-3-amine], delivered to ovalbumin-sensitized Brown Norway rats showed good inhibition of the early response to allergen and of mast cell degranulation, without any effects on systemic mast cells (Ramis et al, 2015), and so is in clinical development for asthma.…”