Abstract
Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU.
Highlights
Bruton’s tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU)
This phase 2, multicenter, randomized, double-blind, placebo-controlled, pilot and dose-ranging study (EudraCT ID 2016-004624-35; ClinicalTrials.gov ID NCT03137069) examined fenebrutinib efficacy and safety compared to placebo in adult patients who had CSU for more than six months and were symptomatic despite treatment with H1 antihistamines
Selective inhibition of BTK, a key protein downstream of FcεRI and B cell receptor (BCR) signaling, with fenebrutinib resulted in clinically meaningful treatment benefit in patients with CSU refractory to antihistamines
Summary
Among patients with IgG-anti-FcεRI autoantibodies, fenebrutinib substantially reduced these autoantibodies at week 8 at all dose levels compared to placebo (median percentage change from baseline: −43.7, −53.6 and −44.0% in 50 mg daily, 150 mg daily and 200 mg twice daily fenebrutinib groups, respectively; placebo, 20.4%) (Fig. 3b) These changes were probably not due to a broader treatment effect on total antibodies; in cohort 1, compared to placebo, fenebrutinib did not cause obvious reductions in IgG subtypes (Extended Data Fig. 8), including IgG1 and IgG3, Articles the predominant subclasses of IgG-anti-FcεRI in CSU37. No other clinically meaningful changes were observed in any other laboratory parameters
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