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Clinical Trial
. 2021 Nov;27(11):1961-1969.
doi: 10.1038/s41591-021-01537-w. Epub 2021 Nov 8.

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial

Martin Metz  1   2 , Gordon Sussman  3 , Rémi Gagnon  4 , Petra Staubach  5 , Tonny Tanus  6 , William H Yang  7 , Jeremy J Lim  8 , Holly J Clarke  8 , Joshua Galanter  8 , Leslie W Chinn  8 , Tom Chu  8 , Anastasia Teterina  9 , Tracy Burgess  8 , D James Haddon  8 , Timothy T Lu  8 , Marcus Maurer  10   11
Affiliations
Clinical Trial

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial

Martin Metz et al. Nat Med. 2021 Nov.

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.

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Conflict of interest statement

M. Metz reports receiving honoraria as a speaker and/or consultant for Amgen, Aralez, argenx, Moxie, Novartis, Roche, Sanofi, Shire and Uriach. G.S. reports serving as a principal investigator for Genentech, Novartis, CSL Behring, Shire, Sanofi, AstraZeneca, DBV Technologies, Aimmune Therapeutics, Greencross, Kedrion, ALK-Abelló, Stallergenes, LEO Pharma, Amgen, BioCryst, Regeneron and Cliantha; serving on advisory boards for Novartis, CSL Behring, Shire, Sanofi, Aralez, Pediapharm and AstraZeneca; serving as a speaker for Novartis, Sanofi, Aralez, Pediapharm, Genentech and AstraZeneca; receiving personal fees from Novartis, CSL Behring, Shire, Sanofi, Aralez, Pediapharm and AstraZeneca. T.T. reports receiving funding from Genentech to his institution for the conduct of this study. W.H.Y. reports receiving speakers’ fees from Novartis, Merck, CSL Behring, Takeda (Shire) and AstraZeneca; serving on advisory boards for Novartis, Takeda (Shire), CSL Behring, Sanofi, BioCryst and Merck; and receiving research grants from Novartis, Takeda (Shire), CSL Behring, BioCryst, AstraZeneca, Regeneron, Sanofi, Genentech, Glenmark, AnaptysBio, Dermira, Galderma, ALK, DBV Technologies, Aimmune Therapeutics, Colgene and Pharming. J.J.L., H.J.C., J.G., L.W.C., T.C., T.B., D.J.H. and T.T.L. are current or former employees of Genentech, a member of the Roche group, at the time this work was performed and own/owned Roche stock and/or options. L.W.C. is currently an employee of Principia Biopharma and owns Principia Biopharma stock and/or options. D.J.H. owns Principia Biopharma stock. T.T.L. is currently an employee of DiCE Molecules. M. Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GI Innovation, Innate Pharma, Kyowa Kirin, LEO Pharma, Lilly, Menarini, Moxie, Merck Sharp & Dohme, Novartis, Roche, Sanofi/Regeneron, Third Harmonic Bio, UCB and Uriach. R.G. and P.S. declare no competing interests.

Figures

Fig. 1
Fig. 1
CONSORT diagram for cohort 2.
Fig. 2
Fig. 2. Effects of fenebrutinib on the UAS7, UAS7 components and proportion of well-controlled responders.
a, Mean profile plot of change from baseline in the UAS7 by study week in the different treatment arms. b,c, Mean change from baseline in UAS7 components: weekly itch score (b) and weekly hive score (c). a–c, n = 23 patients for each arm at the initial time point; no imputation for missing values was performed. The center is the mean and the error bars are the s.e.m.; the blue shaded area is the follow-up period. d, Proportion of patients who were well-controlled responders (UAS7 ≤ 6). The complete patient numbers per arm are shown in Supplementary Table 1.
Fig. 3
Fig. 3. Effects of fenebrutinib on markers of type IIb autoimmunity.
a, UAS7 values, stratified by baseline BHRA, IgG-anti-FcεRI and IgE concentrations in the placebo and fenebrutinib dose groups from baseline through week 12. Thin lines, individual patients; thick lines, means. No imputation for missing values was performed. The blue shaded area represents the follow-up period. b, Percentage change in IgG-anti-FcεRI at week 8. The horizontal bars represent the medians. c, Correlation of percentage change in IgG-anti-FcεR1 with change in UAS7 at week 8. b,c, Analyses were performed in patients who were IgG-anti-FcεRI+ at baseline. The ρ (rho) value is based on a Spearman correlation.
Extended Data Fig. 1
Extended Data Fig. 1. Study design.
Study design.
Extended Data Fig. 2
Extended Data Fig. 2. Study flow in cohort 1.
Study flow in cohort 1.
Extended Data Fig. 3
Extended Data Fig. 3. Complete responders in Cohort 2.
Proportion of patients who were complete responders in Cohort 2.
Extended Data Fig. 4
Extended Data Fig. 4. Time to MID in UAS7 score.
Time to MID (Kaplan-Meier estimate) in UAS7 score (modified intention-to-treat population). (a) Cohort 2. (b) Cohort 1.
Extended Data Fig. 5
Extended Data Fig. 5. UAS7 at Week 8.
UAS7 at Week 8 in all patients and patients stratified by (a) BHRA and (b) IgE in Cohort 2. Stratification by IgG-anti-FcεRI was not performed due to small sample size.
Extended Data Fig. 6
Extended Data Fig. 6. UAS7 stratified by (a) BHRA, (b) IgG-anti-FcεRI, and (c) IgE concentrations in Cohort 1.
UAS7 stratified by (a) BHRA, (b) IgG-anti-FcεRI, and (c) IgE concentrations in Cohort 1. Thin lines, individual patients. Thick lines, means. Blue shaded area, follow-up period.
Extended Data Fig. 7
Extended Data Fig. 7. UAS7 at Week 8 in all patients and patients stratified by (a) BHRA and (b) IgE in Cohort 1.
UAS7 at Week 8 in all patients and patients stratified by (a) BHRA and (b) IgE in Cohort 1. Stratification by IgG-anti-FcεRI was not performed due to small sample size.
Extended Data Fig. 8
Extended Data Fig. 8. Change in total serum concentrations of immunoglobulin subclasses during the treatment period in Cohort 1.
Change in total serum concentrations of immunoglobulin subclasses during the treatment period in Cohort 1. Thin lines, individual patients; thick blue lines, means.
See this image and copyright information in PMC

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