Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren's syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial

Abstract

Objectives: To evaluate the safety and efficacy of remibrutinib in patients with moderate-to-severe Sjögren's syndrome (SjS) in a phase 2 randomised, double-blind trial (NCT04035668; LOUiSSE (LOU064 in Sjögren's Syndrome) study).

Methods: Eligible patients fulfilling 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for SjS, positive for anti-Ro/Sjögren's syndrome-related antigen A antibodies, with moderate-to-severe disease activity (EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (based on weighted score) ≥ 5, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥ 5) received remibrutinib (100 mg) either one or two times a day, or placebo for the 24-week study treatment period. The primary endpoint was change from baseline in ESSDAI at week 24. Key secondary endpoints included change from baseline in ESSDAI over time, change from baseline in ESSPRI over time and safety of remibrutinib in SjS. Key exploratory endpoints included changes to the salivary flow rate, soluble biomarkers, blood transcriptomic and serum proteomic profiles.

Results: Remibrutinib significantly improved ESSDAI score in patients with SjS over 24 weeks compared with placebo (ΔESSDAI -2.86, p=0.003). No treatment effect was observed in ESSPRI score (ΔESSPRI 0.17, p=0.663). There was a trend towards improvement of unstimulated salivary flow with remibrutinib compared with placebo over 24 weeks. Remibrutinib had a favourable safety profile in patients with SjS over 24 weeks. Remibrutinib induced significant changes in gene expression in blood, and serum protein abundance compared with placebo.

Conclusions: These data show preliminary efficacy and favourable safety of remibrutinib in a phase 2 trial for SjS.

Keywords: Patient Reported Outcome Measures; Sjogren's Syndrome; Therapeutics.

Figure 1

Patient disposition. n=number of subjects per treatment group in the analysis set. ALT, alanine aminotransferase; AST, aspartate aminotransferase; bid, two times a day; DMARD, disease-modifying antirheumatic drug; ESSDAI, EULAR Sjögren's Syndrome Disease Activity Index; ESSPRI, EULAR Sjögren's Syndrome Patient Reported Index; INR, international normalised ratio; qd, one time a day.

Figure 2

Change from baseline in ESSDAI total score (A), ESSPRI total score (B), and unstimulated salivary flow rate (C) over 24 weeks in the remibrutinib treatment and placebo groups using the mixed effect model for repeated measures. * = two-sided p<0.05 versus placebo. ESSDAI, EULAR Sjögren’s Syndrome Disease Activity Index; ESSPRI, EULAR Sjögren’s Syndrome Patient Reported Index.

Figure 3

The proportion of ESSDAI and STAR responders in remibrutinib and placebo groups at week 12 and week 24. Error bars represent 95% CI (Clopper-Pearson method). ESSDAI responder was defined as three or more points reduction from baseline. ESSDAI, EULAR Sjögren’s Syndrome Disease Activity Index; STAR, Sjögren’s Tool for Assessing Response

Figure 4

Ratio to baseline in CXCL13, immunoglobulins: IgG, IgM and IgA, and autoantibodies: SS-B antibody, SSA-Ro-60 antibody, SSA-Ro-52/TRIM21 antibody, in remibrutinib and placebo groups over 24 weeks. The geometric mean (SE) is calculated directly from the observed data. CXCL13, C-X-C Motif Chemokine Ligand 13; Ig, immunoglobulin; SSA, Sjögren’s syndrome-related antigen A; SSB, Sjögren’s syndrome-related antigen B; TRIM21, Tripartite Motif Containing Protein 21.

Figure 5

Gene expression profile associated with remibrutinib. Volcano plot representing differentially expressed genes across time with remibrutinib at week 24 versus week 0 (A), and boxplots representing normalised counts for FCRL5, SOX5, SYNPO and TNFRSF17 at week 0 and 24 (B). Adj. p value<0.0001****; <0.001***; <0.01**; <0.05*; >0.1 = not significant.

Figure 6

Volcano plots representing differential expressed serum protein profiles associated with remibrutinib treatment at weeks 4, 12 and 24. The Treatment*Week 4 interaction represents alterations in protein abundance between week 4 and baseline (week 0), in the treated groups while accounting for placebo. Similarly, the Treatment*Week 12 and Treatment*Week 24 interactions represent changes in protein abundance between those time points and baseline (week 0), while accommodating the variability within the ‘Placebo’ and ‘Treatment’ groups. Duplicate appearance of certain proteins is related to different SOMAmer features in SomaScan directed to the same protein.