Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjögren's syndrome: a randomized, phase 2, double-blind, placebo-controlled study

Elizabeth Price, Michele Bombardieri, Alan Kivitz, Franziska Matzkies, Oksana Gurtovaya, Alena Pechonkina, Wendy Jiang, Bryan Downie, Anubhav Mathur, Afsaneh Mozaffarian, Neelufar Mozaffarian, J Eric Gottenberg, Elizabeth Price, Michele Bombardieri, Alan Kivitz, Franziska Matzkies, Oksana Gurtovaya, Alena Pechonkina, Wendy Jiang, Bryan Downie, Anubhav Mathur, Afsaneh Mozaffarian, Neelufar Mozaffarian, J Eric Gottenberg

Abstract

Objective: The aim of this study was to characterize the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in patients with active SS.

Methods: This multicentre, double-blind study randomized patients with active primary or secondary SS [EULAR SS disease activity index (ESSDAI) ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton's tyrosine kinase inhibitor), or placebo. The composite primary end point was the week-12 proportion of patients fulfilling protocol-specified improvement criteria (based on CRP and SS-related symptoms). The EULAR SS patient-reported index (ESSPRI) and the ESSDAI change from baseline (CFB) were secondary end points. Exploratory end points included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes.

Results: The mean of the baseline ESSDAI was 10.1, and of ESSPRI was 6.2 in the 150 patients who were treated; 125 completed the 24-week placebo-controlled treatment period. At week 12, 43.3% of the filgotinib group achieved the primary end point (P = 0.17 vs placebo) vs 42.3% (P = 0.16), 34.7% (P = 0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without DMARDs/CSs. Most AEs were Grade 1 or 2.

Conclusion: Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary end points were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings.

Trial registration: ClinicalTrials.gov, https://ichgcp.net/clinical-trials-registry/NCT03100942" title="See in ClinicalTrials.gov">NCT03100942.

Keywords: Sjögren's syndrome; efficacy; filgotinib; lanraplenib; randomized trial; safety; tirabrutinib.

© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.

Figures

Fig . 1
Fig. 1
Study design and disposition (A) Study schema. After screening, eligible patients were randomized 1:1:1:1 in a blinded fashion to receive FIL 200 mg QD (n = 38), LANRA 30 mg QD (n = 37), TIRA 40 mg QD (n = 39) or PBO (n = 36) for 24 weeks. Initial randomization was stratified by concurrent use of systemic CSs or csDMARDs and by ESSDAI haematologic + biological domain score <2 or ≥2. The primary end point was assessed at W12 and secondary end points at W12 and W24. The FIL, LANRA and TIRA groups continued treatment until W48. At W24, the PBO group was re-randomized 1:1:1 into other treatment groups until W48. All patients had 4-week follow-up at W52. (B) Study disposition by treatment phase. One hundred and fifty-two patients were randomized; 150 patients received at least one dose of a study drug and were included in the safety analysis set. Thirty-four (89.5%) and 30 (78.9%) of the patients in the FIL group completed treatment at W12 and W24, respectively. Thirty (81.1%) and 27 (73.0%) of the patients in the LANRA group completed treatment at W12 and W24, respectively. Thirty-six (92.3%) of the patients in the TIRA group completed treatment at W12 and W24. Thirty-four (94.4%) and 32 (88.9%) of the patients in the PBO group completed treatment at W12 and W24, respectively. BIO: biological component score of ESSDAI; csDMARD: conventional synthetic DMARD; ESSDAI: EULAR SS disease activity index; FIL: filgotinib; HEM: haematologic component score of ESSDAI; LANRA: lanraplenib; PBO: placebo; QD: once daily; TIRA: tirabrutinib; W: week.
Fig . 2
Fig. 2
Primary end point, proportion of responders at W12 The primary end point is summarized using the full analysis set, which includes patients who were randomized and received at least one dose of the study drug. Error bars show 95% CIs. Numbers on graph show difference in response rate vs PBO, 95% CI of differences vs placebo, and the P-value of the active treatment group compared with PBO. FIL: filgotinib; LANRA: lanraplenib; PBO: placebo; TIRA: tirabrutinib; W: week.
Fig . 3
Fig. 3
ESSDAI score–adjusted mean change from baseline (A) Overall study population. Error bars show 95% CI of LS mean. LS means, 95% CIs and P values were obtained from a mixed-effects model for repeated measures with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction. **P < 0.01 vs placebo. The baseline value was the last available value collected on or prior to first dose of the study drug (day 1). (B) ESSDAI score–adjusted mean change from baseline in patients with baseline ESSDAI ≥14. Markers indicate median; error bars indicate interquartile range. Numbers below the graph show numbers of patients. The baseline value was the last available value collected on or prior to the first dose of the study drug (day 1). (C) The ESSDAI score–adjusted mean change from baseline in patients not taking DMARDs/CSs at baseline. Markers indicate median; error bars indicate interquartile range. Numbers below the graph show numbers of patients. The baseline value was the last available value collected on or prior to the first dose of the study drug (day 1). ESSDAI: EULAR SS disease activity index; FIL: filgotinib; LANRA: lanraplenib; LS: least square; PBO: placebo; Q1: first quartile; Q3: third quartile; TIRA: tirabrutinib.
Fig . 4
Fig. 4
Biomarker changes (A) Median percentage change in biomarker activity after treatment. The heat map represents changes from baseline at Weeks 4, 12 and 24 (bottom labels) in each treatment group (top labels). At baseline, 50%, 71.4%, 52.6% and 71.4% of patients in the filgotinib, lanraplenib, tirabrutinib and placebo groups had RF values below the LLOQ; 2.6% of patients in the tirabrutinib group had IgM levels below LLOQ; no patients had IgG levels below LLOQ; and 8.3% of patients in the placebo group had CRP levels below LLOQ. Treated groups were compared with placebo by the Wilcoxon rank-sum test with Hommel’s method for multiplicity adjustment. ***P < 0.001, **P < 0.01, *P < 0.05. (B) Change in Type I IFN signature from baseline by treatment group. The y-axis shows the adjusted mean and 95% CI of change in the pathway activity score following treatment. The outlined circle is a statistically significant difference compared with baseline and placebo. LLOQ: lower limit of quantification.

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