Abstract and Introduction
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://clinicaltrials.gov, NCT03100942.
SS is a systemic autoimmune disease primarily affecting exocrine glands, leading to symptoms of dry eyes and mouth. Systemic manifestations are common, and health-related quality of life can be severely impacted.[2,3] Sjögren's may manifest alone or alongside another autoimmune disease. SS is considered to be among the most common autoimmune disorders; however, due in part to varying diagnostic criteria, prevalence estimates across nations vary considerably (from 0.03% to as high as 2.7%).[1,4]
To date, no disease-modifying treatment has been approved for the treatment of SS. The results of small, open-label or controlled studies evaluating DMARDs or biologics used in related autoimmune diseases have been mixed.[6–11] Larger and controlled clinical trials have been infrequent and thus far have not identified an effective immunomodulatory treatment for the systemic or glandular manifestations.[11–13] Thus, treatment of SS is typically determined by symptoms; modalities may include saliva substitution for severe oral dryness, artificial tears for first-line ocular dryness, and analgesics for musculoskeletal pain. An unmet medical need for novel therapies persists.
In SS patients, proinflammatory cytokines, including Type I and Type II interferons, are overexpressed in glandular tissue and in the peripheral blood, and the Janus kinase (JAK)/signal transducer and activator of transcription proteins (STAT) pathway plays a pivotal role in their signal transduction.[15,16] Two recent studies demonstrated an increased expression of both Bruton's tyrosine kinase (BTK) mRNA and protein in B cells of patients with SS compared with B cells from healthy controls; systemic B cell hyperreactivity is a hallmark of SS. Additionally, spleen tyrosine kinase (SYK) and BTK play a key role in B cell receptor signalling.[17,18] Therefore, JAK/STAT, SYK and BTK appear to be relevant therapeutic targets to evaluate in potential treatments for SS. Filgotinib is a once-daily, oral JAK-1 preferential inhibitor approved in Japan and Europe for the treatment of moderately to severely active RA.[20,21] Lanraplenib is a potent and selective oral inhibitor of SYK that is in development for the treatment of inflammatory and autoimmune diseases. Tirabrutinib is a potent and selective inhibitor of BTK under development for the treatment of B cell malignancies and inflammatory diseases and is approved for the treatment of recurrent or refractory primary CNS lymphoma in Japan. Here, we present the results of a Phase 2 study evaluating the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in adult patients with active primary and secondary SS; the study also examined mechanistic effects via biomarkers.[15,24–26]
Rheumatology. 2022;61(12):4797-4808. © 2022 Oxford University Press