Study to Assess Safety and Efficacy of Filgotinib, Lanraplenib and Tirabrutinib in Adults With Active Sjogren's Syndrome

• Lanraplenib (Drug), also known as GS-9876: 1 x 30 mg tablet administered orally once daily
• Filgotinib (Drug), also known as GS-6034: 1 x 200 mg tablet administered orally once daily
• Tirabrutinib (Drug), also known as GS-4059: 1 x 40 mg tablet administered orally once daily
• Lanraplenib placebo (Drug): 1 x tablet administered orally once daily
• Filgotinib placebo (Drug): 1 x tablet administered orally once daily
• Tirabrutinib placebo (Drug): 1 x tablet administered orally once daily

Primary outcomes

• Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline [Week 12]: Response was defined as: Improvement ≥ 20% in ≥ 3 of 5 participant-reported Sjogren's syndrome (SjS) related visual analogue score (VAS) measures (participant's assessment of global disease, pain, oral dryness, ocular dryness and fatigue), with no increase defined as > 30 mm from baseline (Day 1) in any of the above 5 VAS measures, AND either ≥ 20% improvement in high sensitivity C-reactive protein (hsCRP) (if hsCRP ≥ 1.5 x upper limit of normal \[ULN\] on Day 1) or no increase in hsCRP to ≥ 1.5 x ULN (if hsCRP < 1.5 x ULN on Day 1).

Secondary outcomes

• Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12 [Baseline; Week 12]: The ESSDAI is a physician-administered tool designed to measure disease activity. It consists of 12 organ-specific 'domains' contributing to disease activity associated with the participant's Sjogren's Syndrome only (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. Overall score (ranges from 0 (no activity) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. A negative change from baseline value indicates improvement.
• Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12 [Baseline; Week 12]: The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain is scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A negative change from baseline value indicates improvement.
• Change From Baseline in ESSDAI at Week 24 [Baseline; Week 24]: The ESSDAI is a physician-administered tool designed to measure disease activity. It consists of 12 organ-specific 'domains' contributing to disease activity associated with the participant's Sjogren's Syndrome only (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. Overall score (ranges from 0 (no activity) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. A negative change from baseline value indicates improvement.
• Change From Baseline in ESSPRI at Week 24 [Baseline; Week 24]: The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain is scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A negative change from baseline value indicates improvement.

Sex: All, ages: 18 Years to 75 Years

Key Inclusion Criteria:

* Diagnosed with primary or secondary SjS according to the 2002 American European Consensus Group (AECG) classification
* Active SjS as defined by an European League Against Rheumatism (EULAR) Sjogren's syndrome disease activity index (ESSDAI) ≥ 5
* Seropositivity for antibodies to SjS-associated antigens A and/or B (anti-SSA or anti-SSB)

Key Exclusion Criteria:

* Concurrent treatment with any biologic disease modifying antirheumatic drug (bDMARD) (prior bDMARD treatment allowed with appropriate washout as per study protocol)

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Participant flow

Outcome results

• Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline (Primary), Number, percentage of participants: Lanraplenib 42.9 (25.0 to 60.7); Filgotinib 43.2 (25.9 to 60.6); Tirabrutinib 35.1 (18.4 to 51.9); Placebo 26.5 (10.2 to 42.8) (p 0.1597)
• Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12 (Secondary), Least squares mean, score on a scale: Lanraplenib -2.5 +/- 0.76; Filgotinib -4.7 +/- 0.72; Tirabrutinib -3.2 +/- 0.73; Placebo -3.9 +/- 0.76 (p 0.2066)
• Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12 (Secondary), Least squares mean, score on a scale: Lanraplenib -1.0 +/- 0.34; Filgotinib -1.4 +/- 0.33; Tirabrutinib -1.4 +/- 0.33; Placebo -1.0 +/- 0.34 (p 0.9446)
• Change From Baseline in ESSDAI at Week 24 (Secondary), Least squares mean, score on a scale: Lanraplenib -4.3 +/- 0.81; Filgotinib -5.4 +/- 0.75; Tirabrutinib -4.0 +/- 0.75; Placebo -4.2 +/- 0.78 (p 0.9564)
• Change From Baseline in ESSPRI at Week 24 (Secondary), Least squares mean, score on a scale: Lanraplenib -1.1 +/- 0.34; Filgotinib -0.8 +/- 0.31; Tirabrutinib -1.2 +/- 0.31; Placebo -0.9 +/- 0.33 (p 0.6782)

Adverse events

Time frame: First dose date up to last dose date (Maximum: 50.4 weeks) plus 30 days

Serious adverse events by term

Other adverse events by term

22 more terms not shown.

Limitations and caveats: An unplanned review of unblinded clinical trial data was performed in this study that was not prospectively specified in the protocol. There was no impact on the overall integrity or conclusions of the study.

• Results publication: Price E, Bombardieri M, Kivitz A, Matzkies F, Gurtovaya O, Pechonkina A, Jiang W, Downie B, Mathur A, Mozaffarian A, Mozaffarian N, Gottenberg JE. Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjogren's syndrome: a randomized, phase 2, double-blind, placebo-controlled study. Rheumatology (Oxford). 2022 Nov 28;61(12):4797-4808. doi: 10.1093/rheumatology/keac167. PMID 35377447

• Study Protocol (PDF, 2018-07-12)
• Statistical Analysis Plan (PDF, 2019-05-30)

• Gilead Study Director, Study director, Gilead Sciences

NIH grants: 2016