Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study.

BACKGROUND: Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease. METHODS: This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete. FINDINGS: Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period. INTERPRETATION: The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials. FUNDING: Novartis Pharma.

Unique Sjögren's syndrome patient subsets defined by molecular features.

OBJECTIVE: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. METHODS: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. RESULTS: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. CONCLUSION: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

Comparison of the discontinuation rates and side-effect profiles of pilocarpine and cevimeline for xerostomia in primary Sjögren's syndrome.

OBJECTIVES: There are currently no head-to-head comparisons of sialagogues for Primary Sjögren's syndrome (pSS). We compared the tolerability and side effect profile of pilocarpine and cevimeline in patients with pSS and determined clinical, laboratory and pathological variables associated with therapeutic failure. METHODS: We retrospectively reviewed the use of pilocarpine and cevimeline in 118 patients with pSS who fulfilled the 2002 American European Consensus Group criteria in a University-based setting. Clinical, laboratory and pathological baseline variables were collected. Failure of therapy was defined as the clinician or patient's decision to stop treatment either due to lack of efficacy or side effects. RESULTS: Cevimeline was associated with lower failure rates compared to pilocarpine among first-time users: 27% vs. 47% (p=0.02), and all users: 32% vs. 61% (p<0.001). Severe sweating was the most frequent side effect leading to cessation of therapy and occurred more frequently in pilocarpine (25%) than cevimeline (11%) users (p=0.02). Patients who previously failed one secretagogue were less likely to discontinue treatment with the other agent, 52% of first-time users vs. 27% of second-time users (p=0.004). Only ANA positivity was associated with failure: [59% vs. 38%] (p=0.03). CONCLUSIONS: pSS patients were more likely to continue cevimeline than pilocarpine long-term due to fewer reported side effects with cevimeline. Therapeutic failure of one secretagogue did not predict similar results with the other since second time users were more likely to continue long-term treatment.

CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double-blinded, placebo-controlled, phase 2 trial.

Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 .

Toward better outcomes in Sjögren's syndrome: The promise of a stratified medicine approach.

Sjögren's syndrome is a systemic autoimmune disease defined by its targeted inflammation of the salivary and lacrimal glands, resulting in dry mouth and eyes in the majority and persistent or recurrent salivary gland enlargement in a minority of those affected. Involvement of major organs, an increased risk of lymphoma, and autoantibodies against ubiquitous cellular ribonucleoproteins define some of its systemic features. Those affected have a high symptom burden and the development of disease-modifying therapies is thus an urgent need. A stratified medicine approach offers promise as a means of targeting specific therapies to patients for whom the mechanism of action is most relevant. Implementation of this approach will require an understanding of the pathophysiological processes underlying different patient subsets, and then identifying or developing a drug that targets this pathway. Such therapies would be most effective if implemented early in the disease course before the advent of adverse outcomes or glandular damage. This review will provide a disease overview followed by an analysis of the feasibility of a stratified medicine approach, focusing on the disease heterogeneity, predictors of disease progression and adverse outcomes, and recent advances in the development of relevant outcome measures and new therapies.

Clinical Efficacy and Safety of Baminercept, a Lymphotoxin ß Receptor Fusion Protein, in Primary Sjögren's Syndrome: Results From a Phase II Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To evaluate the clinical efficacy and safety of baminercept, a lymphotoxin ß receptor IgG fusion protein (LTßR-Ig), for the treatment of primary Sjögren's syndrome (SS), and to explore the possible mechanisms of action of this treatment. METHODS: In this multicenter trial, 52 patients with primary SS were randomized in a 2:1 ratio to receive subcutaneous injections of 100 mg of baminercept every week for 24 weeks or matching placebo. The primary end point was the change between screening and week 24 in the stimulated whole salivary flow (SWSF) rate. Secondary end points included the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI), as well as measurements of select chemokines and cytokines and enumeration of peripheral blood B and T cell subsets. RESULTS: The change from baseline to week 24 in the SWSF rate was not significantly different between the baminercept and placebo treatment groups (baseline-adjusted mean change -0.01 versus 0.07 ml/minute; P = 0.332). The change in the ESSDAI during treatment was also not significantly different between the treatment groups (baseline-adjusted mean change -1.23 versus -0.15; P = 0.104). Although the incidence of adverse events was similar between the treatment groups, baminercept therapy was associated with a higher incidence of liver toxicity, including 2 serious adverse events. Baminercept also produced a significant decrease in plasma levels of CXCL13 and significant changes in the number of circulating B and T cells, consistent with its known inhibitory effects on LTßR signaling. CONCLUSION: In this trial, treatment with baminercept failed to significantly improve glandular and extraglandular disease in patients with primary SS, despite evidence from mechanistic studies showing that it blocks LTßR signaling.

Deficits in muscle mass, muscle density, and modified associations with fat in rheumatoid arthritis.

OBJECTIVE: To quantify muscle outcomes, independent of fat mass, in rheumatoid arthritis (RA) patients compared to healthy controls. METHODS: Quantitative computed tomography scans measured calf muscle and fat cross-sectional area (CSA) and muscle density (an index of intramuscular adipose tissue), and isometric dynamometry was used to measure ankle muscle strength in 50 participants with RA ages 18-70 years and 500 healthy controls. Multivariable linear regression models assessed muscle deficits in RA after adjusting for group differences in adiposity and assessing for an altered muscle-fat association. Associations between RA disease characteristics and fat-adjusted muscle outcomes were also assessed. RESULTS: Compared to controls, RA subjects had significantly greater body mass index (BMI) and fat area, and lower muscle area, muscle density, and muscle strength (P < 0.001 for all). Strength deficits were eliminated with adjustment for the smaller muscle area. The magnitude of muscle deficits, relative to controls, was significantly greater (P < 0.03 for interaction) in participants with lower fat area and BMI. Among those in the lower tertiles of adiposity, RA subjects demonstrated more significant deficits compared to controls with similar adiposity. In contrast, among those in the highest tertile for adiposity, RA was not associated with muscle deficits. Among RA, greater Sharp/van der Heijde scores were associated with lower muscle CSA and muscle density. Greater disease activity and disability were associated with low muscle density. CONCLUSION: Deficits in muscle area and muscle density are present in RA patients compared to controls and are most pronounced in subjects with low fat mass. Greater joint destruction is associated with greater muscle deficits.