Summary
This study's objective was to assess the effects of PD‐0360324, a fully human immunoglobulin G2 monoclonal antibody against macrophage colony‐stimulating factor in cutaneous lupus erythematosus (CLE). Patients with active subacute CLE or discoid lupus erythematosus were randomized to receive 100 or 150 mg PD‐0360324 or placebo via intravenous infusion every 2 weeks for 3 months. Blood and urine samples were obtained pre‐ and post‐treatment to analyse pharmacokinetics and pharmacodynamic changes in CD14+ CD16+ monocytes, urinary N‐terminal telopeptide (uNTX), alanine/aspartate aminotransferases (ALT/AST) and creatine kinase (CK); tissue biopsy samples were taken to evaluate macrophage populations and T cells using immunohistochemistry. Clinical efficacy assessments included the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Among 28 randomized/analysed patients, peak/trough plasma concentrations increased in a greater‐than‐dose‐proportional manner with dose increases from 100 to 150 mg. Statistically significant differences were observed between active treatment and placebo groups in changes from baseline in CD14+ CD16+ cells, uNTX, ALT, AST and CK levels at most time‐points. The numbers, density and activation states of tissue macrophages and T cells did not change from baseline to treatment end. No between‐group differences were seen in CLASI. Patients receiving PD‐0360324 reported significantly more adverse events than those receiving placebo, but no serious adverse events. In patients with CLE, 100 and 150 mg PD‐0360324 every 2 weeks for 3 months suppressed a subset of circulating monocytes and altered activity of some tissue macrophages without affecting cell populations in CLE skin lesions or improving clinical end‐points.
Background
The efficacy and safety of oral ritlecitinib (JAK3/TEC inhibitor) and brepocitinib (TYK2/JAK1 inhibitor) were assessed in a 32-week Phase 2b induction-maintenance umbrella study (VIBRATO) in participants with moderate to severe active ulcerative colitis who had inadequate or loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies. We report efficacy and safety results from the 8-week induction period of the VIBRATO study.
Methods
Adult participants with Total Mayo Score ≥6 and centrally-read Mayo endoscopic subscore ≥1 were randomised to receive oral ritlecitinib 20, 70, or 200 mg; brepocitinib 10, 30, or 60 mg; or placebo once-daily (QD) for 8 weeks. Participants then continued in their respective treatment cohorts to receive ritlecitinib 50 mg or brepocitinib 30 mg QD for 24 weeks. The proportions of patients who achieved remission (Total Mayo Score ≤2; no individual subscore >1; rectal bleeding subscore 0), modified remission (Modified Mayo Score: Total Mayo without Physician’s Global Assessment; stool frequency subscore ≤1; rectal bleeding subscore 0; endoscopic subscore ≤1), or endoscopic improvement (Mayo endoscopic subscore ≤1) were analysed.
Results
319 participants were randomised: baseline mean (standard deviation [SD]) age 40.3 (13.8) years; mean (SD) Total Mayo Score 9.0 (1.5); and median (range) disease duration 4.8 (0.24, 36.5) years. Ritlecitinib and brepocitinib were generally safe and well tolerated. At Week 8, a dose–response relationship was observed across all efficacy endpoints for ritlecitinib and brepocitinib. The proportions of participants achieving remission were significantly higher (P<0.05) with ritlecitinib 70 and 200 mg and brepocitinib 30 and 60 mg vs placebo (Figure 1). The proportions of participants achieving endoscopic improvement and modified remission were significantly higher in all ritlecitinib and brepocitinib groups vs placebo (Figures 2 and 3).
Conclusion
Ritlecitinib 70 and 200 mg QD and brepocitinib 30 and 60 mg QD demonstrated significant improvement in remission, modified remission, and endoscopic improvement in participants with moderate to severe active ulcerative colitis.
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