These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate-to-severe psoriasis.

No abstract

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.

Background Two recent meta-analyses are available in the literature (Lee et al., 2010 and Volkmann et al., 2010). In this meta-analysis we included additional recently published studies (nine in all) and analyzed all the RA disease activity endpoints at week 24 focusing on both anti-TNF naïve and experienced patients. Objectives To compare and evaluate RA disease activity endpoints in several similar published studies in the last decade in order to examine the effect of B cell depleting therapy on RA disease activity. Methods Unlike the other meta-analysis that exclusively uses logit method, this analysis used the method of Mantel-Hansel (MH) for the analysis of the ACR20, 50 and 70. The MH method was chosen for the current analysis due to its relative simplicity and its wide use in the medical literature. For DAS28, the effect sizes were combined using the inverse variance as the weighting factor so that studies with larger sample sizes were given more weight than smaller studies. In addition, we looked at the disease activity at week 24 for all studies. Results The estimated effect was comparable in all studies at week 24 although the treatment effect is slightly lower in IMAGE study. The confidence intervals for the Ocrelizumab (ACTION) and Rituximab (EDWARDS) studies were wider due to the relative smaller sample size. The trends were similar for anti-TNF naïve and experienced patients. Similar observations were made for ACR50, ACR70 and DAS28. Conclusions This meta-analysis indicates that in recent trials with B-cell depleting therapy, the therapies have a large and highly reproducible effect on RA disease activity which is not affected by prior receipt of anti-TNF therapy. Disclosure of Interest None Declared

Background Ritlecitinib (PF-06651600) is an oral Janus kinase 3/TEC inhibitor, demonstrated to be safe, well-tolerated and efficacious in moderate to severe active ulcerative colitis. The aim of this pre-specified biomarker study was to develop serum signatures that could serve as non-invasive indicators of endoscopic improvement and histologic remission after ritlecitinib therapy. Methods Colon biopsies and peripheral blood were obtained from participants for biomarker profiling before and after receiving 8-week induction therapy with oral ritlecitinib (20mg,70mg, 200mg, or placebo N=39, 39, 33, 18 respectively) once daily. Responders were defined by endoscopic improvement (Mayo endoscopic sub-score <=1) or histologic remission (Geboes Score ≤ 3.0). RNA from colon biopsy samples were processed using RNA sequencing (Fulgent Therapeutics, CA). Serum proteins were measured using the Olink Explore Inflammation panel (Olink, Proteomics, Sweden). Linear mixed models were used to estimate the change from baseline (CFB) of each protein/gene at Week 8 by treatment and clinical response. Differences between response groups and treatment arms were also analyzed. Results Analysis of serum revealed 37 proteins significantly changed at week 8 compared to baseline in responders (FDR < 0.05). Changes in four of these proteins (IL4R, TNFRSF4, SPINK4 and LAIR-1) correlate with both endoscopic improvement and histological remission and were able to separate responders from non-responders AUC (area under the ROC curve) = 0.71 [0.61–0.81] based on endoscopic improvement and AUC = 0.60 [0.48–0.71] based on histological remission). To determine if these 37 proteins reflect tissue inflammation, we evaluated the differential expression of genes encoding these proteins with RNA-seq of inflamed biopsies. Ten genes (CXCL1, FCAR, CKAP4, SPINK4, CXCL17, OSM, CD4, CXCL9, IL17A, GZMB) had significant changes from baseline between responders and non-responders at Week 8 (FDR < 0.1) in either endoscopic improvement or histological remission. Furthermore, these ten genes were significantly increased at baseline between inflamed and non-inflamed colon biopsies. Finally, colon biopsy transcription levels of TNFRSF4, SPINK4 and LAIR1 were modulated with marginal significance (P-value < 0.1) in either endoscopic improvement or histological remission at Week 8. Conclusion Serum proteomics revealed a promising signature of endoscopic improvement and histologic remission in UC participants treated with ritlecitinib. Changes in a subset of these serum proteins parallel tissue gene expression and offer insight into a potential non-invasive companion monitoring test to guide clinical management of patients treated with ritlecitinib.