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Objective To assess the effect of filgotinib, which preferentially inhibits Janus kinase 1 (JAK1), on MRI measures of structural change in the SI joint in patients with active AS in the TORTUGA trial. Methods Adults with active AS and inadequate response/intolerance to two or more NSAIDs were randomized 1:1 to filgotinib 200 mg (n = 58) or placebo (n = 58) once daily for 12 weeks. In this post hoc analysis, T1-weighted MRI scans of the SI joint were evaluated by two independent readers using Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint Structural Score (SSS) definitions for erosion, backfill, fat metaplasia and ankylosis. Correlations between SPARCC SSS and improvement in clinical outcomes were also assessed. Results MRI scans from 87 patients (48 filgotinib, 39 placebo) were evaluated. At baseline there were no notable differences between filgotinib and placebo for any MRI structural lesion types. From baseline to week 12, filgotinib was associated with a significant reduction in SI joint erosion score (P = 0.02) and an increase in backfill score (P = 0.005) vs placebo, with no significant between-group differences for ankylosis (P = 0.46) or fat metaplasia (P = 0.17). At week 12, the change in SPARCC MRI SI joint inflammation scores correlated positively with erosion scores but negatively with backfill scores. Conclusion The significant changes in MRI structural lesions induced by filgotinib in the SI joint by week 12 demonstrate that tissue repair can be observed very soon after starting treatment with a JAK1 preferential inhibitor. This could have prognostic implications for development of ankylosis. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT03117270

Objectives To assess the effects of filgotinib on inflammatory and structural changes at various spinal locations, based on MRI measures in patients with active AS in the TORTUGA trial. Methods In the TORTUGA trial, patients with AS received filgotinib 200 mg (n = 58) or placebo (n = 58) once daily for 12 weeks. In this post hoc analysis, spine MRIs were evaluated using the Canada–Denmark (CANDEN) MRI scoring system to assess changes from baseline to week 12 in total spine and subscores for inflammation, fat, erosion and new bone formation (NBF) at various anatomical locations. Correlations were assessed between CANDEN inflammation and clinical outcomes and Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores and between baseline CANDEN NBF and baseline BASFI and BASMI scores. Results MRIs from 47 filgotinib- and 41 placebo-treated patients were evaluated. There were significantly larger reductions with filgotinib vs placebo in total spine inflammation score and most inflammation subscores, including posterolateral elements (costovertebral joints, transverse/spinous processes, soft tissues), facet joints and vertebral bodies. No significant differences were observed for corner or non-corner vertebral body inflammation subscores, spine fat lesion, bone erosion or NBF scores. In the filgotinib group, the change from baseline in the total inflammation score correlated positively with the SPARCC spine score. Baseline NBF scores correlated with baseline BASMI but not BASFI scores. Conclusions Compared with placebo, filgotinib treatment was associated with significant reductions in MRI measures of spinal inflammation, including in vertebral bodies, facet joints and posterolateral elements. Trial registration ClinicalTrials.gov (https://clinicaltrials.gov), NCT03117270.

In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant. Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0–52) or placebo (weeks 0–12) followed by toreforant 30 mg/day (weeks 12–52). Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics. Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected. While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation.

Objective.To evaluate the efficacy and safety of poseltinib (formerly LY3337641/HM71224), an irreversible covalent inhibitor of Bruton’s tyrosine kinase in a 2-part, phase II trial (RAjuvenate; ClinicalTrials.gov: NCT02628028) in adults with active rheumatoid arthritis (RA).Methods.In Part A, 36 patients with mildly active RA were randomized 1:1:1:1 to oral poseltinib 5, 10, or 30 mg or placebo once daily for 4 weeks to assess safety and tolerability. No safety signals precluded moving to Part B, where 250 patients with moderate-to-severe RA were randomized 1:1:1:1 to oral poseltinib 5 mg (n = 63), 10 mg (n = 62), or 30 mg (n = 63), or placebo (n = 62) once daily for 12 weeks. Parts A and B permitted stable doses of background disease-modifying antirheumatic drugs. The primary endpoint in Part B was proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 12. Logistic regression compared each poseltinib dose to placebo for primary and secondary endpoints. Nonresponder imputation was used for missing data.Results.After interim analysis showed low likelihood of demonstrating significant efficacy, the sponsor discontinued Part B of the study. One hundred and eighty-nine (76%) patients completed 12 weeks in Part B; 61 discontinued study treatment (27 [44%] due to study termination by sponsor). There was no statistically significant difference in ACR20 response between any dose of poseltinib and placebo at Week 12 (P > 0.05 for all comparisons). Five serious adverse events occurred (n = 2, placebo; n = 3, 30 mg); there was 1 death due to a fall.Conclusion.While no safety findings precluded continuation, the study was terminated after interim data demonstrated low likelihood of benefit in RA.

Background LY3337641 is an irreversible covalent inhibitor of Bruton’s tyrosine kinase (BTK), a key signaling molecule in the B-cell-receptor and Fc-receptor pathways and mediator of B-cell– and myeloid-cell–dependent inflammatory arthritis.1,2 RA-JUVENATE was a multicenter, randomized, double-blind, placebo-controlled, 2-part Phase 2 trial with long-term extension (LTE) in adult patients (pts) with rheumatoid arthritis (RA). Objectives The objective of this analysis is to present the primary results from Part B of the study. Methods In Part A, 36 pts with at least mildly active RA were randomized 1:1:1:1 to receive oral LY3337641 5, 10, or 30 mg or placebo (PBO) once daily (QD) for 4 weeks (wks) with the primary objective of safety and tolerability. There were no safety signals to preclude moving to Part B; pts in Part A were not eligible to participate in Part B. In Part B, 250 pts with active moderate to severe RA were randomized 1:1:1:1 receive oral LY3337641 5 (N=63), 10 (N=62), or 30 mg (N=63) or PBO (N=62) QD for 12 wks. The primary endpoint of Part B was the proportion of pts achieving ≥20% improvement in American College of Rheumatology criteria (ACR20) at Wk 12. A logistic regression model was used to compare each LY3337641 dose to PBO for primary and secondary endpoints. Nonresponder imputation was used to impute missing data. After an interim analysis showed a low likelihood of demonstrating significant efficacy at the conclusion of the trial, the sponsor discontinued Part B of the study, including the LTE. Efficacy results (except analysis of low disease activity and remission) included pts who completed through Wk 12 at the time of study discontinuation; safety was results included all pts who received ≥1 dose of study drug. Results Of the 250 pts (mean age 51.0 years; 86.4% female; mean disease duration 11.2 years) randomized in Part B, 189 (75.6%) completed 12 weeks and 180 entered the LTE (72.0%); 61 discontinued study treatment in Part B.. The most common reasons for discontinuation were study terminated by sponsor (27 [10.8%]), withdrawal by subject (8 [3.2%]), adverse event (8 [3.2%]), and lack of efficacy (4 [1.6%]). There was no statistically significant difference in the ACR20 response between any treatment group of LY3337641 and PBO at Wk 12 (p>0.05 for all comparisons; Table); a high placebo rate was noted, but no underlying reason was identified in post hoc analyses. There were 5 serious adverse events: 2 in PBO pts (joint dislocation and cholecystitis acute) and 3 in 30-mg pts (foot fracture, multiple injuries, and venous thrombosis). There was 1 death (30-mg pt, multiple injuries after 4-story fall down elevator shaft). There were no safety findings that precluded continuation of the study. Conclusion Although there were no safety findings that precluded continuation of the study, the study sponsor determined that the observed benefit-risk profile of LY3337641 in the study did not warrant its continuation. References [1] Di Paolo JA, et al. Nat Chem Biol. 2011;7:41-50 [2] Chakravarty SD, et al. Clin Immunol. 2013;148:66-78. Disclosure of Interests Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm, Alberto Spindler: None declared, Akira Sagawa Paid instructor for: ONO Pharmaceutical co., ltd, Eli Lilly Japan K.K., Takeda Pharmaceutical Company Limited, AYUMI Pharmaceutical, ISSEI PHARMACEUTICAL CO., LTD., CHUGAI PHARMACEUTICAL CO.,LTD., Asahi Kasei Pharma Corporation, Janssen Pharmaceutical, Won Park Consultant for: Celltrion, Inc, Anna Dudek: None declared, Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Jeannie Chao Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Lai Shan (Melanie) Chan Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, William Barchuk Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ajay Nirula Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company

In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant.Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0-52) or placebo (weeks 0-12) followed by toreforant 30 mg/day (weeks 12-52).Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics.Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected.While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation.

Guselkumab, a human monoclonal antibody that binds to the p19 subunit of interleukin 23, has been approved for the treatment of moderate-to-severe psoriasis. Psoriatic arthritis is a common comorbidity of psoriasis with an umet need for novel treatments. We assessed the efficacy and safety of guselkumab in patients with active psoriatic arthritis.We did a randomised, double-blind, placebo-controlled, phase 2a trial at 34 rheumatology and dermatology practices in Canada, Germany, Poland, Romania, Russia, Spain, and the USA. Eligible participants were aged 18 years or older with active psoriatic arthritis and plaque psoriasis affecting at least 3% of their body surface area, with three or more of 66 tender joints and three or more of 68 swollen joints, who had an inadequate response or intolerance to standard treatments. We randomly assigned patients (2:1) via a central interactive web-response system using computer-generated permuted blocks with a block size of six, stratified by previous anti-tumour necrosis factor-α use, to receive subcutaneous guselkumab 100 mg or placebo at week 0, week 4, and every 8 weeks thereafter for 24 weeks. Patients, investigators, and site staff were masked to treatment assignment until final database lock at week 56. At week 16, patients with less than 5% improvement in swollen and tender joint counts were eligible for early escape to ustekinumab. At week 24, the remaining placebo-treated patients crossed over to receive guselkumab 100 mg at weeks 24, 28, 36, and 44 and guselkumab-treated patients received a placebo injection at week 24, followed by guselkumab injections at weeks 28, 36, and 44. The primary endpoint was the proportion of patients with at least 20% improvement at week 24 in signs and symptoms of psoriatic arthritis according to American College of Rheumatology criteria (ACR20) in the modified intention-to-treat population (ie, all randomly assigned patients who received at least one dose of study treatment). Safety analyses included patients according to the study drug received. This study is registered with ClinicalTrials.gov, number NCT02319759.Between March 27, 2015, and Jan 17, 2017, we randomly assigned 149 patients to treatment: 100 to guselkumab and 49 to placebo. 17 (35%) of 49 patients in the placebo group and ten (10%) of 100 patients in the guselkumab group were eligible for early escape to ustekinumab at week 16. 29 (59%) of 49 patients in the placebo group crossed over and received guselkumab at week 24. Three (6%) of 49 patients in the placebo group, one (3%) of 29 patients who crossed over from placebo to guselkumab, and six (6%) of 100 patients in the guselkumab group discontinued study treatment before week 44. 58 (58%) of 100 patients in the guselkumab group and nine (18%) of 49 patients in the placebo group achieved an ACR20 response at week 24 (percentage difference 39·7% [95% CI 25·3-54·1]; p0·0001). Between week 0 and week 24, 36 (36%) of 100 guselkumab-treated patients and 16 (33%) of 49 placebo-treated patients had at least one adverse event. The most frequent adverse event was infection in both groups (16 [16%] of 100 patients in the guselkumab group vs ten [20%] of 49 patients in the placebo group). The prevalence of adverse events between week 0 and week 56 in guselkumab-treated patients (51 [40%] of 129) indicated no disproportional increase with longer guselkumab exposure. No deaths occurred.Guselkumab, a novel anti-interleukin 23p19 antibody, significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 44 weeks of treatment. The results of this study support further development of guselkumab as a novel and comprehensive treatment in psoriatic arthritis.Janssen ResearchDevelopment.