Abstract Background Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. Methods Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes. Results Patients with diabetes ( n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes ( n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was − 0.28 (− 0.40, − 0.16; nominal p < 0.0001) and − 0.42 (− 0.54, − 0.31; nominal p < 0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was − 0.13 (− 0.22, − 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA. Conclusions In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings. Trial registration ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.
Sarilumab is a human immunoglobulin G1 anti-interleukin-6 (IL-6) receptor monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor α. This bridging study assessed the efficacy and safety of sarilumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA) and inadequate response to MTX (MTX-IR). In this phase III study, 243 patients were randomized 2:2:1:1 to receive subcutaneous sarilumab 150 mg every 2 weeks (q2w), sarilumab 200 mg q2w, placebo switching to sarilumab 150 mg q2w + MTX at 24 weeks, or placebo switching to sarilumab 200 mg q2w at 24 weeks, all in combination with MTX, for a total of 52 weeks (double-blind, placebo-controlled 24-week period followed by a single-blind 28-week extension). The primary endpoint was the proportion of patients achieving American College of Rheumatology 20% improvement criteria (ACR20) responses at week 24. ACR20 response rates at week 24 were 67.9%, 57.5%, and 14.8% for sarilumab 150 mg, sarilumab 200 mg, and placebo, respectively. Serious treatment-emergent adverse events were reported by 9.9%, 6.3%, 0%, and 13.3% of patients in the sarilumab 150 mg, sarilumab 200 mg, placebo to sarilumab 150 mg, and placebo to sarilumab 200 mg groups, respectively. No deaths occurred. The incidence of infections ranged from 52.5 to 67.9%, with five serious infections for the sarilumab 150 mg group and one for the group switched from placebo to 200 mg sarilumab. Absolute neutrophil count < 1.0 Giga/l occurred in 13.6% and 7.5% of patients in the sarilumab 150 and 200 mg groups, respectively, and was not associated with infection. In Japanese MTX-IR RA patients treated with sarilumab (150 and 200 mg q2w) in combination with MTX, sustained clinical efficacy was shown by significant improvement in signs, symptoms, and physical function; bridging between this and a previous global study was achieved. At week 52, the safety profiles of both doses of sarilumab were generally similar, as previously observed and as expected based on IL-6 class. ClinicalTrials.gov, NCT02293902 . Registered on 19 November 2014.
Trial design Pemphigus is a rare, but life-threatening autoimmune disease requiring long-term treatment that minimizes corticosteroid (CS) exposure while providing consistent disease control. The phase 2 pemphigus study of oral, reversible, covalent Bruton tyrosine kinase (BTK) inhibitor rilzabrutinib demonstrated rapid and sustained efficacy with well-tolerated safety. Methods Adults (18–80 y) were randomized 1:1 to rilzabrutinib 400 mg (n=65) or placebo (n=66) twice daily (with CS ≤0.5 mg/kg/d) for 37 weeks in the phase 3 PEGASUS study in moderate-to-severe pemphigus vulgaris/foliaceus (PV/PF). Results The primary endpoint of complete remission (CR) from week 29–37 with the amended endpoint CS dose ≤10 mg/d was not significant for 13/54 (24%) rilzabrutinib vs. 10/55 (18%) placebo patients with PV (P=0.45). Secondary endpoints showed numerical, but non-significant, improvements with rilzabrutinib (vs. placebo) in reduced CS use, prolonged CR duration, and faster time to first CR. Conclusions Overall, rilzabrutinib was well-tolerated with similar adverse events reported in both groups. Using minimal CS dose ≤10 mg/d and excluding remote observations, the primary efficacy endpoint was not met. However, results from a prespecified sensitivity analysis using CS dose ≤5 mg/d, considering all observations, and including all patients support BTK inhibition as a viable therapeutic approach for pemphigus.
Abstract Background To evaluate baseline hemoglobin (Hb) and radiographic progression over time in patients enrolled in the Brigham and Women’s Rheumatoid Arthritis Sequential Study (BRASS) registry. Methods The BRASS is a prospective observational registry of patients with rheumatoid arthritis. BRASS Hb data and total sharp score data were matched with the main BRASS patients. Hb at baseline was categorized per the World Health Organization guidelines. Mean Hb, mean total sharp score, and mean changes over time from baseline to month 120 were summarized (overall, by low/normal Hb, and by current medication at baseline). All analyses were descriptive. Results Out of the total ( N = 1114) rheumatoid arthritis patients included in the analysis, patients with low Hb at baseline ( n = 224 [20%]) had longer disease duration and higher disease activity and reported more pain compared with patients with normal Hb at baseline ( n = 890 [80%]). Patients with low Hb at baseline continued to have lower Hb than patients with normal Hb throughout 10 years; although, on average, patients in the low Hb subgroup exhibited a steady increase in Hb levels. A larger increase in total sharp score over time was observed for patients with low Hb than for patients with normal Hb. No meaningful differences potentially attributable to medication at baseline were detected. Conclusions Patients with low Hb levels at baseline tended to have increased radiographic progression as measured by total sharp score compared with patients with rheumatoid arthritis having normal Hb levels. Patients with low Hb experienced sustained improvements in Hb levels over time, regardless of the class of medication used. Trial registration ClinicalTrials.gov NCT01793103.
The effect of active rheumatoid arthritis (RA) on participation, active and meaningful engagement by patients in activities important to them, has significant individual and societal costs. Sarilumab is an investigational human anti–interleukin 6 (IL-6) receptor monoclonal antibody. In the phase 3 TARGET study (NCT01709578), sarilumab + conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) demonstrated efficacy in adults with moderate-to-severe, active RA and inadequate response to TNF inhibitors. The most common treatment-emergent adverse events were infections, neutropenia, and increased transaminases; laboratory changes were consistent with IL-6 signaling blockade.
Objectives
To evaluate the effect of sarilumab treatment on patient productivity within and outside of the home; requirement for outside help; and family, social, or leisure activities in the past month as assessed by the RA-specific Work Productivity Survey (WPS-RA).1
Methods
The intent-to-treat population included 546 patients randomized 1:1:1 to placebo, sarilumab 150 mg, or sarilumab 200 mg every 2 wks (q2w) subcutaneously (SC) + background csDMARDs. The WPS-RA was assessed for patients employed outside of (completed all 8 items) and within the home (completed only the 5 items related to productivity within the home and participation in family, social, and leisure activities) at baseline and wks 4 (not reported), 12, and 24. Mixed-model repeated measures analyses were used to evaluate differences in individual WPS-RA items at a significance level of 0.05 if O9Brien9s global test2 showed significance (P<0.025).
Results
At baseline, 544 patients were administered the WPS-RA, 33.1%, 33.7%, and 35.7% (placebo, sarilumab 150, and sarilumab 200 mg q2w SC, respectively) of whom were currently employed outside of the home. Global testing indicated significantly greater overall improvement in patients treated with sarilumab 150 mg q2w SC (wk 12, P=0.0010; wk 24, P=0.0004) and sarilumab 200 mg q2w SC (wk 12, P=0.0036; wk 24, P=0.0003) vs placebo. At wk 24, patients currently employed outside of the home receiving sarilumab 200 mg q2w SC reported significantly greater reductions in number of work days missed due to RA and less interference with work productivity. Patients receiving both doses reported significantly greater reductions in number of days missed engaging in household work, days requiring hired help, and rate of arthritis interference in household work and less time missed engaging in family, social, and leisure activities.
Conclusions
Sarilumab treatment was associated with significant improvements in participation in work; household work; and family, social, and leisure activities. Improvements in productivity outside of the home were also significant among patients in the sarilumab 200 mg q2w SC group vs placebo, although only a proportion of patients worked outside of the home. These data indicate important improvements in overall participation following sarilumab treatment.
References
Osterhaus et al. Arthritis Res Ther. 2009;11:R73 Tandon. Stat Med. 1990;9:819–827
Acknowledgement
This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.
Disclosure of Interest
V. Strand Consultant for: has received consulting fees from AbbVie, Amgen, AstraZeneca, Biogen, BMS, Celgene, Celltrion, Consortium of Rheumatology Researchers of North America (CORRONA), Crescendo/Myriad Genetics, EMD Serono, Genentech/Roche, GSK, Janssen, Eli Lilly, Novartis, Pfizer Inc, Regeneron Pharmaceuticals, Inc, Sandoz, Sanofi, and UCB., P. Mahajan Shareholder of: Sanofi, Employee of: Sanofi, C. Chen Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, H. van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, E. Mangan Shareholder of: an employee of Regeneron Pharmaceuticals, Inc, and may hold stock and/or stock options in Pfizer Inc and Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc, O. Hagino Shareholder of: Sanofi, Employee of: Sanofi, N. Graham Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, G. da R.C. Pinheiro Consultant for: has received consulting fees from AbbVie, AstraZeneca, GSK, Hospira, Janssen, Pfizer Inc, Roche, RuiYi, and Sanofi., A. Kivitz Consultant for: has received consulting fees from Celgene, Genentech/Roche, GSK, Janssen, Pfizer Inc, Regeneron Pharmaceuticals, Inc, Sanofi, and UCB.
In patients with clinical depression, elevated interleukin-6 (IL-6) levels have been associated with higher symptom severity and greater resistance to standard antidepressant treatments. Depression and IL-6 elevation are highly prevalent in patients with rheumatoid arthritis (RA), and their co-occurrence may have an impact on health-related quality of life (HRQoL). Sarilumab is a human immunoglobulin G1 anti IL-6 receptor α (anti-IL-6Rα) monoclonal antibody for treatment of moderately-to-severely active RA.
Objectives:
To explore the effect of sarilumab on HRQoL in patients with moderate-to-severely active RA with co-existing symptoms of depression.
Methods:
Post-hoc statistical analyses were performed on the Medical Outcomes Study Short Form 36 (SF-36) in 2 randomized controlled trials, MOBILITY (NCT01061736) and TARGET (NCT01709578), of sarilumab subcutaneous 150 mg or 200 mg every 2 weeks vs placebo, each combined with conventional synthetic disease modifying anti-rheumatic drugs. Patients were classified at baseline for probable major depressive disorder1 (PMDD; SF-36 mental health (MH) domain score ≤56) or probable depressed mood and anhedonia2 (PDMA; score ≤10 on both items of the MH domain: "Have You Felt Downhearted and Depressed" and "Have You Felt So down in the Dumps that nothing could cheer you up"). Analyses of least squares mean differences in changes from baseline in SF-36 domain scores for sarilumab versus placebo in the PMDD and PDMA subgroups were performed at Weeks 4, 12 and 24 for TARGET and Weeks 24 and 52 for MOBILITY. Sensitivity analysis adjusted for baseline Disease Activity Score 28 C-reactive protein (DAS28-CRP).
Results:
Of the 546 patients from TARGET and 1197 from MOBILITY, 59.5% and 60.2% were classified as PMDD respectively, and 50.4% and 51.6% as PDMA. In both RCTs disease duration and baseline DAS-28 CRP, tender and swollen joint count (table 1) and SF-36 domain scores (figure 1) were similar between sarilumab and placebo within the PMDD and PMDA subpopulations. TARGET: MH scores for PMDD and PDMA subgroups were nominally higher (p<0.05) for sarilumab 200 mg versus placebo at all assessments. Both subgroups also scored nominally higher (p<0.05) in the domains of physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT) and social functioning (SF) but not role-emotional (RE) in the PMDD subgroup at Week 24 (figure 1). MOBILITY: all scores except PF and RE were nominally higher (p<0.05) for sarilumab 200 mg versus placebo for Weeks 24 (figure 1). Sensitivity analysis provided similar results. Exploratory results also suggested reduced prevalence of depressive symptoms over the course of the trial.
Conclusions:
In patients with RA and depressive symptoms, sarilumab provided clinically meaningful improvements in most domains of health status/HRQoL compared with placebo, which may be a function of targeting the IL-6Rα and subsequent reduction in disease activity.
References
[1]Matcham, et al. BMC Musculoskeletal Disorders2016;17:224. [2]Sun Y, et al. EULAR Congress2017June 14–17; Madrid, Spain.
Acknowledgements:
Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.
Disclosure of Interest:
V. Strand Consultant for: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi and UCB, O. Hagino Shareholder of: Sanofi, Employee of: Sanofi, S. Guillonneau Shareholder of: Sanofi, Employee of: Sanofi, S. Boklage Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., M. Reaney Shareholder of: Sanofi, Employee of: Sanofi, J. Sadeh Shareholder of: Sanofi, Employee of: Sanofi, N. Narcisse Consultant for: Sanofi, E. Mangan Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., T. Kirmura Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc.
In the MONARCH Phase 3 randomised controlled trial (RCT) [NCT02332590], sarilumab subcutaneous (SC) 200 mg every 2 weeks (q2w) improved clinical outcomes and multiple aspects of health status/health-related quality of life (HRQoL), as measured by the Medical Outcomes Survey Short Form (SF-36) questionnaire, to levels greater than adalimumab SC 40 mg q2w. Both treatments were administered as monotherapy in patients with active rheumatoid arthritis (RA) who had discontinued treatment with methotrexate. Depression/mood disorder is a common co-morbidity in people with RA.
Objectives
To explore whether observed differences in health status/HRQoL following treatment with sarilumab compared with adalimumab are also seen in the subgroup of patients in the MONARCH trial with probable depressive symptoms.
Methods
Post-hoc statistical analyses were performed. Patients were categorised as having probable major depressive disorder1 (PMDD; SF-36 mental health (MH) domain score ≤56) or probable depressed mood and anhedonia2 (PDMA; score ≤10 on both items of the MH domain: "Have You Felt Downhearted and Depressed" and "Have You Felt So down in the Dumps that nothing could cheer you up"). Least squares mean (LSM) differences in changes from baseline (CFB) in SF-36 domains at Week 24 were calculated for sarilumab PMDD/PDMA versus adalimumab PMDD/PDMA. Sensitivity analysis included adjustment for Disease Activity Score 28 C-reactive protein (DAS28-CRP) at baseline.
Results
Of the 369 patients from MONARCH, 250 (67.78%) were categorised with PMDD (mean age 52 years, 85% female) and 194 (52.6%) with PDMA (mean age 52 years, 87% female). Disease duration, DAS-28 CRP, tender and swollen joint counts (table 1) and SF-36 domain scores (figure 1) were similar between sarilumab and adalimumab within the PMDD and PDMA subpopulations at baseline. LSM differences in CFB in SF-36 domains were greater for sarilumab versus adalimumab at Week 24 in physical functioning (PF), bodily pain (BP), vitality (VT) and social functioning (SF) domains in both the PMDD and PDMA subgroups, and role-physical (RP) in the PMDD subgroup (nominal p<0.05) (figure 1). Sensitivity analysis showed similar results.
Conclusions
Among patients with RA and probable depressive symptoms, sarilumab SC 200 mg q2w monotherapy was more effective than adalimumab SC 40 mg q2w monotherapy in demonstrating clinically meaningful improvements in some domains of health status/HRQoL. This may be a function of the different target of sarilumab (soluble IL-6 receptor [sIL-6R]) and associated improvements in disease activity versus adalimumab (tumour necrosis factor [TNFα]).
References
[1] Matcham, et al. BMC Musculoskeletal Disorders2016;17:224. [2] Sun Y, et al. EULAR Congress2017; June 14–172017; Madrid, Spain.
Acknowledgements
Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.
Disclosure of Interest
V. Strand Consultant for: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Celltrion, Corrona, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Horizon, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Samsung, Sandoz, Sanofi and UCB, O. Hagino Shareholder of: Sanofi, Employee of: Sanofi, S. Guillonneau Shareholder of: Sanofi, Employee of: Sanofi, S. Boklage Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., M. Reaney Shareholder of: Sanofi, Employee of: Sanofi, J. Sadeh Shareholder of: Sanofi, Employee of: Sanofi, N. Narcisse Consultant for: Sanofi, E. Mangan Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., T. Kimura Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc.
ABSTRACT Objectives To describe the immunogenicity profile of sarilumab in Japanese patients with rheumatoid arthritis (RA). Methods Patients enrolled in the KAKEHASI and HARUKA studies were included in our analysis. In these studies, patients received sarilumab 150 mg or 200 mg every 2 weeks for 52 or 28 weeks in combination with methotrexate (MTX) (KAKEHASI), or for 52 weeks as monotherapy or in combination with non-MTX conventional synthetic disease-modifying anti-rheumatic drugs (HARUKA). Anti-drug antibodies (ADAs) and neutralising antibodies (NAbs) were assessed in the pooled population. Results Positive ADA assay responses occurred in 10/149 (7.1%) patients treated with sarilumab 150 mg and 13/185 (7.0%) patients treated with sarilumab 200 mg, with persistent responses in 2 (1.4%) and 4 (2.2%) patients, respectively. Peak ADA titre was 30. No patients treated with the 150 mg dose and one patient (0.5%) treated with the 200 mg dose exhibited NAbs. There was no evidence of an association between ADA formation and hypersensitivity reactions or reduced efficacy. Conclusions ADAs, which occurred at a low frequency and titre, did not affect the safety or efficacy of sarilumab 150 or 200 mg administered as monotherapy or combination therapy in Japanese patients with RA in the KAKEHASI or HARUKA studies.
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