Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study

Genovese, Mark C.; Fleischmann, Roy; Fürst, Daniel E.; Janssen, Namieta M.; Carter, John; Dasgupta, Bhaskar; Bryson, Judy C.; Duncan, Benjamin; Zhu, Wei; Pitzalis, Costantino; Durez, Patrick; Kretsos, Kosmas

doi:10.1136/annrheumdis-2013-204760

Cited by 125 publications

(92 citation statements)

References 25 publications

(11 reference statements)

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“…Rates of serious infections were similar to those reported in other studies of biologic and immunosuppressive therapies. Laboratory abnormalities that were detected following treatment with sarilumab were consistent with the effects of IL-6 signaling blockade (43)(44)(45)(46). The results from the MOBILITY study suggest that sarilumab holds promise as a treatment option for RA patients.…”

Section: Discussionsupporting

confidence: 64%

Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study

Genovese

Fleischmann

Kivitz

et al. 2015

Arthritis & Rheumatology

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Objective To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). Methods Adults with moderate‐to‐severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co–primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52. Results Baseline characteristics were similar among the groups. For all 3 co–primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [P < 0.0001]; least squares mean change in HAQ DI at week 16, −0.53, −0.55, and −0.29, respectively [P < 0.0001]; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively [P < 0.0001]). The most common treatment‐emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3‐fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 109/liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 109/liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts. Conclusion In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin‐6 signaling blockade.

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Section: Discussionsupporting

confidence: 64%

Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study

Genovese

Fleischmann

Kivitz

et al. 2015

Arthritis & Rheumatology

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219

229

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“…Intravenous administration of olokizumab effectively reduced the signs and symptoms of arthritis, improved histology findings, reduced C-reactive protein levels and improved bone erosion scores [88]. The therapeutic efficacy and safety of olokizumab was also examined in a 12-week phase IIb clinical trial, in a total of 221 RA patients with moderate-to-severe disease activity and inadequate therapeutic response to anti-TNF treatment [94]. The patients were randomized to receive either placebo or different doses/different therapeutic intervals of olokizumab under a background MTX treatment.…”

Section: Page 28 Of 64mentioning

confidence: 99%

Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers

Luo

Lai

2015

Biochemical Pharmacology

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“…DAS28-CRPdefined improvements from baseline to week 12 for olokizumab versus placebo (-1.16 to -2.68 vs. -0.19 to -0.78; all P\0.05) were reported, as were improvements in ACR20 response rates (32.5-73.8% vs. 17.1-29.9%) [122,123]. A second phase 2 study in 119 patients with RA reported greater improvements in all olokizumab treatment arms versus placebo for DAS28-CRP-defined improvements from baseline (all P\0.0001) and ACR20 rates (all P\0.05) at week 12 [123].…”

Section: Olokizumabmentioning

confidence: 99%

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

et al. 2018

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Tocilizumab (TCZ) is the first humanized antiinterleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the longterm efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti-IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although longterm data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents. Keywords: Interleukin-6; Rheumatoid arthritis; Tocilizumab TOCILIZUMAB: THE FIRST INTERLEUKIN-6 RECEPTOR-NEUTRALIZING BIOLOGICInterleukin-6 (IL-6) is a multifunctional cytokine that plays an important role in both acute and chronic inflammatory responses. Consequently, the dysregulated or persistent production of IL-6 can lead to the development of inflammatory disorders [1]. Elevated levels of IL-6 in serum, synovial fluid, and various tissues have been correlated with disease activity in patients with rheumatoid arthritis (RA) [2], juvenile idiopathic arthritis (JIA) [3,4], Castleman's disease [5,6], systemic sclerosis (SSc) [7], giant cell arteritis (GCA) [8,9], adult-onset Still's disease (AOSD) [10], familial Mediterranean fever (FMF) [11,12], Schnitzler's syndrome [13,14], polychondritis [15], and amyloidosis [1]. These associations suggest a pathogenetic role for IL-6 in multiple inflammatory conditions and form the basis of the rationale for the development of anti-IL-6 therapies.Tocilizumab (TCZ) is the first humanized monoclonal antibody targeting the IL-6 receptor subunit alpha (IL-6Ra) [16], and its mechanism of action has been described in detail in previous reviews [17,18]. Briefly, TCZ targets both membrane-bound and soluble IL-6Ra, which prevents t...

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Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study

Cited by 125 publications

References 25 publications

Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study

Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study

Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

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