A phase II, double-blind, randomised, placebo-controlled study of BMS945429 (ALD518) in patients with rheumatoid arthritis with an inadequate response to methotrexate

Mease, Philip J.; Strand, Vibeke; Shalamberidze, L.; Dimić, Aleksandar; Раскина, Т. А.; Xu, Lian; Liu, Y; Smith, Jeff

doi:10.1136/annrheumdis-2011-200704

Cited by 90 publications

(47 citation statements)

References 48 publications

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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

223

229

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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

223

229

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“…Clazakizumab, previously known as BMS945429, exerted greater affinity (K D = 4 pM) compared to olokizumab and it also has prolonged half-life (Shakib et al 2010). Clazakizumab has proved clinical efficacy in Phase II clinical study with the improved results in ACR20 response and DAS28-based remission rates (Mease et al 2012). Clinical study of clazakizumab monotherapy in comparison to TCZ has not been carried out so far, thus the relative efficacy to TCZ is unidentified.…”

Section: Agents Targeting Il-6mentioning

confidence: 98%

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

et al. 2015

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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

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“…BMS945429, a humanised monoclonal antibody that potently binds IL-6 completed a phase II double blind randomised placebo-controlled trial [40]. 127 patients who were MTX-IR were randomised to 1:1:1:1 to BMS945429 (80, 160 or 320 mg; administered intravenously) or placebo plus methotrexate.…”

Section: Tocilizumab and Other Il-6 Agents Currently Under Developmentmentioning

confidence: 99%

Targeting Interleukin-6 in Rheumatoid Arthritis

Yusof

Emery

2013

Drugs

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A phase II, double-blind, randomised, placebo-controlled study of BMS945429 (ALD518) in patients with rheumatoid arthritis with an inadequate response to methotrexate

Abstract: In this phase II study, BMS945429 was associated with rapid and significant improvements in disease activity and HRQoL in patients with active rheumatoid arthritis and an inadequate response to methotrexate.

Cited by 90 publications

References 48 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

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

Targeting Interleukin-6 in Rheumatoid Arthritis

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