Objective. To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to diseasemodifying antirheumatic drugs (DMARDs), including biologic agents.Methods. A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n ‫؍‬ 149], 500 mg [n ‫؍‬ 124], or 1,000 mg [n ‫؍‬ 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted.Results. Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (؊1.79, ؊2.05, ؊0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo.Conclusion. Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.

ObjectivesThis phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment.MethodsPatients with active disease on stable MTX (10–25 mg/week) were randomised to rituximab 2×500 mg (n=168), rituximab 2×1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) ≥2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2×500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48.ResultsAt week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2×500 mg) + MTX, rituximab (2×1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48.ConclusionsRituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses.

Background: Biologic disease modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis (r-axSpA), otherwise known as ankylosing spondylitis, when conventional therapies fail. We report efficacy and safety results of a Phase 3 study of ixekizumab, a high-affinity monoclonal antibody that selectively targets IL-17A, in bDMARDnaïve patients with r-axSpA. Methods: In this randomized, double-blind, Phase 3 study, adult patients with inadequate response/intolerance to NSAIDs, an established diagnosis of r-axSpA, and with radiographic sacroiliitis centrally defined by modified New York criteria and ≥1 spondyloarthritis feature according to Assessment of Spondyloarthritis International Society (ASAS) criteria were recruited from 84 sites (12 countries) in Europe, Asia, and North America. Patients were randomized 1:1:1:1 using a computer-generated random sequence to 80 mg subcutaneous ixekizumab every two (Q2W) or four (Q4W) weeks, 40 mg adalimumab Q2W (active reference arm), or placebo. The primary endpoint was the proportion of patients achieving an ASAS40 response at Week 16. Findings: Between June 20, 2016 and August 22, 2017, 341 patients were randomized to placebo (N=87), adalimumab (N=90), ixekizumab Q2W (N=83), or ixekizumab Q4W (N=81). At Week 16, significantly more patients achieved ASAS40 with ixekizumab Q2W (n=43, 51•8%, p<0•0001), ixekizumab Q4W (n=39, 48•1%, p<0•0001), and adalimumab (n=32, 35•6%; p=0•0053) versus placebo (n=16, 18•4%). One serious infection occurred in each of the ixekizumab Q2W (1•2%), ixekizumab Q4W (1•2%), and adalimumab (1•1%) arms; none were reported with placebo. One (1•1%) Candida infection occurred in the adalimumab arm and one (1•2%) patient receiving ixekizumab Q2W was adjudicated as having probable Crohn's disease. No opportunistic infections, malignancies, or deaths occurred. Interpretation: Each dosing regimen of ixekizumab was superior to placebo for improving r-axSpA signs and symptoms in bDMARD-naïve patients; the safety profile was consistent with previous studies of ixekizumab. The adalimumab control arm performed as expected. Funding: Eli Lilly and Company Research in context Evidence before this study Pubmed was searched using the terms "ankylosing spondylitis", "axial spondyloarthritis", and "disease-modifying anti-rheumatic drugs", including articles through May 30, 2018. Axial spondyloarthritis (axSpA) is a chronic immune-mediated disease characterized by inflammation of the spine and sacroiliac joint (SIJ), peripheral joint involvement, extra articular manifestations, and a strong genetic association with human leukocyte antigen (HLA)-B27. Radiographic axSpA (r-axSpA) was previously classified as ankylosing spondylitis (AS) in 1984 and updated to r-axSpA as part of the ASAS criteria. Both criteria sets require the same radiographically confirmed structural damage to the sacroiliac joint as well as at least one accompanying clinical element. Recommendations for the management of r-axSpA generally include exercise and physiothera...

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BackgroundCT-P13 (Remsima®, Inflectra®) is a biosimilar of the infliximab reference product (RP; Remicade®). The aim of this study was to compare the 54-week efficacy, immunogenicity, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of CT-P13 and RP in patients with active rheumatoid arthritis (RA).MethodsIn this multinational phase III double-blind study, patients with active RA and an inadequate response to methotrexate (MTX) were randomized (1:1) to receive CT-P13 (3 mg/kg) or RP (3 mg/kg) at weeks 0, 2, 6 and then every 8 weeks to week 54 in combination with MTX (12.5–25 mg/week). Efficacy endpoints included American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates, Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), European League Against Rheumatism (EULAR) response rates, patient-reported outcomes and joint damage progression. Immunogenicity, safety and PK/PD outcomes were also assessed.ResultsOf 606 randomized patients, 455 (CT-P13 233, RP 222) were treated up to week 54. At week 54, ACR20 response rate was highly similar between groups (CT-P13 74.7 %, RP 71.3 %). ACR50 and ACR70 response rates were also comparable between groups (CT-P13 43.6 % and 21.3 %, respectively; RP 43.1 % and 19.9 %, respectively). DAS28, SDAI and CDAI decreased from baseline to week 54 to a similar extent with CT-P13 and RP. Radiographic progression measured by Sharp scores as modified by van der Heijde was also comparable. With both treatments, patient assessments of pain, disease activity and physical ability, as well as mean scores on the Medical Outcomes Study Short Form Health Survey (SF-36), improved markedly at week 14 and remained stable thereafter up to week 54. The proportion of patients positive for antidrug antibodies at week 54 was similar between the two groups: 41.1 % and 36.0 % with CT-P13 and RP, respectively. CT-P13 was well tolerated and had a similar safety profile to RP. PK/PD results were also comparable between CT-P13 and RP.ConclusionsCT-P13 and RP were comparable in terms of efficacy (including radiographic progression), immunogenicity and PK/PD up to week 54. The safety profile of CT-P13 was also similar to that of RP.Trial registrationClinicalTrials.gov identifier: NCT01217086. Registered 4 Oct 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0981-6) contains supplementary material, which is available to authorized users.

ObjectiveThe 24‐week equivalent efficacy and comparable safety results of the biosimilar SB5 and reference adalimumab (ADA) from the phase III randomized study in patients with moderate‐to‐severe rheumatoid arthritis (RA) have been reported previously. We undertook this transition study to evaluate patients who switched from ADA to SB5 or who continued to receive SB5 or ADA up to 52 weeks.MethodsIn this phase III study, patients were initially randomized 1:1 to receive SB5 or ADA (40 mg subcutaneously every other week). At 24 weeks, patients receiving ADA were rerandomized 1:1 to continue with ADA (ADA/ADA group) or to switch to SB5 (ADA/SB5 group) up to week 52; patients receiving SB5 continued with SB5 for 52 weeks (SB5 group). Efficacy, safety, and immunogenicity were evaluated up to 52 weeks.ResultsThe full analysis set population consisted of 542 patients (269 in the SB5 group, 273 in the ADA overall group [patients who were randomized to receive ADA at week 0], 125 in the ADA/SB5 group, and 129 in the ADA/ADA group). The percentages of patients meeting the American College of Rheumatology 20%, 50%, or 70% improvement criteria (achieving an ACR20, ACR50, or ACR70 response) at week 24 were maintained after the transition from ADA to SB5, and these response rates were comparable across treatment groups throughout the study. ACR20 response rates ranged from 73.4% to 78.8% at week 52. Radiographic progression was minimal and comparable across treatment groups. The safety profile and the incidence of antidrug antibodies were comparable across treatment groups after transition.ConclusionSB5 was well tolerated over 1 year in patients with RA, with efficacy, safety, and immunogenicity comparable to those of ADA. Switching from ADA to SB5 had no treatment‐emergent issues such as increased adverse events, increased immunogenicity, or loss of efficacy.

Objective SB5 is a biosimilar agent for adalimumab (ADA). The aim of this study was to evaluate the efficacy, pharmacokinetics (PK), safety, and immunogenicity of SB5 in comparison with reference ADA in patients with rheumatoid arthritis (RA).MethodsIn this phase III, randomized, double‐blind, parallel‐group study, patients with moderately to severely active RA despite treatment with methotrexate were randomized 1:1 to receive SB5 or reference ADA at a dosage of 40 mg subcutaneously every other week. The primary efficacy end point was the response rate based on the American College of Rheumatology 20% improvement criteria (ACR20) at week 24 in the per‐protocol set (completer analysis). Additional end points included efficacy, PK, safety, and immunogenicity assessments.ResultsOf the 544 patients randomized to receive a study drug, the full analysis set comprised 542 patients (269 in the SB5 group, 273 in the reference ADA group) and the per‐protocol set comprised 476 patients (239 receiving SB5, 237 receiving reference ADA). The ACR20 response rate at week 24 in the per‐protocol set was equivalent between those receiving SB5 and those receiving reference ADA (72.4% and 72.2%, respectively); the difference in the ACR20 response rate (0.1%, [95% confidence interval −7.83%, 8.13%]) was within the predefined equivalence margin (±15%). Similar results were seen in the full analysis set (missing data being considered a nonresponse). The SB5 and reference ADA treatment groups were comparable across other end points, including the ACR 50% and ACR 70% improvement response rates, Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate, PK data, incidence of treatment‐emergent adverse events, and the antidrug antibody response. Subgroup analyses showed that the efficacy and safety of SB5 and reference ADA were comparable regardless of antidrug antibody status.ConclusionThe ACR20 response rate at week 24 was equivalent between patients treated with the biosimilar agent SB5 and those treated with reference ADA. SB5 and reference ADA were both well tolerated, with comparable safety profiles, in patients with RA.

Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.