Jinglan Pei

Low immunogenicity of tocilizumab in patients with rheumatoid arthritis

Objective Subcutaneous (SC) and intravenous formulations of tocilizumab (TCZ) are available for the treatment of patients with rheumatoid arthritis (RA), based on the efficacy and safety observed in clinical trials. Anti-TCZ antibody development and its impact on safety and efficacy were evaluated in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Methods Data from 5 TCZ-SC and 8 TCZ-IV phase III clinical trials and 1 TCZ-IV clinical pharmacology safety study (>50 000 samples) were pooled to assess the immunogenicity profile of TCZ-SC and TCZ-IV (8974 total patients). The analysis included antidrug antibody (ADA) measurement following TCZ-SC or TCZ-IV treatment as monotherapy or in combination with csDMARDs, after dosing interruptions or in TCZ-washout samples, and the correlation of ADAs with clinical response, adverse events or pharmacokinetics (PK). Results The proportion of patients who developed ADAs following TCZ-SC or TCZ-IV treatment was 1.5% and 1.2%, respectively. ADA development was also comparable between patients who received TCZ monotherapy and those who received concomitant csDMARDs (0.7–2.0%). ADA development did not correlate with PK or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy. Conclusions The immunogenicity risk of TCZ-SC and TCZ-IV treatment was low, either as monotherapy or in combination with csDMARDs. Anti-TCZ antibodies developed among the small proportion of patients had no evident impact on PK, efficacy or safety.

Impact of tocilizumab monotherapy on patient-reported outcomes in patients with rheumatoid arthritis from two randomised controlled trials

Objective Two randomised controlled trials, AMBITION (NCT00109408) and ADACTA (NCT01119859), showed tocilizumab (TCZ) monotherapy superior to methotrexate (MTX) and adalimumab (ADA) monotherapy, respectively, for improving rheumatoid arthritis (RA) disease activity. This study compared the benefit of TCZ versus MTX or ADA monotherapy for improving patient-reported outcomes (PROs) in patients with RA. Methods PROs included patient global assessment (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and Short Form-36 (SF-36) physical component summary (PCS) and mental component summary (MCS) and eight domain scores. Outcomes included proportions of patients reporting changes from baseline in PRO scores ≥minimum clinically important differences (MCID) and ≥age-matched and gender-matched normative values at 24 weeks. Results In AMBITION, TCZ-treated patients reported significantly greater mean improvements in HAQ (−0.7 vs −0.5), FACIT-Fatigue (8.7 vs 5.7), SF-36 PCS (9.8 vs 7.8) and five SF-36 domains at week 24 than with MTX; 45.0%–84.0% of TCZ-treated patients reported improvements ≥MCID, and 24.3%–52.1% reported scores ≥normative values across all PROs versus 39.4%–81.8% and 14.5%–45.0%, respectively, with MTX. In ADACTA, TCZ-treated patients reported significantly greater improvements in PtGA (−42.3 vs −31.8), pain (−40.1 vs −28.7), SF-36 MCS (7.9 vs 5.0) and three SF-36 domains than with ADA; 57.7%–83.3% of TCZ-treated patients reported improvements ≥MCID, and 22.1%–49.3% reported scores ≥normative values across all PROs versus 13.6%–37.8%, respectively, with ADA. Conclusions TCZ monotherapy resulted in more patients reporting clinically meaningful PRO improvements and PRO scores ≥normative values compared with MTX or ADA monotherapy. Trial registration numbers NCT00109408 and NCT01119859; Post-results.

Sustained Response Following Discontinuation of Methotrexate in Patients With Rheumatoid Arthritis Treated With Subcutaneous Tocilizumab: Results From a Randomized, Controlled Trial

To evaluate whether tocilizumab (TCZ) monotherapy is noninferior to treatment with TCZ plus methotrexate (MTX) for maintaining clinical responses in patients with rheumatoid arthritis (RA) in whom low disease activity is achieved with TCZ plus MTX.

RAPID3 and ACR/EULAR Provisional Remission Definitions as Predictors of Radiographic Outcome in a Rheumatoid Arthritis Clinical Trial With Tocilizumab

The American College of Rheumatology/European League Against Rheumatism established definitions of remission for rheumatoid arthritis (RA) based on composite scores, including tender (TJC) and swollen joint counts (SJC), patient global visual analog scale (VAS) score, laboratory tests, and, in the Simplified Disease Activity Index (SDAI), the physician global score. Time constraints on a physicians schedule demand an easy yet accurate tool to measure disease activity. We assessed the predictive ability of the Routine Assessment of Patient Index Data 3 (RAPID3) with and without a single swollen joint versus the SDAI and/or Boolean remission criteria for functional and radiographic outcomes.

Impact of tocilizumab administered intravenously or subcutaneously on patient-reported quality-of-life outcomes in patients with rheumatoid arthritis

Objective Randomised controlled trials (RCTs) have shown tocilizumab (TCZ) administered intravenously or subcutaneously with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to be superior to csDMARDs alone for improving rheumatoid arthritis (RA) disease activity. This study evaluated the effect of TCZ-intravenous and TCZ-subcutaneous on patient-reported outcomes (PROs) in three RCT populations. Methods OPTION (NCT00106548), BREVACTA (NCT01232569) and SUMMACTA (NCT01194414) were independent RCTs evaluating the efficacy and safety of TCZ-intravenous and/or TCZ-subcutaneous with csDMARDs in patients with RA. PROs included patient global assessment, pain, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue and Short Form-36. Study outcomes included the proportions of patients reporting changes from baseline in PRO scores ≥ minimum clinically important differences (MCID) and scores ≥ age and gender-matched normative values. Results In OPTION, more patients who received TCZ-intravenous reported improvements in PROs ≥MCID (50%–82% vs 31%–57%) and scores ≥ normative values (16%–44% vs 5%–28%) at week 16 compared with placebo. Similarly, a greater proportion of patients in BREVACTA who received TCZ-subcutaneous reported improvements ≥ MCID (54%–73% vs 42%–55%) and scores ≥ normative values (8%–34% vs 4%–25%) at week 12 compared with placebo. In SUMMACTA, 61%–84% of patients who received TCZ-subcutaneous and 64%–84% of those who received TCZ-intravenous reported improvements ≥ MCID and 14%–41% and 15%–24%, respectively, scores ≥ normative values at week 24. Conclusions TCZ-intravenous or TCZ-subcutaneous with csDMARDs resulted in more patients reporting clinically meaningful improvements and PRO scores ≥ normative values compared with placebo. These improvements were similar with TCZ-intravenous and TCZ-subcutaneous.

Long-Term Safety of Rituximab in Rheumatoid Arthritis: Analysis From the SUNSTONE Registry

OBJECTIVE To evaluate the long-term safety of rituximab in an observational cohort of patients with rheumatoid arthritis (RA) who had an inadequate response to ≥ 1 antitumor necrosis factor therapies in the United States (SUNSTONE Registry). METHODS In this prospective, observational cohort study, patients received rituximab according to their physicians standard practice and were evaluated at standard-of-care follow-up visits at least every 6 months. The primary outcome was the incidence of protocol-defined significant infections. Secondary outcomes included serious adverse events potentially associated with rituximab, cardiovascular or thrombotic (CVT) events, seizures, deaths and pregnancies. Posthoc analyses assessed outcomes by concomitant medication use. RESULTS Overall, 989 patients (safety-evaluable population) received ≥ 1 dose of rituximab, with a total follow-up of 3844 patient-years (PYs; mean duration, 3.9 years). In total, 341 significant infections occurred in 197 patients (19.9%). The incidence rates (95% CI) for significant infections, CVT events, and seizures were 8.87 (7.98, 9.86), 1.95 (1.56, 2.45), and 0.18 (0.09, 0.38) per 100 PYs, respectively. The incidence of significant infections did not increase with time or with cumulative rituximab exposure. During the study, 64 patients died (crude mortality [95% CI]: 1.66 per 100 PYs [1.30, 2.13]). The most common causes of death were infections (19 patients), malignancy (14), and cardiovascular events (13). Eight pregnancies were reported in 7 patients. CONCLUSION In patients with RA treated with rituximab for up to 5 years, the rates of significant infections were stable over time and higher in patients who received long-term systemic steroid treatment. This article is protected by copyright. All rights reserved.To evaluate the long‐term safety of rituximab in an observational cohort of patients with rheumatoid arthritis (RA) who had an inadequate response to ≥1 anti–tumor necrosis factor therapy in the US (SUNSTONE [Study of the Safety of Rituxan in Patients With Rheumatoid Arthritis After an Inadequate Response to Previous Anti‐TNF Therapy] registry).

AB0448 Patient-reported outcomes following discontinuation of methotrexate in patients with rheumatoid arthritis treated with subcutaneous tocilizumab: results from a randomised controlled trial

Background Patients with rheumatoid arthritis (RA) often receive methotrexate (MTX) in combination with biologics; however, MTX may be discontinued due to intolerance or to reduce the medication burden once disease control is achieved. Whereas previous studies have established the efficacy of tocilizumab (TCZ) initiated as monotherapy (MONO) for the treatment of RA,1,2 patient-reported outcomes (PROs) after MTX withdrawal in patients achieving good clinical response to TCZ +MTX have not been evaluated. PROs are important measures when determining response to therapy in patients with RA with respect to health-related quality of life (HRQOL).3,4 Objectives This study evaluated PROs between patients with RA who achieved low disease activity with TCZ +MTX and then continued or discontinued MTX in the COMP-ACT trial (NCT01855789). Methods US patients with RA who were inadequate responders to MTX were enrolled; initial combination therapy included MTX (≥15 mg/week orally) plus TCZ 162 mg subcutaneous either weekly (qw) or every 2 weeks (q2w). Patients who achieved DAS28-ESR≤3.2 at Week 24 were randomised 1:1 to receive TCZ-MONO or continue TCZ +MTX until week 52 (double-blind). Changes in PRO scores were measured between Week 24 and Weeks 40 and 52, and included patient global assessment of disease activity (PtGA; visual analogue score [VAS], 0–100 mm), pain (VAS), Health Assessment Questionnaire Disability Index (HAQ-DI, 0–3) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Results Of the 296 randomised patients (TCZ +MTX, n=148; TCZ-MONO, n=148), 74.8% were women, mean age was 55.5 years, mean RA duration was 6.8 years and mean DAS28-ESR was 6.3 at baseline. At Week 24 (randomization), PRO scores were similar between the randomised treatment groups. The mean changes in PtGA, pain, HAQ-DI and FACIT-fatigue scores from Week 24 to Weeks 40 were similar between the TCZ +MTX and TCZ-MONO groups (table 1). The proportion of patients with HAQ-DI <0.5 was similar between the groups at Week 24 (randomization), and remained similar at Weeks 40 and 52.Abstract AB0448 – Table 1 Changes in Patient-Reported Outcomes from Week 24 (Randomization) to Week 40 and Week 52 FACIT, Functional Assessment of Chronic Illness Therapy; HAQ-DI, Health Assessment Questionnaire Disability Index; MONO, monotherapy; MTX, methotrexate; PtGA, patient global assessment; SEM, standard error of the mean; TCZ, tocilizumab. * A negative change in score represents an improvement in the respective PRO except for Fatigue. † Estimated means from ANCOVA model includes Week 24 value as a covariate, treatment group, and the randomization stratification factors: DAS28 remission status at Week 24 (<2.6,≥2.6 to≤3.2), baseline weight-by-dosing group (<80 kg every 2 weeks [q2w],<80 kg weekly [qw], 80 to <100 kg q2w, 80 to <100 kg qw,≥100 kg qw), patient anti-TNF exposure (Yes or No). Conclusions Patients receiving TCZ who discontinue MTX appear to have similar PROs across multiple measures compared with patients continuing TCZ +MTX. Differences observed in clinical parameters between TCZ-MONO and TCZ +MTX did not appear to achieve a threshold that would be considered clinically meaningful. Similarities in PROs on both treatments were consistent with the clinical efficacy measures previously reported from COMP-ACT. References [1] Jones G, et al. J Rheumatol2017;44(2):142–6. [2] Dougados M, et al. Ann Rheum Dis. 2013;72(1):43–50. [3] Deshpande PR, et al. Perspect Clin Res. 2011;2(4):137–44. [4] Her M, Kavanaugh A. Curr Opin Rheumatol. 2012;24(3):327–34. Acknowledgements This study was funded by Genentech, Inc. Disclosure of Interest J. Kremer Shareholder of: Corrona, LLC, Consultant for: Abbvie, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Genentech, GlaxoSmithKline, Pfizer, Regeneron and Sanofi, W. Rigby Consultant for: Roche/Genentech, N. Singer Grant/research support from: Merck/EMD Serono (in kind lab resources) and unrestricted educational grants from several companies to MetroHealth for 2016 Cleveland Society of Rheumatology, C. Birchwood Employee of: Genentech, Inc., D. Gill Employee of: Genentech, Inc., W. Reiss Employee of: Genentech, Inc., J. Best Employee of: Genentech, Inc., J. Pei Employee of: Genentech, Inc., M. Michalska Employee of: Genentech, Inc.

FRI0253 Patient-reported outcomes in patients with rheumatoid arthritis treated with subcutaneous tocilizumab compared with placebo or intravenous tocilizumab in combination with csdmards

Background Two previous randomized, controlled trials (RCTs), BREVACTA and SUMMACTA, showed subcutaneous tocilizumab (TCZ-SC) was superior to placebo (PBO) and comparable to intravenous TCZ (TCZ-IV) in combination with csDMARDs for improving RA disease activity.1,2 Objectives To compare the efficacy of TCZ-SC with PBO or TCZ-IV + csDMARDs for improvement in patient-reported outcomes (PROs) in 2 RCT populations. Methods Both RCTs enrolled patients (pts) with inadequate responses to DMARDs; up to 20% had inadequate responses to tumor necrosis factor inhibitors. In BREVACTA, pts received blinded TCZ-SC 162 mg or PBO every 2 weeks (q2w) + csDMARDs for 24 weeks. In SUMMACTA, pts received TCZ-SC 162 mg weekly or TCZ-IV 8 mg/kg q4w + csDMARDs for the 24-week double-blind period. PROs, assessed at 12 weeks (prior to rescue) in BREVACTA and 24 weeks in SUMMACTA, included patient global assessment (PtGA; visual analog score [VAS], 0–100 mm), pain (VAS), Health Assessment Questionnaire Disability Index (HAQ-DI, 0–3) and Short Form-36 (SF-36) physical and mental component summary (PCS, MCS: 0–50) and domain (0–100) scores. The proportions of pts reporting scores ≥ minimum clinically important differences (MCID) and ≥ age/gender-matched normative values were assessed for each treatment group. Results Baseline PRO scores were mostly comparable between treatment groups in each study and between study populations. In BREVACTA, significantly more pts who received TCZ-SC reported scores ≥ MCID for all PROs at week 12 compared with PBO (54% to 73% vs 42% to 55%, respectively; number needed to treat [NNT], 5.2 to 13.0). Compared with 1% to 20% at baseline, 8% to 34% of pts who received TCZ-SC and 4% to 25% of PBO pts reported scores ≥ normative values in all PROs at week 12 (Table). In SUMMACTA, similar proportions of pts who received TCZ-SC and TCZ-IV reported scores ≥ MCID in all PROs at week 24 (61% to 84% vs 64% to 84%, respectively). The proportion of patients who reported scores ≥ normative values was comparable between the TCZ-SC and TCZ-IV groups across all PROs; compared with 0.2% to 23% at baseline, 14% to 41% of pts who received TCZ-SC and 15% to 42% of pts who received TCZ-IV reported scores ≥ normative values at week 24 (Table). Conclusions In BREVACTA, TCZ-SC + csDMARDs resulted in significantly greater improvements across all PROs and significantly more pts reporting scores ≥ MCID at week 12 compared with PBO. Similarly, more pts receiving TCZ-SC reported scores ≥ normative values at week 12 compared with PBO, despite few pts with such scores at baseline. Responses were similar between pts treated with TCZ-SC and TCZ-IV + csDMARDs in SUMMACTA at week 24. These data show TCZ treatment resulted in clinically meaningful improvements in PROs and indicate that attainment of normative scores is a realistic goal in treatment of pts with active RA. References Kivitz A, et al. Arthritis Care Res (Hoboken). 2014;66:1653–61. Burmester G, et al. Ann Rheum Dis. 2014;73:69–74. Acknowledgements This study was funded by F. Hoffmann-La Roche/Genentech. Disclosure of Interest V. Strand Consultant for: Abbvie; Amgen; AstraZeneca; Biogen Idec; Boehringer Ingelheim; Celltrion; Crescendo; Genentech/Roche; GlaxoSmithKline; Janssen; Lilly; Merck; Novartis; Pfizer; Regeneron; Samsung; Sanofi; UCB, K. Lampl Employee of: Genentech, Inc, C. Birchwood Employee of: Genentech, Inc, J. Pei Employee of: Genentech, Inc, K. Tuckwell Shareholder of: Roche, Employee of: Roche, R. Finch Shareholder of: Roche, Employee of: Roche, A. Kivitz Consultant for: Genentech; Novartis; Pfizer; Sanofi-Regeneron; UCB, G. Burmester Grant/research support from: Roche, Consultant for: Roche