Margaret Michalska

Catalysis-assisted plasma technology for carbon tetrachloride destruction

Catalysis-assisted plasma technology is a new concept developed to decompose carbon tetrachloride (CCl/sub 4/), one of the greenhouse gases. A laboratory-scale plasma reactor used a packed-bed reactor with 1 to 3 mm spherical BaTiO/sub 3/ pellets. One configuration of the system used a two-stage process in which the packed-bed reactor was followed by a 1% Pt/Al/sub 2/O/sub 3/ catalyst reactor. The other configuration employed a unique one-stage catalysis/plasma process in which the BaTiO/sub 3/ pellets were coated by active catalysts such as Co, Cu, Cr, Ni, and V. The power supplies used for these experiments were either a 50 Hz neon transformer or an 18 kHz invertor neon transformer. Experiments were performed to characterize the catalytic plasma reactor performance on CCl/sub 4/ destruction. Special attention was focused on the enhancement of the CCl/sub 4/ destruction and the reduction of byproduct CO production by catalyst selection in the one-stage reactor. >

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.

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.

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.