Angelika Jahreis

Integrated safety in tocilizumab clinical trials

IntroductionThe efficacy and safety of tocilizumab in patients with rheumatoid arthritis have been evaluated in a comprehensive phase 3 program. Patients from these randomized trials could receive tocilizumab treatment in open-label extension trials. Here, the long-term safety profile of tocilizumab, using pooled data from all of these trials, is reported.MethodsCumulative safety data (as of February 6, 2009) from five core phase 3 trials, two ongoing extension trials, and one clinical pharmacology study were analyzed. Two patient populations were evaluated: an all-control population (n = 4,199), which included all patients randomly assigned in the placebo-controlled portions of the five core studies, and an all-exposed population (n = 4,009), which included patients from any of the eight studies who received at least one dose of tocilizumab.ResultsTotal exposure to tocilizumab was 8,580 patient years (PY), and total duration of observation was 9,414 PY. Overall adverse event (AE) and serious AE (SAE) rates were 278.2/100 PY and 14.4/100 PY, respectively. These events included serious infections (4.7/100 PY), opportunistic infections (0.23/100 PY), gastrointestinal perforations (0.28/100 PY), malignancy (1.1/100 PY), myocardial infarction (0.25/100 PY), and stroke (0.19/100 PY). The rates of SAEs and serious infections were stable over time; no increase with prolonged exposure was noted.ConclusionsThe longer-term safety profile of tocilizumab (mean treatment duration, 2.4 years) is consistent with that observed in the phase 3 studies (duration up to 1 year).

Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: Evaluation of an antidrug antibody ELISA using clinical adverse event-driven immunogenicity testing.

BACKGROUND Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody directed against the interleukin-6 receptor. In Europe, TCZ is approved for use in combination with methotrexate in the treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have failed to respond to or were unable to tolerate previous therapy with one or more disease-modifying antirheumatic drugs or tumor necrosis factor (TNF) antagonists; in the United States, it is approved for the treatment of adult patients with moderate to severe active RA who have failed to respond to one or more TNF antagonists. As part of the Phase III clinical development program, the immunogenicity of TCZ was evaluated using a bridging ELISA; however, this assay is considered limited in detecting low-affinity or immunoglobulin G4 subisotype antidrug antibodies (ADAs). OBJECTIVE This study assessed the validity of the ELISA for detecting anti-TCZ ADAs by using complementary bioanalytic assays to test samples from a subgroup of patients with clinical adverse events (AEs) of a potentially immunogenic nature, who were considered highly likely to have ADAs. The goal was to determine whether use of these additional assays led to detection of ADAs not found on the ELISA, thus minimizing the risk of false-negative results. METHODS The Phase III program for TCZ consisted of 5 core studies in which adult patients with RA received either TCZ 4 or 8 mg/kg IV or control every 4 weeks, with or without concomitant antirheumatic therapy. Blood samples obtained at baseline and at regular intervals thereafter were tested using the ELISA for ADA screening and confirmation. Regardless of the results on ADA screening, samples from patients who developed clinical AEs of a potentially immunogenic nature (ie, falling within predefined system organ classes, occurring during or within 24 hours of TCZ infusion, considered related to TCZ therapy, or leading to study withdrawal) were subjected to additional testing with a surface plasmon resonance (SPR) assay for isotyping and epitope localization and a standard ImmunoCAP immunoglobulin E (IgE) assay made specific for TCZ. RESULTS The 5 core studies and their open-label, longterm extension studies enrolled a total of 4199 adult patients with RA (82.1% female; 74.0% white; mean age, 52.0 years [range, 18-89 years]; mean weight, 73.4 kg [range, 35-150 kg]); 2928 patients received TCZ and 1271 received control. Of the 2816 samples from TCZ-treated patients tested, 64 (2.3%) had samples that tested positive at least once on the ELISA screening and confirmation assay, 48 (75.0%) of them at baseline. A clinical AE of a potentially immunogenic nature occurred during TCZ treatment in 21 patients, 8 of whom had an anaphylactic reaction. Eleven of the samples from these 21 patients had tested negative for AD As on the screening ELISA. Only 1 of these 11 patients tested positive for ADAs on both additional assays; all others tested negative. The results of the ELISA, SPR, and IgE assays were consistent for 16 of 18 tested patients (88.9%) who provided data on at least 2 of the 3 assays. CONCLUSIONS Based on the findings of this analysis in a relevant patient population, the bridging-type screening and confirmation ELISA was a valid method of detecting anti-TCZ ADAs. Immunogenicity testing of samples from patients with clinical AEs of a potentially immunogenic nature using assays complementary to the ELISA added valuable information about the incidence and character of ADAs.

Effect of rituximab on physical function and quality of life in patients with rheumatoid arthritis previously untreated with methotrexate

To assess the effect of rituximab plus methotrexate (MTX) compared with MTX alone on patient‐reported outcomes (PROs) and health‐related quality of life (HRQOL) in patients with active early rheumatoid arthritis (RA) previously untreated with MTX.

Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate)

Objectives Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study. Methods Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96. Results Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period. Conclusions Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab. Trial registration number NCT01532869; Results.

Using Registries to Identify Adverse Events in Rheumatic Diseases

The proven effectiveness of biologics and other immunomodulatory products in inflammatory rheumatic diseases has resulted in their widespread use as well as reports of potential short- and long-term complications such as infection and malignancy. These complications are especially worrisome in children who often have serial exposures to multiple immunomodulatory products. Post-marketing surveillance of immunomodulatory products in juvenile idiopathic arthritis (JIA) and pediatric systemic lupus erythematosus is currently based on product-specific registries and passive surveillance, which may not accurately reflect the safety risks for children owing to low numbers, poor long-term retention, and inadequate comparators. In collaboration with the US Food and Drug Administration (FDA), patient and family advocacy groups, biopharmaceutical industry representatives and other stakeholders, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Duke Clinical Research Institute (DCRI) have developed a novel pharmacosurveillance model (CARRA Consolidated Safety Registry [CoRe]) based on a multicenter longitudinal pediatric rheumatic diseases registry with over 8000 participants. The existing CARRA infrastructure provides access to much larger numbers of subjects than is feasible in single-product registries. Enrollment regardless of medication exposure allows more accurate detection and evaluation of safety signals. Flexibility built into the model allows the addition of specific data elements and safety outcomes, and designation of appropriate disease comparator groups relevant to each product, fulfilling post-marketing requirements and commitments. The proposed model can be applied to other pediatric and adult diseases, potentially transforming the paradigm of pharmacosurveillance in response to the growing public mandate for rigorous post-marketing safety monitoring.

OP0054 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis: Week 48 Data from the Fasscinate Trial

Background Systemic sclerosis (SSc) is a debilitating disease with limited treatment options. Data indicate a key role for interleukin-6 (IL-6) in the pathogenesis of SSc.1,2 In murine models of SSc, IL-6 receptor (IL-6R) inhibition prevented and reversed skin fibrosis.3,4 Objectives To assess safety and efficacy of the IL-6R inhibitor tocilizumab (TCZ) in pts with SSc. Methods In this first double-blind, placebo-controlled, phase 2, proof-of-concept study, the effect of inhibiting IL-6 in SSc was explored. Pts ≥18 y with active SSc (1980 ACR criteria,5 ≤5 y disease duration, modified Rodnan skin score (mRSS) 15-40, and elevated acute-phase reactants) were randomized 1:1 to TCZ 162 mg or placebo (PBO) subcutaneously (SC) wkly for 48 wks. Primary end point was mean change in mRSS from baseline at wk 24. Mean change in mRSS at wk 48, pt-reported outcomes (PROs), and pulmonary function at wk 48 were secondary/exploratory measures. Results 87 pts (43 TCZ, 44 PBO) were enrolled. Baseline characteristics were similar between arms including mean [SD] mRSS (TCZ 26 [7.2]; PBO 26 [5.9]). At wk 24, a favorable but not statistically significant effect of TCZ over PBO on mRSS was noted (–3.9 vs –1.2; adjusted mean difference, –2.7 [95% CI: –5.85, 0.45], p=0.09; Table). At wk 48, a numerically larger change was noted in the TCZ vs PBO arm (–6.3 vs –2.8; adjusted mean difference, –3.6 [95% CI: –7.23, 0.12], p=0.06). Though not statistically significant, higher proportions of TCZ vs PBO pts had mRSS improvement from baseline of ≥20% (40% vs 27%), ≥40% (21% vs 7%), or ≥60% (12% vs 0). There were numerically greater improvements in the TCZ arm than in the PBO arm for PROs (HAQ-DI, pt global assessment VAS, and FACIT-fatigue) at wk 48 (Table). The proportion of pts with HAQ-DI improvement ≥0.22 was 28% (12/43) in the TCZ arm and 7% (3/44) in the PBO arm at wk 48 (p=0.01). Fewer TCZ vs PBO pts showed a decline in % predicted forced vital capacity (%FVC <0; 57% vs 84%) and a >10% absolute decrease in %FVC (10% vs 23%; Table) at wk 48. Adverse events (AEs)/serious AEs occurred in 98%/33% of TCZ and 91%/34% of PBO pts by wk 48. One death occurred in the PBO arm and 3 deaths in TCZ pts by wk 48; all were unrelated to study drug except for a fatal lung infection in 1 TCZ pt. Conclusions Treatment with TCZ resulted in consistent, but not statistically significant, improvements in skin sclerosis (mRSS) at wks 24 and 48 and in PROs (HAQ-DI, pt global assessment VAS, and FACIT-fatigue) at wk 48. A trend toward less FVC decline with TCZ than with PBO noted at wk 24 persisted at wk 48. Observed AEs were consistent with SSc complications and the safety profile of TCZ. Overall, the effect of TCZ on skin sclerosis, PROs, and pulmonary function and the observed safety profile suggest a positive risk/benefit profile for TCZ in SSc and support further evaluation of TCZ in pts with SSc. References J Rheumatol 1998;25:308. Pathobiology 1993;61:239. Am J Pathol 2012;180:165. Arthritis Rheum 2014:66:S1312. Arthritis Rheum 1980;23:581. Disclosure of Interest D. Khanna Grant/research support from: Actelion, Bayer, BMS, EMD Seerono, Gilead, InterMune, NIH/NIAMS, NIH/NIAID, Scleroderma Foundation, Pulmonary Hypertension Association, Consultant for: Actelion, Bayer, BMS, EMD Serono, InterMune, Biogen Idec, Genentech/Roche, Cytori, Lycera, Sanofi-Aventis/Genzyme, GSK, C. Denton Grant/research support from: Roche, Novartis, Consultant for: Roche, Actelion, GlaxoSmithKline, A. Jahreis Shareholder of: Roche, Employee of: Genentech, J. van Laar Consultant for: Pfizer, Tigenix, Novartis, Roche, Eli Lilly, S. Cheng Employee of: Genentech, H. Spotswood Shareholder of: Roche, Employee of: Roche, J. Pope: None declared, Y. Allanore Grant/research support from: Actelion, BMS, Genentech/ Roche, Inventiva, Pfizer, Servier, Consultant for: Actelion, Bayer, Biogen Idec, BMS, Genentech/ Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, UCB, U. Müller-Ladner Consultant for: Roche, Chugai, Speakers bureau: Roche, Chugai, J. Siegel Employee of: Roche, D. Furst Grant/research support from: Genentech, Consultant for: Genentech

Effect of concomitant statins on rituximab efficacy in patients with rheumatoid arthritis

Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease. In order to lower this risk, statins are used in clinical practice in addition to biologics.1 Rituximab, an anti-CD20 antibody approved for the treatment of RA, induces B-cell apoptosis by crosslinking and redistributing CD20 to cholesterol-rich lipid rafts.2 Statins have been shown in vitro to induce conformational changes on the CD20 epitope, potentially influencing the apoptotic effect of rituximab.3 There are conflicting reports about the effect of statins on the clinical efficacy of rituximab in RA.4–6 We investigated the impact of statin coadministration on rituximab efficacy in patients from a global clinical trial programme in RA. This was a retrospective, pooled, observed case analysis from four placebo-controlled phase II/III randomised clinical trials (DANCER, REFLEX, SERENE and IMAGE)7–10 in patients with moderate-to-severe active RA. All patients received concomitant methotrexate 10−25 mg/week at a stable dose and were permitted to receive stable background doses of oral corticosteroids (prednisolone ≤10 mg/day or equivalent) and non-steroidal anti-inflammatory drugs throughout. Efficacy responses (change in Disease Activity Score 28 using erythrocyte sedimentation rate (DAS28-ESR) from baseline, American College of Rheumatology 20% or 50% (ACR20/50) …

Skin Gene Expression Is Prognostic for the Trajectory of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis

At present, there are no clinical or laboratory measures that accurately forecast the progression of skin fibrosis and organ involvement in patients with systemic sclerosis (SSc). The goal of this study was to identify skin biomarkers that could be prognostic for the progression of skin fibrosis in patients with early diffuse cutaneous SSc (dcSSc).

Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis

Objectives Skin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFβ) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment—the faSScinate study—in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor. Methods We analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains. Results The hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFβ-regulated genes and molecular pathways. Conclusions We demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases. Trial registration number NCT01532869; Post-results.

Tocilizumab treatment of patients with systemic sclerosis: clinical data

Systemic sclerosis (SSc) is an immune-mediated disease characterized by progressive, and often severe, inflammation and fibrosis of the skin and internal organs, such as the lungs, heart, kidneys, and gastrointestinal tract. There is an unmet medical need to treat patients with SSc given the high SSc-related mortality rate. Furthermore, disease-modifying therapies are lacking, and current treatment options focus on the management of individual organ-specific complications associated with the disease. Immunosuppressive therapies are the mainstay of pharmacologic management of major SSc-associated complications, such as skin and lung manifestations, but their overall effectiveness is limited and toxicity issues are common. Advances in understanding of the pathological processes involved in the immunologic and fibrotic mechanisms of SSc have led to clinical research focusing on targeted immunotherapies, in an effort to develop much needed disease-modifying treatment options. The interleukin-6 receptor-alpha antagonist tocilizumab has demonstrated promising efficacy in a phase 2 trial and is being investigated in a phase 3 trial. This article provides an overview of current pharmacologic treatment options for the management of SSc-related complications and discusses tocilizumab for the treatment of SSc in clinical trials.