Study synopsis of the global non-interventional study SWITCH-RA

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1 Study synopsis of the global non-interventional study SWITCH-RA Protocol number: MA22401 Title of Study: A global multi-centre observational study in RA patients who are non-responders or intolerant to a single TNF inhibitor. Sponsor: Roche Pharma AG, Grenzach-Wyhlen Company division: Pharmaceutical Product name: MabThera Generic name: Rituximab Therapeutic area: Rheumatoid Arthritis Clinical study summary: This multicenter, prospective, observational study was designed to assess the efficacy of MabThera/Rituximab and alternative TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) who were non-responders or intolerant to a single previous TNFi. Data were collected from each patient from the time of change in biologic therapy for 12 months. Study center(s): 261 centers in Canada, Colombia, France, Germany, Greece, Italy, Mexico, Norway, Portugal, Spain, and United Kingdom (19 centers in Germany) Phase of development: IV Objectives: The primary objective was to describe, in routine clinical practice, the relative efficacy outcomes in patients suffering from RA who have been prescribed MabThera/Rituximab or an alternative TNFi after experiencing an insufficient response or intolerance to a single previous TNFi. The secondary objectives were as follows: To describe quality of life, health economics, and safety outcomes on the second biologic therapy. To capture the reason for initial TNFi discontinuation and the various parameters that drive the choice of the second biologic therapy. Methodology: This was a multicenter, prospective, observational study conducted in 11 countries. Patient demographics were collected at baseline. During the observational phase of the study, disease activity (DAS28-ESR, tender joint count, swollen joint count, inflammatory markers, global assessment of disease activity, severity of pain and morning stiffness), treatment-regimen, safety, and quality of life data were collected.

2 Number of patients (planned/analyzed): 1239 patients enrolled; 1230 patients analyzed (55 patients enrolled and analyzed in Germany) Diagnosis and main criteria for inclusion: Patients with rheumatoid arthritis who had not responded or had been intolerant to a single TNFi therapy, and who commenced MabThera/Rituximab or an alternative TNFi therapy, in accordance with the relevant summary of product characteristics, and age 18 years. Test product, dose and mode of administration or test procedure: Duration of treatment: Reference therapy, dose and mode of administration or reference procedure: Criteria for evaluation (efficacy, safety): Efficacy: Primary endpoint: mean change in Disease Activity Score (DAS)28-Erthrythrocyte Sedimentation Rate (ESR), 6 months following the change in biologic therapy (considered to be baseline). Secondary endpoints: Safety Mean change in DAS28-ESR, 12 months following the change in biologic therapy (considered to be baseline). Mean change over time in tender joint count (TJC), swollen joint count (SJC), ESR and C-reactive protein (CRP), at 6 and 12 months. Demographics and disease characteristics of the patients at the time of their switch to a second biologic therapy. Reasons for discontinuation of the first TNFi therapy. Previous TNFi therapy history. Previous non-biologic disease-modifying anti-rheumatic drug RA therapy history Patient characteristics and reasons that drove the physicians choice of a second biologic therapy following an insufficient response or intolerance to a single previous TNFi. Proportion of patients who remained on their second biologic therapy at 6 and 12 months after start of second biologic therapy (for rituximab, the proportion of patients awaiting a next course of therapy was recorded). Reasons for stopping the second biologic therapy and subsequent therapy choice. Incidence of infusion reactions during the study Follow-up of infectious events during the study Incidence of serious and non-serious adverse events (AEs) during the study Quality of life: Health Assessment Questionnaire (HAQ) data If the patient stopped working while on first TNFi, the time off work and the time to return to work will be recorded, where available.

3 Statistical methods: The mean change in DAS28-ESR, based on DAS28(3)-ESR, 6 months following the change in biologic therapy was assessed using an analysis of covariance (ANCOVA) model with treatment, baseline DAS28(3)-ESR and rheumatoid factor (RF) status (positive/negative) and other appropriate baseline characteristics as explanatory terms in the model. Mean change in DAS28-ESR, based on DAS28(3)-ESR, 12 months following the change in biologic therapy was assessed using an ANCOVA model with treatment, baseline DAS28-3-ESR, RF status (positive/negative) and other appropriate baseline characteristics as explanatory terms in the model. Change over time in TJC, SJC, CRP and/or ESR, were summarized by treatment type and by reason for change from first TNFi biologic (inefficacy, intolerance or other). All other secondary efficacy endpoints were summarized descriptively by treatment group. 95% confidence interval (CIs) and/or p-values were provided as appropriate. All data relating to quality of life (HAQ) were listed and summarized descriptively by treatment group. 95% CIs and/or p-values were provided as appropriate. Incidence of AEs were summarized descriptively by treatment group, reason for change, sero-status, treatment and sero-status, treatment (alternative TNFi) and sero-status, reason for change (inefficacy) and sero-status, reason for change (intolerance) and sero-status, and reason for change (other) and sero-status. Summary (efficacy, safety, other results): Efficacy Patients switching to MabThera/Rituximab following discontinuation of a TNFi achieved improved effectiveness as demonstrated by significantly greater decrease in DAS28(3)-ESR over 6 months compared with patients switching to an alternative TNFi. This was particularly evident in seropositive pts. switching to RTX following interruption of therapy due to inefficacy, compared with pts switching to an alternative TNFi. Furthermore, patients achieved a significantly decrease in ESR over 6 months, compared with patients switched to an alternative TNFi. At Month 6, the mean change in patient global assessment of disease was significantly greater in the MabThera/Rituximab group compared with the alternative TNFi group. At Month 6, mean changes in physician global assessment of disease, patient visual analogue scale (VAS) pain score, and duration of morning stiffness were numerically greater in the MabThera/Rituximab group compared with the alternative TNFi group. At Month 12, the mean change in patient VAS pain score was significantly greater in the MabThera/Rituximab group compared with the alternative TNFi group. At Month 12 mean changes in DAS28(3)-ESR, ESR, physician global assessment of disease, and duration of morning stiffness were numerically greater in the MabThera/Rituximab group compared with the alternative TNFi group.

4 MabThera/ Rituximab Alternative TNFi p-value Primary endpoint Mean change in DAS28(3)-ESR at 6 months Secondary endpoints LsMean change in DAS28(3)-ESR at 12 months LsMean change in ESR at 6 months months LsMean change in CRP 6 months months LsMean change in TJC 6 months months LsMean change in SJC 6 months months LsMean change in physician global assessment of disease 6 months months LsMean change in patient global assessment of disease 6 months months LsMean change in patient VAS pain score 6 months months LsMean change in HAQ-DI score 6 months months LsMean change in duration of morning stiffness (in minutes) 6 months months a. LsMean and p-value are based on an ANCOVA model adjusted for significant factors leading to selection of new biologic therapy and unbalanced covariates at baseline. Bold p-values indicate statistical significance versus an α level of Note: Sample size (N) is varies for each secondary efficacy parameter. Safety The overall safety profile of MabThera/Rituximab and TFNi therapy was similar to previously reported outcomes, and did not reveal any new safety signals. The incidence of AEs was comparable between the treatment groups (48.2% in the MabThera/ Rituximab group and 47.5% in the alternative TNFi group). In total, 63 patients reported 82 severe AEs during the study and the incidence was similar between the treatment groups (6.3% and 4.9%, respectively). Thirteen patients had AEs that were considered life-threatening in intensity; 9 patients (1.5%) in the MabThera/Rituximab group and 4 patients (0.8%) in the alternative TNFi group. Treatment-related AEs were reported for 124 patients (20.5%) and 121 patients (23.9%) in the MabThera/Rituximab and alternative TNFi groups, respectively.

5 The most common type of AEs in both treatment groups were reported in the system organ class of infections and infestations (18.2% in the MabThera/Rituximab group and 17.8% in the alternative TNFi group). The most common AEs in both treatment groups were urinary tract infection, headache, RA (worsening of disease), lower respiratory tract infection, nausea, cough, and rash. The most common treatment-related AEs were rash, headache, lower respiratory tract infection, injection site reaction, pruritus, cough, and nausea. The majority of AEs were mild or moderate in intensity. The incidence of infusion-related AEs was higher in the MabThera/Rituximab group compared with the alternative TNFi group (10.9% vs 3.9%, respectively), and the majority of infusion related AEs were mild or moderate in intensity in both treatment groups. One infusion related AE (headache) was considered to be severe in intensity, and was reported for a patient in the MabThera/Rituximab group. Eleven patients died as a result of an AE during the study: 7 patients (1.2%) in the MabThera/ Rituximab group and 4 patients (0.8%) in the alternative TNFi group. None of the deaths were considered to be related to study treatment. Overall, 191 serious AEs were reported for 138 patients: 82 patients (13.6%) in the MabThera/Rituximab group and 56 patients (11.0%), in the alternative TNFi group. In total, 56 patients had an AE that led to withdrawal from the study, and the incidence was higher in the alternative TNFi group compared with the MabThera/Rituximab group (39 patients [7.7%] vs 17 patients [2.8%], respectively). MabThera/Rituximab (N = 604) Alternative TNFi (N = 507) Total (N = 1111) Patients with event, n (%) Any AE 291 (48.2) 241 (47.5) 532 (47.9) Severe 38 (6.3) 25 (4.9) 63 (5.7) Life-threatening 9 (1.5) 4 (0.8) 13 (1.2) Treatment-related 124 (20.5) 121 (23.9) 245 (22.1) Any Serious AE 82 (13.6) 56 (11.0) 138 (12.4) AE leading to withdrawal 17 (2.8) 39 (7.7) 56 (5.0) Death on study 7 (1.2) 4 (0.8) 11 (1.0) Infusion-related reactions Any 66 (10.9) 20 (3.9) 86 (7.7) Severe 1 (0.2) 0 1 (0.1) Conclusions: Date of report: MabThera/Rituximab significantly reduced DAS28(3)-ESR compared with alternative TNFi treatment at 6 months (primary endpoint). MabThera/Rituximab significantly reduced ESR compared with alternative TNFi treatment at 6 months. Patients treated with MabThera/Rituximab as a second biologic therapy showed a significant improvement in the patient global assessment of disease at 6 months, compared with patients treated with a second alternative TNFi. Patients treated with MabThera/Rituximab showed a significant improvement in VAS pain score at 12 months compared with patients treated with a second alternative TNFi. The safety profiles of MabThera/Rituximab and alternative TNFi were similar to those previously reported and did not reveal any new safety signals.