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SYNOPSIS OF CLINICAL STUDY REPORT Individual Study Table (For National Authority Use Only) Name of Referring to Part of the Sponsor/Company: Dossier Genentech, Inc. Name of Finished Product: Volume: MabThera/Rituxan Name of Active Ingredient: Page: Rituximab Title of Study: A Phase II/III, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab (MAbThera/Rituxan) in Adults with Primary Progressive Multiple Sclerosis II/III Kathleen Hawker, M.D. Hawker KS, O'Connor P, Freedman MS, et al. Efficacy and safety of rituximab in patients with primary progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, multicenter trial. Mult Scler 2008;14:S299 [Abstract]. Hawker K, O'Connor P, Freedman M, et al. Efficacy and safety of rituximab in patients with primary progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, multicenter trial. Neurology 2009;72(S3):A254 [Abstract]. Study Period: Objectives Primary: · To assess the efficacy of rituximab relative to placebo, as measured by the time to confirmed disease progression (CDP) over a 96-week treatment period · To evaluate the safety and tolerability of rituximab in patients with primary progressive multiple sclerosis (PPMS) Secondary: · The change in total volume of brain T2 lesions on MRI scan from baseline to Week 96 · The change in brain volume (i.e., brain atrophy) on MRI scan from baseline to Week 96 Methodology This was a Phase II/III, randomized, double-blind, parallel-group, placebo-controlled, multicenter study to evaluate the safety and efficacy of rituximab in adults with PPMS. The study was conducted by Genentech, Inc.; rituximab for MS is being developed by Genentech and Biogen Idec, Inc. Each site had two investigators: a principal/treating investigator and an examining investigator or rater. The examining investigator who was responsible for administration of the EDSS and MSFCS was masked to patient treatment and laboratory and MRI results. The MSFCS may have been delegated to an examining technician at the discretion of the investigator, but the examining investigator must have performed the EDSS. All other study activities, including, but not limited to, interactions with the Sponsor and IRBs or ECs, review of laboratory and MRI results, and recording of safety data, were performed by the principal/treating investigator and his or her designees. These requirements were in place to ensure appropriate medical care and safety assessment without compromising masking during patient ratings. The study consisted of four periods: a screening period (Week -4 to Week -2 [Days -28 to -15]), a pretreatment period (Week -2 to Week 0 [Days -14 to -1]), a treatment period (Week 0 [Day 1] 16 June 2004 to 28 February 2008

Phase of Development: Lead Investigator: Publications:

Clinical Study Report: Rituximab (MabThera/Rituxan)--Genentech, Inc. 2\CSR U2786g

SYNOPSIS OF CLINICAL STUDY REPORT (cont'd) Individual Study Table (For National Authority Use Only) Name of Referring to Part of the Sponsor/Company: Dossier Genentech, Inc. Name of Finished Product: Volume: MabThera/Rituxan Name of Active Ingredient: Page: Rituximab to Week 96), and a follow-up period (Weeks 97 to 122). The first course of study drug treatment was administered on Days 1 and 15. Patients were dosed every 24 weeks, with the fourth and last course of treatment administered at Weeks 72 and 74. When patients completed the 96-week treatment period, they entered the follow-up period. Patients who withdrew or discontinued from the study early were followed for collection of safety data for 48 weeks from the time of their last dose of study drug. Patients continued to be followed and had B cells measured for safety at regular intervals (every 12 weeks [± 7 days]) if their B-cell counts had not returned to baseline or the lower limit of normal (LLN) by Week 122 or Safety Follow-Up Week 48 for patients who terminated early. Patients who experienced confirmed progression or a relapse prior to Week 96 may have discontinued from the treatment period and received alternative treatment during the safety follow-up period, if judged appropriate by the Principal Investigator. Patients with an exacerbation were allowed to continue in the treatment period, if judged clinically appropriate by the Principal Investigator. Number of Patients (Planned and Analyzed): The study was expected to enroll approximately 435 patients at up to 60 sites in the United States and Canada. A total of 439 patients from 59 investigative sites were enrolled and randomized into the study. Patients were randomized in a 2:1 ratio into the rituximab and placebo groups, with 292 in the rituximab group and 147 in the placebo group. Diagnosis and Main Criteria for Inclusion: · Ability and willingness to provide written informed consent and to comply with the schedule of protocol assessments · Age 18­65 years · Definitive diagnosis of PPMS (as defined by McDonald et al. 2001) · Disease duration of 1 year · EDSS at baseline between 2.0 and 6.5 points, inclusive · Score of 2.0 on the Functional Systems (FS) scale for the pyramidal system or gait that was due to lower extremity findings · Presence of at least one of the following in a CSF specimen obtained during the screening period and analyzed by the central laboratory or results from a CSF sample obtained during the previous 24 months: IgG oligoclonal bands Elevated CSF IgG index · For patients of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, vaginal ring, intrauterine device, physical barrier) during study treatment and for 1 year following the last dose of study drug Test Product, Dose, and Mode of Administration: Rituximab is formulated for IV administration as a sterile product in 9.0 mg/mL sodium chloride, 0.7 mg/mL polysorbate 80, 7.35 mg/mL sodium citrate dehydrate, and Sterile Water for Injection (pH 6.5). The antibody is supplied for market use in 10 mL and 50 mL vials at a concentration of 10.0 mg/mL. The 10 mL vials contain 100 mg of antibody. The 50 mL vials contain 500 mg of antibody. No preservative is used since the vial is designed for single use. Study sites were supplied 50 mL vials of 500 mg rituximab and 50 mL vials of matching placebo. The first course of treatment consisted of a dose of 1 g IV rituximab or placebo equivalent administered on each of Days 1 and 15. Patients received prophylactic treatment with Clinical Study Report: Rituximab (MabThera/Rituxan)--Genentech, Inc. 3\CSR U2786g

SYNOPSIS OF CLINICAL STUDY REPORT (cont'd) Individual Study Table (For National Authority Use Only) Name of Referring to Part of the Sponsor/Company: Dossier Genentech, Inc. Name of Finished Product: Volume: MabThera/Rituxan Name of Active Ingredient: Page: Rituximab acetaminophen (1 g) and diphenhydramine HCl (50 mg), or equivalent, by mouth 30­60 minutes prior to the start of each infusion. Subsequent courses of treatment were administered starting at Week 24 (Day 169), Week 48 (Day 337), and Week 72 (Day 505). The second infusion of the subsequent courses of treatment was 14 ± 1 days after the first infusion. Patients received rituximab or placebo as assigned for the first treatment course. Criteria for Evaluation Efficacy: The primary efficacy outcome measure was the time to CDP. Disease progression was defined as an increase of 1.0 point from baseline EDSS, if the baseline EDSS was between 2.0 and 5.5 points (inclusive), or an increase of 0.5 points, if the baseline EDSS was > 5.5 points, for which change was not attributable to another etiology (e.g., fever, concurrent illness, MS relapse or exacerbation, or concomitant medication). Confirmation of disease progression must have occurred at a regularly scheduled visit that was at least 12 weeks ( 84 days) after the initial progression. Secondary efficacy outcome measures in support of the primary efficacy outcome measure were change from baseline to Week 96 in the total volume of T2 lesions on brain MRI scan, and change from baseline to Week 96 in brain volume on brain MRI scan. Safety: Safety was assessed through regular neurologic and physical examinations and MRI assessments. In addition, the following were collected and analyzed: · Adverse events · Vital signs · Complete routine hematology, chemistry, and urinalyses · Circulating B cells, T cells, natural killer cells, and other leukocytes · Quantitative immunoglobulins: total, IgG, IgM, and IgA · Immunity panel: antibody titers for mumps, rubella, and tetanus · Thyroid tests: TSH and total T4 · HACA formation Statistical Methods All efficacy outcomes in this study were analyzed according to the intention-to-treat principle and included all patients who were randomized. To be evaluable for safety, a patient had to have received any amount of study drug (i.e., rituximab or placebo). Because of the importance of assessing safety based on the actual study drug that patients received, patients were grouped according to the treatment that patients actually received rather than the treatment assigned in all safety analyses. The final analysis of study results was performed when all patients completed the entire trial (follow-up period or safety follow-up period) or discontinued early. The treatment assignment was unblinded when data were monitored, cleaned, verified, and locked. Data from the patients' B-cell follow-up visits are not part of the finalized locked data. Some patients may still be continuing their B-cell follow-up visits at the time of database lock and final analyses. The postbaseline MRI data Clinical Study Report: Rituximab (MabThera/Rituxan)--Genentech, Inc. 4\CSR U2786g

SYNOPSIS OF CLINICAL STUDY REPORT (cont'd) Individual Study Table (For National Authority Use Only) Name of Referring to Part of the Sponsor/Company: Dossier Genentech, Inc. Name of Finished Product: Volume: MabThera/Rituxan Name of Active Ingredient: Page: Rituximab were available to the analysis team (programmers and statisticians only) prior to the database lock and unblinding of individual treatment assignments for data cleaning and programming purposes. The baseline assessment was defined as the latest assessment prior to the first infusion. All assessments at Day 1 were performed prior to infusion (unless otherwise specified in the protocol) and hence were used to define baseline assessment. The SAP superseded the plan specified in Protocol U2786g Amendment 5. Three analysis populations were defined for this study: intent-to-treat (ITT) population, safety-evaluable population, and pharmacokinetic-evaluable population. The number of randomized patients was tabulated by site and treatment group. Patient disposition (treated, discontinued, and completed the study) was tabulated by treatment group. Reasons for premature study discontinuation were listed and summarized by treatment group. The number of patients completing a scheduled visit was tabulated by treatment group and by visit. Eligibility criteria exceptions and other major protocol deviations were also summarized by treatment group. Demographic and baseline disease characteristics, such as age, sex, race/ethnicity, weight, prior key therapies (interferon -a, interferon -1b, glatiramer acetate, azathioprine, immune globulin, or steroid), duration of disease (onset of symptoms and diagnosis), EDSS, FSS, MSFCS, MRI results, and presence of oligoclonal bands and elevated CSF IgG index were summarized for all randomized patients by treatment group using descriptive statistics. All efficacy analyses were based on the ITT population. Comparisons of efficacy were performed between rituximab and placebo. All statistical tests were two-sided. Primary Endpoint: The primary efficacy analysis for this trial compared the time to CDP, during the 96-week treatment period, between rituximab and placebo. Time to CDP was defined as the time from randomization to the first disease progression, which was confirmed at the next regularly scheduled visit 84 days after the initial disease progression. Disease progression was defined as an increase of 1.0 point from baseline EDSS, if the baseline EDSS was between 2.0 and 5.5 points (inclusive), or an increase of 0.5 points, if the baseline EDSS was > 5.5 points. The initial disease progression can be determined using EDSS assessments at any visit (scheduled or unscheduled) in the treatment period, but the confirmation of disease progression had to be determined using the next EDSS assessment at a regularly scheduled visit that was at least 84 days after the initial disease progression. If a patient missed one or more scheduled visits taking place at least 84 days after an initial progression, then the confirmation of disease progression was based on the next available EDSS assessment at a later scheduled visit. There may have been EDSS assessments (at unscheduled or scheduled visits that were < 84 days after the initial progression) between the initial progression visit and the confirmatory visit. These EDSS values should have been at least as high as the minimum change required for progression, otherwise, the initial progression could not be confirmed at the confirmatory visit. The assessment of disease progression was based on reported EDSS scores and not on the investigator's independent assessment of disease progression. This analysis only included data from the treatment period; that is, EDSS assessments after the date of discontinuation from or completion of the treatment period were not used to determine disease progression (initial as well as confirmation). Patients who completed the treatment period without initial or CDP were censored at the date of their last EDSS assessment. Patients who completed the treatment period and had initial disease progression at the last EDSS assessment were censored at the date of their last EDSS assessment. Patients who discontinued the treatment period early with no confirmatory Clinical Study Report: Rituximab (MabThera/Rituxan)--Genentech, Inc. 5\CSR U2786g

SYNOPSIS OF CLINICAL STUDY REPORT (cont'd) Individual Study Table (For National Authority Use Only) Name of Referring to Part of the Sponsor/Company: Dossier Genentech, Inc. Name of Finished Product: Volume: MabThera/Rituxan Name of Active Ingredient: Page: Rituximab EDSS assessments after the initial disease progression were considered as having CDP. In these patients, the non-confirmatory EDSS assessments (if any) after the initial progression should have been at least as high as the minimum change required for progression. Also, patients who discontinued from the study early or who were lost to follow up and had not had CDP at any time during the treatment period and had not had initial progression at the last EDSS assessment in the treatment period were censored at the last EDSS assessment. Some patients may have experienced relapse during the treatment period. For these patients, EDSS values assessed during relapse (defined as within 30 days from the start of the relapse) were not used to confirm the progression. But, these EDSS assessments were used to determine initial progression. The EDSS values during a relapse should have been at least as high as the minimum change required for progression if the occurrence of the relapse was between the initial progression and the confirmatory visit. Data for patients who received exclusionary MS therapies prior to experiencing the CDP in the treatment period were censored at the time of the last EDSS assessment prior to receiving the exclusionary MS medication. Exclusionary MS medications are defined as natalizumab, mitoxantrone hydrochloride, IFN-, IFN--1a, IFN--1b, and glatiramer acetate. Data for patients who did not have any postbaseline EDSS assessments in the treatment period were censored at the randomization date. The overall type I error rate for the two-sided test for the primary endpoint was controlled at = 0.05. The final primary analysis was performed at = 0.0499 to account for 0.0001 alpha spent at one preplanned interim analysis. Time to CDP was formally compared between rituximab and placebo using a two-sided stratified log-rank test. The stratification factors were prior MS therapies with IFN- or glatiramer acetate (none, therapies ended > 90 days prior to randomization, therapies ended within 90 days prior to randomization) and baseline EDSS ( 4.0, > 4.0). The stratification factors were determined by the CRF data collected at the time of randomization and not from the IVRS unless the CRF data were missing. Results from an unstratified log-rank test were also presented. The proportion of patients with CDP was estimated using Kaplan-Meier methodology. Estimation of the hazard ratio was based on a stratified Cox regression model with the same two stratification factors used in the stratified log-rank test above. The estimates of the unstratified hazard ratio were also presented. Secondary Endpoints: Secondary efficacy endpoints included change from baseline to Week 96 in the total volume of T2 lesions and change from baseline to Week 96 in brain volume. A Hochberg-Bonferroni procedure was used to control the type I error rate in testing these two secondary endpoints. If the p-values for both the endpoints were 0.05, the results for both the endpoints were considered statistically significant. If the p-value for one endpoint was > 0.05, the result for the other endpoint was considered statistically significant if the p-value for this endpoint was 0.025. Change from baseline to Week 96 in the total volume of T2 lesions was compared between rituximab and placebo using ranked analysis of variance (ANOVA). The model included the following factors: prior MS therapies with IFN- or glatiramer acetate (none, therapies ended > 90 days prior to randomization, therapies ended within 90 days prior to randomization) and baseline EDSS ( 4.0, > 4.0). The last-observed value available before the treatment period discontinuation was carried forward to impute the missing values. The baseline value was carried forward for patients who did not have any postbaseline observations. Patients with missing Clinical Study Report: Rituximab (MabThera/Rituxan)--Genentech, Inc. 6\CSR U2786g

SYNOPSIS OF CLINICAL STUDY REPORT (cont'd) Individual Study Table (For National Authority Use Only) Name of Referring to Part of the Sponsor/Company: Dossier Genentech, Inc. Name of Finished Product: Volume: MabThera/Rituxan Name of Active Ingredient: Page: Rituximab baseline values were excluded. Change from baseline to Week 96 in brain volume was analyzed similarly. Summary of Results and Conclusions Efficacy and Pharmacokinetic/Pharmacodynamic Conclusions: · The study did not provide evidence of a significant difference in time to CDP (defined by specific increase in EDSS) between the rituximab and placebo arms; however, rituximab tended to delay the time to CDP compared with placebo as measured by a stratified hazard ratio of 0.77 (p = 0.1442). At Week 96, the proportion of patients who had CDP was lower in the rituximab group compared with the placebo group. · Rituximab significantly slowed the accumulation of T2 lesions from baseline to Week 96. · The change in brain volume was similar between rituximab-treated patients compared and placebo-treated patients. · The exploratory endpoint analyses related to T2 lesions and the Timed 25-Foot Walk tests showed some evidence of potential treatment benefit. · Long-term treatment with rituximab may increase terminal elimination half-life. However, the magnitude of change over time is unlikely to be clinically significant because of the long dosing interval. Safety Conclusions: · Overall, the incidence of adverse events through 122 weeks following up to 4 treatment courses (8 infusions) was comparable between patients receiving rituximab and placebo, although a higher incidence of infusion reactions and serious infections was observed in rituximab-treated patients. · The incidence of any infection was similar in the placebo and rituximab groups. The most common infections in rituximab-treated patients were urinary tract infection, nasopharyngitis, and upper respiratory tract infection. The proportion of patients with serious infection-related adverse events was higher in the rituximab group (4.5%) than in the placebo group (< 1%). Serious infections occurring in more than 1 patient in the rituximab group included pneumonia, urinary tract infection, and lower extremity cellulitis. Serious infections in the rituximab group were seen more commonly in patients over 55 years of age (9 of 13). · A higher proportion of rituximab-treated patients than placebo-treated patients experienced infusion-associated adverse events following initial infusions, but diminished to rates comparable with placebo. Of the 215 rituximab-treated patients who had infusion-associated adverse events, the majority (198) of these patients experienced events that were mild to moderate (Grade 1 or 2) in severity. Grade 3 infusion-associated events included dyspepsia, fatigue, asthenia, chest pain, chills, influenza-like illness nasopharyngitis, arthralgia, syncope, syncope vasovagal, headache, sciatica, hypertonia, dyspnea, throat tightness, dry throat, throat irritation, pruritus, and urticaria. No Grade 4 infusion-associated events were reported. · Rituximab-treated patients had lower IgM compared with patients in the placebo arm. However, there was no evidence of significant association between infection and low IgM.

Clinical Study Report: Rituximab (MabThera/Rituxan)--Genentech, Inc. 7\CSR U2786g

SYNOPSIS OF CLINICAL STUDY REPORT (cont'd) Individual Study Table (For National Authority Use Only) Name of Referring to Part of the Sponsor/Company: Dossier Genentech, Inc. Name of Finished Product: Volume: MabThera/Rituxan Name of Active Ingredient: Page: Rituximab Overall Conclusions: The study did not provide evidence of a significant difference in time to CDP (defined by specific increase in EDSS) between the rituximab and placebo arms; however, rituximab tended to delay the time to CDP compared with placebo as measured by a stratified hazard ratio of 0.77 (p = 0.1442). At Week 96, the proportion of patients who had CDP was lower in the rituximab group compared with the placebo group. The study showed that rituximab significantly slowed the accumulation of T2 lesions. The change in brain volume was similar between the rituximab group and placebo group. Exploratory endpoint analyses related to T2 lesions and Timed 25-Foot Walk tests showed some evidence of potential treatment effect. Post hoc sensitivity analyses using the average EDSS before first dose as the baseline EDSS showed that rituximab may delay time to confirmed disability progression compared with placebo. Furthermore, when disease progression is defined by other disability measurements (e.g., the Timed 25-Foot Walk or 9-Hole Peg Test or a combination of these with EDSS), rituximab delayed the time to confirmed disability progression compared with placebo. Planned and post hoc subgroup analyses suggested that rituximab may provide greater treatment benefits for patients who are younger, have Gd lesions, or have higher MSSS. Overall, rituximab was generally safe and well tolerated. The incidence of adverse events, serious adverse events, overall infections were comparable between groups. However, a higher rate of serious infections was observed in the rituximab group. Adverse events during an infusion or within 24 hours post-infusion occurred in a higher proportion of rituximab-treated than placebo-treated patients. As expected, the frequency of these events was higher during the first infusion than subsequent infusions, consistent with prior studies with rituximab in RRMS in which patients were also not pre-medicated with glucocorticoids. Such events included fever, chills, rigors, nausea, pruritus, asthenia, and hypotension and are consistent with those reported in patients with RA treated with rituximab. Date of the Report 22 April 2009

Clinical Study Report: Rituximab (MabThera/Rituxan)--Genentech, Inc. 8\CSR U2786g

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