Avtozma Drug Information

Rheumatoid Arthritis – Intravenous

Administration The efficacy and safety of intravenously administered tocilizumab was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Tocilizumab was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V). Study I (NCT00109408) evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response.

In this study, 67% of patients were MTX-naïve, and over 40% of patients had rheumatoid arthritis less than 2 years. Patients received tocilizumab 8 mg per kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of tocilizumab patients who achieved an ACR 20 response at Week 24. Study II (NCT00106535) was a 104-week study with an optional 156-week extension phase that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with tocilizumab 8 mg per kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a greater than 70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted.

The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score. Study III (NCT00106548) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Study IV (NCT00106574) evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs.

Patients received tocilizumab 8 mg per kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Study V (NCT00106522) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization.

Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Clinical Response The percentages of intravenous tocilizumab-treated patients achieving ACR 20, 50 and 70 responses are shown in Table 4. In all intravenous studies, patients treated with 8 mg per kg tocilizumab had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo-treated patients at week 24. During the 24 week controlled portions of Studies I to V, patients treated with tocilizumab at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with tocilizumab 8 mg per kg. Table 4 Clinical Response at Weeks 24 and 52 in Active and Placebo Controlled Trials of Intravenous Tocilizumab (Percent of Patients) Percent of Patients Response Rate Study I Study II Study III Study IV Study V MTX Tocilizumab 8 mg per kg Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + DMARDs Tocilizumab 8 mg per kg + DMARDs Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX N=284 N=286 (95% CI ) N=393 N=399 (95% CI CI: 95% confidence interval of the weighted difference to placebo adjusted for site (and disease duration for Study I only) ) N=398 (95% CI ) N=204 N=213 (95% CI ) N=205 (95% CI ) N=413 N=803 (95% CI ) N=158 N=161 (95% CI ) N=170 (95% CI ) ACR 20 Week 24 53% 70% 27% 51% 56% 27% 48% 59% 24% 61% 10% 30% 50% Week 52 N/A N/A 25% 47% 56% N/A N/A N/A N/A N/A N/A N/A N/A ACR 50 Week 24 34% 44% 10% 25% 32% 11% 32% 44% 9% 38% 4% 17% 29% Week 52 N/A N/A 10% 29% 36% N/A N/A N/A N/A N/A N/A N/A N/A ACR 70 Week 24 15% 28% 2% 11% 13% 2% 12% 22% 3% 21% 1% 5% (-0.06, 0.14) 12% Week 52 N/A N/A 4% 16% 20% N/A N/A N/A N/A N/A N/A N/A N/A Major Clinical Responses Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week periodHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activitiesThe same patients may not have responded at each timepoint.sThe same patients may not have responded at each timepoint.Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week periodHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activitiesThe same patients may not have responded at each timepoint. Week 52 N/A N/A 1% 4% 7% N/A N/A N/A N/A N/A N/A N/A N/A In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg tocilizumab + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo +MTX treated patients at week 52. The proportion of tocilizumab-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in Table 5. Table 5 Proportion of Patients with DAS28-ESR Less Than 2.6 with Number of Residual Active Joints in Trials of Intravenous Tocilizumab Study II Placebo + MTX N = 393 Tocilizumab 4 mg per kg + MTX N = 399 Tocilizumab 8 mg per kg + MTX N = 398 *n denotes numerator of all the percentage.

Denominator is the intent-to-treat population. Not all patients received DAS28 assessments at Week 52. DAS28-ESR less than

Proportion of responders at week 52 (n) 95% confidence interval 3% 18%

0.10, 0.19 32% 0.24, 0.34 Of responders, proportion with 0 active joints (n) 33% 27% 21% Of responders, proportion with 1 active joint (n) 8% 19% 13% Of responders, proportion with 2 active joints (n) 25% 13% 20% Of responders, proportion with 3 or more active joints (n) 33% 41% 47% The results of the components of the ACR response criteria for Studies III and V are shown in Table 6. Similar results to Study III were observed in Studies I, II and IV. Table 6 Components of ACR Response at Week 24 in Trials of Intravenous Tocilizumab Study III Study V Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + MTX N=213 N=205 N=204 N=161 N=170 N=158 Component (mean) Baseline Week 24 Data shown is mean at week 24, difference in adjusted mean change from baseline compared with placebo + MTX at week 24 and 95% confidence interval for that difference Baseline Week 24 Baseline Week 24 Baseline Week 24 Baseline Week 24 Baseline Week 24 Number of tender joints (0-68) 33 19 -7.0 (-10.0, -4.1) 32 14.5 -9.6 (-12.6, -6.7) 33 25 31 21 -10.8 (-14.6, -7.1) 32 17 -15.1 (-18.8, -11.4) 30 30 Number of swollen joints (0-66) 20 10 -4.2 (-6.1, -2.3) 19.5 8 -6.2 (-8.1, -4.2) 21 15 19.5 13 -6.2 (-9.0, -3.5) 19 11 -7.2 (-9.9, -4.5) 19 18 Pain Visual analog scale: 0 = best, 100 = worst 61 33 -11.0 (-17.0, -5.0) 60 30 -15.8 (-21.7, -9.9) 57 43 63.5 43 -12.4 (-22.1, -2.1) 65 33 -23.9 (-33.7, -14.1) 64 48 Patient global assessment 66 34 -10.9 (-17.1, -4.8) 65 31 -14.9 (-20.9, -8.9) 64 45 70 46 -10.0 (-20.3, 0.3) 70 36 -17.4 (-27.8, -7.0) 71 51 Physician global assessment 64 26 -5.6 (-10.5, -0.8) 64 23 -9.0 (-13.8, -4.2) 64 32 66.5 39 -10.5 (-18.6, -2.5) 66 28 -18.2 (-26.3, -10.0) 67.5 43 Disability index (HAQ) Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week periodHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activitiesThe same patients may not have responded at each timepoint.sThe same patients may not have responded at each timepoint.Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week periodHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activitiesThe same patients may not have responded at each timepoint. 1.64 1.01 -0.18 (-0.34, -0.02) 1.55 0.96 -0.21 (-0.37, -0.05) 1.55 1.21 1.67 1.39 -0.25 (-0.42, -0.09) 1.75 1.34 -0.34 (-0.51, -0.17) 1.70 1.58 CRP (mg per dL) 2.79 1.17 -1.30 (-2.0, -0.59) 2.61 0.25 -2.156 (-2.86, -1.46) 2.36 1.89 3.11 1.77 -1.34 (-2.5, -0.15) 2.80 0.28 -2.52 (-3.72, -1.32) 3.705 3.06 The percent of ACR 20 responders by visit for Study III is shown in Figure 1. Similar response curves were observed in studies I, II, IV, and V. Figure 1 Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX) Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week periodHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activitiesThe same patients may not have responded at each timepoint.sThe same patients may not have responded at each timepoint.Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week periodHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activitiesThe same patients may not have responded at each timepoint. Figure 1 Radiographic Response In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number.

The results from baseline to week 52 are shown in Table 7. Tocilizumab 4 mg per kg slowed (less than 75% inhibition compared to the control group) and tocilizumab 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52. Table 7 Mean Radiographic Change from Baseline to Week 52 in Study II Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX N=294 N=343 N=353 SD = standard deviation Week 52 Week 52 analysis employs linearly extrapolated data for patients after escape, withdrawal, or loss to follow up. Total Sharp-Genant Score, Mean (SD) 1.17 0.33 0.25 Adjusted Mean difference Difference between the adjusted means (tocilizumab + MTX - Placebo + MTX) (95%CI) -0.83 (-1.13, -0.52) -0.90 (-1.20, -0.59) Erosion Score, Mean (SD) 0.76 0.20 0.15 Adjusted Mean difference (95%CI) -0.55 (-0.76, -0.34) -0.60 (-0.80, -0.39) Joint Space Narrowing Score, Mean (SD) 0.41 0.13 0.10 Adjusted Mean difference (95%CI) -0.28 (-0.44, -0.11) -0.30 (-0.46, -0.14) The mean change from baseline to week 104 in Total Sharp-Genant Score for the tocilizumab 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group.

In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the tocilizumab 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to tocilizumab 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients. Health Related Outcomes In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of tocilizumab demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, and placebo treatment groups, respectively.

Sixty-three percent (63%) and sixty percent (60%) of patients in the tocilizumab 8 mg per kg and tocilizumab 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group. Other Health-Related Outcomes General health status was assessed by the Short Form Health Survey (SF-36) in Studies I – V. Patients receiving tocilizumab demonstrated greater improvement from baseline compared to placebo in the Physical Component Summary (PCS), Mental Component Summary (MCS), and in all 8 domains of the SF-36. Cardiovascular Outcomes Study WA25204 (NCT01331837) was a randomized, open-label (sponsor-blinded), 2-arm parallel-group, multicenter, non-inferiority, cardiovascular (CV) outcomes trial in patients with a diagnosis of moderate to severe RA. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with tocilizumab compared with a TNF inhibitor standard of care (etanercept). The study included 3,080 seropositive RA patients with active disease and an inadequate response to non- biologic disease-modifying anti-rheumatic drugs, who were aged ≥50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV tocilizumab 8 mg/kg Q4W or SC etanercept 50 mg QW and followed for an average of 3.2 years. The primary endpoint was the comparison of the time-to-first occurrence of any component of a composite of major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke, or CV death), with the final intent-to-treat analysis based on a total of 161 confirmed CV events (83/1538 for tocilizumab; 78/1542 for etanercept) reviewed by an independent and blinded adjudication committee.

Non-inferiority of tocilizumab to etanercept for cardiovascular risk was determined by excluding >80% relative increase in the risk of MACE. The estimated hazard ratio (HR) for the risk of MACE comparing tocilizumab to etanercept was 1.05; 95% CI.

Rheumatoid Arthritis – Subcutaneous

Administration The efficacy and safety of subcutaneously administered tocilizumab was assessed in two double-blind, controlled, multicenter studies in patients with active RA. One study, SC-I ( NCT01194414 ), was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously to 8 mg per kg intravenously every four weeks. The second study, SC-II ( NCT01232569 ), was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneously to placebo. Both SC-I and SC-II required patients to be >18 years of age with moderate to severe active rheumatoid arthritis diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline (SC-I) or at least 8 tender and 6 swollen joints at baseline (SC-II), and an inadequate response to their existing DMARD therapy, where approximately 20% also had a history of inadequate response to at least one TNF inhibitor.

All patients in both SC studies received background non-biologic DMARD(s). In SC-I, 1262 patients were randomized 1:1 to receive tocilizumab-SC 162 mg every week or intravenous tocilizumab 8 mg/kg every four weeks in combination with DMARD(s). In SC-II, 656 patients were randomized 2:1 to tocilizumab-SC 162 mg every other week or placebo, in combination with DMARD(s). The primary endpoint in both studies was the proportion of patients who achieved an ACR20 response at Week 24. The clinical response to 24 weeks of tocilizumab-SC therapy is shown in Table 8. In SC-I, the primary outcome measure was ACR20 at Week 24. The pre-specified non-inferiority margin was a treatment difference of 12%. The study demonstrated non-inferiority of tocilizumab with respect to ACR20 at Week 24; ACR50, ACR70, and DAS28 responses are also shown in Table 8. In SC-II, a greater portion of patients treated with tocilizumab 162 mg subcutaneously every other week achieved ACR20, ACR50, and ACR70 responses compared to placebo-treated patients (Table 8). Further, a greater proportion of patients treated with tocilizumab 162 mg subcutaneously every other week achieved a low level of disease activity as measured by a DAS28-ESR less than 2.6 at Week 24 compared to those treated with placebo (Table 8). Table 8 Clinical Response at Week 24 in Trials of Subcutaneous Tocilizumab (Percent of Patients) SC-I Per Protocol Population SC-II Intent To Treat Population TCZ SC 162 mg every week + DMARD TCZ IV 8mg/kg + DMARD TCZ SC 162 mg every other week + DMARD Placebo + DMARD N=558 N=537 N=437 N=219 TCZ = tocilizumab ACR20 Week 24 69% 73.4% 61% 32% Weighted difference (95% CI) -4% (-9.2, 1.2) 30% ACR50 Week 24 47% 49% 40% 12% Weighted difference (95% CI) -2% (-7.5, 4.0) 28% ACR70 Week 24 24% 28% 20% 5% Weighted difference (95% CI) -4% (-9.0, 1.3) 15% Change in DAS28 Week 24 -3.5 -3.5 -3.1 -

Adjusted mean difference (95% CI) 0 (-0.2, 0.1) -1.4 (-1.7, -1.1)

DAS28 <

Week 24 38.4% 36.9% 32.0% 4.0% Weighted difference (95% CI) 0.9 (-5.0

6.8)

The results of the components of the

ACR response criteria and the percent of ACR20 responders by visit for tocilizumab-SC in Studies SC-I and SC-II were consistent with those observed for tocilizumab-IV. Radiographic Response In study SC-II, the progression of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified total Sharp score (mTSS). At week 24, significantly less radiographic progression was observed in patients receiving tocilizumab-SC every other week plus DMARD(s) compared to placebo plus DMARD(s); mean change from baseline in mTSS of 0.62 vs. 1.23, respectively, with an adjusted mean difference of -0.60 (-1.1, -0.1). These results are consistent with those observed in patients treated with intravenous tocilizumab. Health Related Outcomes In studies SC-I and SC-II, the mean decrease from baseline to week 24 in HAQ-DI was 0.6, 0.6, 0.4 and 0.3, and the proportion of patients who achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) was 65%, 67%, 58% and 47%, for the subcutaneous every week, intravenous 8 mg/kg, subcutaneous every other week, and placebo treatment groups, respectively. Other Health-Related Outcomes General health status was assessed by the SF-36 in Studies SC-I and SC-II. In Study SC-II, patients receiving tocilizumab every other week demonstrated greater improvement from baseline compared to placebo in the PCS, MCS, and in all 8 domains of the SF-36. In Study SC-I, improvements in these scores were similar between tocilizumab-SC every week and tocilizumab-IV 8 mg/kg.

Giant Cell Arteritis – Subcutaneous

Administration The efficacy and safety of subcutaneously administered tocilizumab was assessed in a single, randomized, double-blind, multicenter study in patients with active GCA. In Study WA28119 (NCT01791153), 251 screened patients with new-onset or relapsing GCA were randomized to one of four treatment arms. Two subcutaneous doses of tocilizumab (162 mg every week and 162 mg every other week) were compared to two different placebo control groups (pre-specified prednisone-taper regimen over 26 weeks and 52 weeks) randomized 2:1:1:1. The study consisted of a 52-week blinded period, followed by a 104-week open-label extension. All patients received background glucocorticoid (prednisone) therapy.

Each of the tocilizumab-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 52 weeks designed to be more in keeping with standard practice. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined by a patient attaining a sustained absence of GCA signs and symptoms from Week 12 through Week 52, normalization of erythrocyte sedimentation rate (ESR) (to < 30 mm/hr without an elevation to ≥ 30 mm/hr attributable to GCA) from Week 12 through Week 52, normalization of C-reactive protein (CRP) (to < 1 mg/dL, with an absence of successive elevations to ≥ 1mg/dL) from Week 12 through Week 52, and successful adherence to the prednisone taper defined by not more than 100 mg of excess prednisone from Week 12 through Week 52. Tocilizumab 162 mg weekly and 162 mg every other week + 26 weeks prednisone taper both showed superiority in achieving sustained remission from Week 12 through Week 52 compared with placebo + 26 weeks prednisone taper (Table 9). Both tocilizumab treatment arms also showed superiority compared to the placebo + 52 weeks prednisone taper (Table 9). Table 9 Efficacy Results from Study WA28119 PBO + 26 weeks prednisone taper N=50 PBO + 52 weeks prednisone taper N=51 TCZ 162mg SC QW + 26 weeks prednisone taper N=100 TCZ 162 mg SC Q2W + 26 weeks prednisone taper N=49 Patients not completing the study to week 52 were classified as non-responders in the primary and key secondary analysis: PBO+26: 6 (12.0%), PBO+52: 5 (9.8%), TCZ QW: 15 (15.0%), TCZ Q2W: 9 (18.4%). CRP = C-reactive protein ESR = erythrocyte sedimentation rate PBO = placebo Q2W = every other week dose QW = every week dose TCZ = tocilizumab Sustained remission Sustained remission was achieved by a patient meeting all of the following components: absence of GCA signs and symptoms b, normalization of ESR c, normalization of CRP d and adherence to the prednisone taper regimen e Responders, n (%) 7 (14.0%) 9 (17.6%) 56 (56.0%) 26 (53.1%) Unadjusted difference in proportions vs PBO + 26 weeks taper (99.5% CI) N/A N/A 42.0% 39.1% Unadjusted difference in proportions vs PBO + 52 weeks taper (99.5% CI) N/A N/A 38.4% 35.4% Components of Sustained Remission Sustained absence of GCA signs and symptoms Patients who did not have any signs or symptoms of GCA recorded from Week 12 up to Week 52., n (%) 20 (40.0%) 23 (45.1%) 69 (69.0%) 28 (57.1%) Sustained ESR<30 mm/hr Patients who did not have an elevated ESR ≥30 mm/hr which was classified as attributed to GCA from Week 12 up to Week 52., n (%) 20 (40.0%) 22 (43.1%) 83 (83.0%) 37 (75.5%) Sustained CRP normalization Patients who did not have two or more consecutive CRP records of ≥ 1mg/dL from Week 12 up to Week 52., n (%) 17 (34.0%) 13 (25.5%) 72 (72.0%) 34 (69.4%) Successful prednisone tapering Patients who did not enter escape therapy and received ≤ 100mg of additional concomitant prednisone from Week 12 up to Week 52., n (%) 10 (20.0%) 20 (39.2%) 60 (60.0%) 28 (57.1%) The estimated annual cumulative prednisone dose was lower in the two tocilizumab dose groups (medians of 1887 mg and 2207 mg on tocilizumab QW and Q2W, respectively) relative to the placebo arms (medians of 3804 mg and 3902 mg on placebo + 26 weeks prednisone and placebo + 52 weeks prednisone taper, respectively).

Giant Cell Arteritis – Intravenous

Administration Intravenously administered tocilizumab in patients with GCA was assessed in WP41152 (NCT03923738), an open-label PK-PD and safety study to determine the appropriate intravenous dose of tocilizumab that achieved comparable PK-PD profiles to the tocilizumab-SC regimen. At enrollment, all patients (n=24) were in remission on tocilizumab-IV. In Period 1, all patients received open- label tocilizumab-IV 7 mg/kg every 4 weeks for 20 weeks. Patients who completed Period 1 and remained in remission (n=22) were eligible to enter Period 2, and received open-label tocilizumab-IV 6 mg/kg every 4 weeks for 20 weeks.

The efficacy of intravenous tocilizumab 6 mg/kg in adult patients with GCA is based on pharmacokinetic exposure and extrapolation to the efficacy established for subcutaneous tocilizumab in patients with GCA .

Polyarticular Juvenile Idiopathic Arthritis – Intravenous

Administration The efficacy of tocilizumab was assessed in a three-part study, WA19977 (NCT00988221), including an open- label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e.g., TNF antagonists or T cell costimulation modulator) were not permitted in the study.

Part I consisted of a 16-week active tocilizumab treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received tocilizumab at 8 mg/kg intravenously once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either tocilizumab 8 mg/kg or 10 mg/kg intravenously every four weeks.

At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy. In Part II, patients (ITT, n=163) were randomized to tocilizumab (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use.

Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape. The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16. Tocilizumab treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% versus 48% ; adjusted difference in proportions -21%, 95% CI: -35%, -8%). During the withdrawal phase (Part II), more patients treated with tocilizumab showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo.

Polyarticular Juvenile Idiopathic Arthritis – Subcutaneous

Administration Subcutaneously administered tocilizumab in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) was assessed in WA28117 (NCT01904279), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of tocilizumab that achieved comparable PK/PD profiles to the tocilizumab-IV regimen. PJIA patients aged 1 to 17 years with an inadequate response or inability to tolerate MTX, including patients with well-controlled disease on treatment with tocilizumab-IV and tocilizumab-naïve patients with active disease, were treated with subcutaneous tocilizumab based on body weight. Patients weighing at or above 30 kg (n = 25) were treated with 162 mg of tocilizumab-SC every 2 weeks and patients weighing less than 30 kg (n = 27) received 162 mg of tocilizumab-SC every 3 weeks for 52 weeks.

Of these 52 patients, 37 (71%) were naive to tocilizumab and 15 (29%) had been receiving tocilizumab-IV and switched to tocilizumab-SC at baseline. The efficacy of subcutaneous tocilizumab in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous tocilizumab in polyarticular JIA patients and subcutaneous tocilizumab in patients with RA .

Systemic Juvenile Idiopathic Arthritis – Intravenous

Administration The efficacy of tocilizumab for the treatment of active SJIA was assessed in WA18221 (NCT00642460), a 12- week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (tocilizumab:placebo = 2:1) to one of two treatment groups: 75 patients received tocilizumab infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response.

After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab in the open-label extension phase at weight appropriate dosing. The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ). Primary endpoint result and JIA ACR response rates at Week 12 are shown in Table 10. Table 10 Efficacy Findings at Week 12 Tocilizumab N=75 Placebo N=37 Primary Endpoint: JIA ACR 30 response + absence of fever Responders 85% 24% Weighted difference (95% CI) 62 - JIA ACR Response Rates at Week 12 JIA ACR 30 Responders 91% 24% Weighted difference The weighted difference is the difference between the tocilizumab and Placebo response rates, adjusted for the stratification factors (weight, disease duration, background oral corticosteroid dose and background methotrexate use). 67 - (95% CI) CI: confidence interval of the weighted difference.

JIA ACR 50 Responders 85% 11% Weighted difference 74 - (95% CI) JIA ACR 70 Responders 71% 8% Weighted difference 63 - (95% CI) The treatment effect of tocilizumab was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks). Systemic Features Of patients with fever or rash at baseline, those treated with tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks). Corticosteroid Tapering Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), tocilizumab patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction.

Seventeen (24%) tocilizumab patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) tocilizumab patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more. Health Related Outcomes Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the tocilizumab treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group.

Systemic Juvenile Idiopathic Arthritis – Subcutaneous

Administration Subcutaneously administered tocilizumab in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) was assessed in WA28118 (NCT01904292), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of tocilizumab that achieved comparable PK/PD profiles to the tocilizumab-IV regimen. Eligible patients received tocilizumab subcutaneously dosed according to body weight, with patients weighing at or above 30 kg (n = 26) dosed with 162 mg of tocilizumab every week and patients weighing below 30 kg (n = 25) dosed with 162 mg of tocilizumab every 10 days (n=8) or every 2 weeks (n=17) for 52 weeks. Of these 51 patients, 26 (51%) were naive to subcutaneous tocilizumab and 25 (49%) had been receiving tocilizumab intravenously and switched to subcutaneous tocilizumab at baseline.

The efficacy of subcutaneous tocilizumab in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous tocilizumab in systemic JIA patients .

Cytokine Release Syndrome - Intravenous

Administration The efficacy of tocilizumab for the treatment of CRS was assessed in a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies for hematological malignancies. Evaluable patients had been treated with tocilizumab 8 mg/kg (12 mg/kg for patients < 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CRS; only the first episode of CRS was included in the analysis. The study population included 24 males and 21 females (total 45 patients) of median age 12 years (range, 3–23 years); 82% were Caucasian.

The median time from start of CRS to first dose of tocilizumab was 4 days (range, 0-18 days). Resolution of CRS was defined as lack of fever and off vasopressors for at least 24 hours. Patients were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, if no more than 2 doses of tocilizumab were needed, and if no drugs other than tocilizumab and corticosteroids were used for treatment. Thirty-one patients (69%; 95% CI: 53%–82%) achieved a response.

Achievement of resolution of CRS within 14 days was confirmed in a second study using an independent cohort that included 15 patients (range: 9–75 years old) with CAR T cell-induced CRS. 14.10 COVID-19 – Intravenous Administration The efficacy of tocilizumab for the treatment of COVID-19 was based on RECOVERY ( NCT04381936 ), a randomized, controlled, open-label, platform study, and supported by the results from EMPACTA ( NCT04372186 ), a randomized, double-blind, placebo-controlled study. Results of two other randomized, double-blind, placebo-controlled studies, COVACTA ( NCT04320615 ) and REMDACTA ( NCT04409262 ) which evaluated the efficacy of tocilizumab for the treatment of COVID-19 are also summarized. RECOVERY (Randomised Evaluation of COVID-19 Therapy) Collaborative Group Study in Hospitalized Adults Diagnosed with COVID-19 RECOVERY was a randomized, controlled, open-label, multicenter platform study conducted in the United Kingdom to evaluate the efficacy and safety of potential treatments in hospitalized adult patients with severe COVID-19 pneumonia.

Eligible patients for the tocilizumab portion of the study had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical contraindications to any of the treatments and had clinical evidence of progressive COVID-19 (defined as oxygen saturation <92% on room air or receiving oxygen therapy, and CRP ≥75 mg/L). Patients were then randomized to receive either standard of care (SoC) or intravenous tocilizumab at a weight-tiered dosing comparable to the recommended dosage in addition to SoC. Efficacy analyses were performed in the intent-to-treat (ITT) population comprising 4116 adult patients who were randomized to the tocilizumab + SoC arm (n=2022) or to the SoC arm (n=2094). The mean age of participants was 64 years (range: 20 to 101), and patients were 67% male, 76% White, 11% Asian, 3% Black or African American, and 1% mixed race. At baseline, 0.2% of patients were not on supplemental oxygen, 45% of patients required low flow oxygen, 41% of patients required non-invasive ventilation or high-flow oxygen, and 14% of patients required invasive mechanical ventilation; 82% of patients were reported to be receiving systemic corticosteroids. The primary efficacy endpoint was time to death through Day 28. The results for the overall population and the subgroups of patients who were or were not receiving systemic corticosteroids at time of randomization are summarized in Table 11. Table 11 Mortality through Day 28 in RECOVERY Tocilizumab+ SoC N=2022 n (%) P-value reflects that the RECOVERY trial primary analysis results were statistically significant at the two-sided significance level of α = 0.05. SoC N=2094 n (%) Hazard Ratio (95% CI) Risk Difference (95% CI) Mortality 621 (30.7%) 729 (34.9%) 0.85 p= 0.0028 -4.1% (-7.0, -1.3) By baseline receipt of corticosteroid use Mortality for patients receiving systemic corticosteroids at randomization Probabilities of dying by Day 28 were estimated by the Kaplan-Meier method. 482/1664 (29.0%) 600/1721 (34.9%) 0.79 -5.9% (-9.1, -2.8) Mortality for patients not receiving systemic corticosteroids at randomization 139/357 (39.0%) 127/367 (34.6%) 1.16 4.4% (-2.6, 11.5) EMPACTA EMPACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with SoC in hospitalized, non-ventilated adult patients with COVID-19 pneumonia.

Eligible patients were at least 18 years of age, had confirmed SARS-CoV-2 infection by a positive reverse-transcriptase polymerase chain reaction (RT-PCR) result, had pneumonia confirmed by radiography, and had SpO2 < 94% on ambient air. Of the 389 patients randomized, efficacy analyses were performed in the modified intent-to-treat (mITT) population comprising 377 patients who were randomized and received study medication (249 in the tocilizumab arm; 128 in the placebo arm). The mean age of participants was 56 years (range: 20 to 95); 59% of patients were male, 56% were of Hispanic or Latino ethnicity, 53% were White, 20% were American Indian/Alaska Native, 15% were Black/African American and 2% were Asian. At baseline, 9% patients were not on supplemental oxygen, 64% patients required low flow oxygen, 27% patients required high-flow oxygen, and 73% were on corticosteroids.

The primary efficacy endpoint evaluated time to progression to mechanical ventilation or death through Day 28. The hazard ratio comparing tocilizumab to placebo was 0.56 (95% CI, 0.33 to 0.97), a statistically significant result (log-rank, p-value = 0.036). The cumulative proportion of patients who required mechanical ventilation or died by Day 28 was 12.0% (95% CI, 8.5% to 16.9%) in the tocilizumab arm and 19.3% (95% CI, 13.3% to 27.4%) in the placebo arm. Mortality at Day 28 was 10.4% in the tocilizumab arm versus 8.6% in the placebo arm (weighted difference (tocilizumab arm - placebo arm): 2.0% ). COVACTA COVACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with SoC for the treatment of adult patients hospitalized with severe COVID- 19 pneumonia. The study randomized 452 patients who were at least 18 years of age with confirmed SARS-CoV- 2 infection by a positive RT-PCR result, had pneumonia confirmed by radiography, and had oxygen saturation of 93% or lower on ambient air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mmHg or less.

At baseline, 3% of patients were not on supplemental oxygen, 28% were on low flow oxygen, 30% were on non-invasive ventilation or high flow oxygen, 38% were on invasive mechanical ventilation, and 22% were on corticosteroids. The primary efficacy endpoint was clinical status on Day 28 assessed on a 7-category ordinal scale that ranged from "discharged" to "death." There were no statistically significant differences observed in the distributions of clinical status on the 7-category ordinal scale at Day 28 when comparing the tocilizumab arm to the placebo arm. Mortality at Day 28 was 19.7% in the tocilizumab arm versus 19.4% in the placebo arm (weighted difference (tocilizumab arm - placebo arm): 0.3% ). REMDACTA REMDACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with intravenous remdesivir (RDV) 200 mg on Day 1 followed by 100 mg once daily for a total of 10 days in hospitalized patients with severe COVID-19 pneumonia.

The study randomized 649 adult patients with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction (PCR) result, pneumonia confirmed by radiography, and who required supplemental oxygen > 6 L/min to maintain SpO2 >93%. At baseline, 7% of patients were on low flow oxygen, 80% were on non-invasive ventilation or high flow oxygen, 14% were on invasive mechanical ventilation, and 84% were on corticosteroids. The primary efficacy endpoint was time from randomization to hospital discharge or 'ready for discharge' up to Day 28. There was no statistically significant difference between the treatment arms with respect to time to hospital discharge or "ready for discharge" through Day 28. Mortality at Day 28 was 18.1% in the tocilizumab + RDV arm versus 19.5% in the placebo +RDV arm (weighted difference (tocilizumab arm - placebo arm): -1.3% ). Mortality Across Studies in Patients Receiving Baseline Corticosteroids A study-level meta-analysis was conducted on EMPACTA, COVACTA, REMDACTA and RECOVERY studies. For each of the four studies, the risk difference through Day 28 was estimated by the Kaplan-Meier method in the subgroup of patients receiving baseline corticosteroids, summarized in Figure 2. Patients from the RECOVERY trial represent 78.8% of the total sample size in this meta-analysis.

The combined risk difference showed that tocilizumab treatment (n=2261) resulted in a 4.61% absolute reduction in the risk of death at Day 28 (risk difference=-4.6%; 95% CI: -7.3% to -1.9%) compared to SoC (n=2034). Figure 2 Risk Differences Through Day 28 for Baseline Corticosteroid Use Subpopulation in RECOVERY, EMPACTA, COVACTA and REMDACTA studies Figure 2