Satralizumab

1 INDICATIONS AND USAGE ENSPRYNG is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. ENSPRYNG is an interleukin-6 (IL-6) receptor antagonist indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. ( 1 )

2 DOSAGE AND ADMINISTRATION Hepatitis B virus, tuberculosis, and liver transaminase screening is required before the first dose. ( 2.1 ) Prior to every use, determine if there is an active infection. ( 2.2 ) The recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks. ( 2.2 ) See Full Prescribing Information for important preparation and administration instructions. ( 2.3 ) 2.1 Assessments Prior to the First Dose of ENSPRYNG Hepatitis B Virus Screening Prior to initiating ENSPRYNG, perform Hepatitis B virus (HBV) screening. ENSPRYNG is contraindicated in patients with active HBV confirmed by positive results for surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with ENSPRYNG [see Contraindications (4) and Warnings and Precautions (5.1) ] . Tuberculosis Screening Prior to initiating ENSPRYNG, evaluate for active tuberculosis and test for latent infection. For patients with active tuberculosis or positive tuberculosis screening without a history of appropriate treatment, consult infectious disease experts before initiating treatment with ENSPRYNG [see Contraindications (4) and Warnings and Precautions (5.1) ] . Liver Transaminase Screening Liver transaminases and serum bilirubin should be assessed prior to initiation of treatment with ENSPRYNG [see Warnings and Precautions (5.2) ] . Caution should be exercised when considering initiation of ENSPRYNG treatment in patients whose aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels are greater than 1.5 times the upper limit of normal (ULN). Vaccinations Because vaccination with live-attenuated or live vaccines is not recommended during treatment with ENSPRYNG, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ENSPRYNG for non-live vaccines [see Warnings and Precautions (5.1) ]. 2.2 Recommended Dosage For subcutaneous use only. Prior to every use of ENSPRYNG, advise patients to consult with their healthcare professional (HCP) if they suspect an active infection, including localized infections. In case of active infection, delay use of ENSPRYNG until the infection is resolved [see Warnings and Precautions (5.1) ] . The recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks. Missed Dose If a dose of ENSPRYNG is missed for any reason other than increases in liver enzymes [see Dosage and Administration (2.4) ] , administer as described in Table 1 . Table 1 Recommended Dosage for Delayed or Missed Doses Last Dose Administered Recommended Dosage for Delayed or Missed Doses Less than 8 weeks during the maintenance period or missed a loading dose Administer 120 mg by subcutaneous injection as soon as possible, and do not wait until the next planned dose. Maintenance period After the delayed or missed dose is administered, reset the dose schedule to every 4 weeks. Loading period If the second loading dose is delayed or missed, administer as soon as possible and administer the 3 rd and final loading dose 2 weeks later. If the third loading dose is delayed or missed, administer as soon as possible and administer the 1 st maintenance dose 4 weeks later. 8 weeks to less than 12 weeks 120 mg by subcutaneous injection at 0 "0 weeks" refers to time of the first administration after the missed dose. and 2 weeks, followed by 120 mg every 4 weeks. 12 weeks or longer 120 mg by subcutaneous injection at 0 , 2, and 4 weeks followed by 120 mg every 4 weeks. 2.3 Important Administration Instructions ENSPRYNG is intended for patient self-administration by subcutaneous injection under the guidance of a health care professional (HCP). After proper training in subcutaneous injection technique, a patient may self-inject ENSPRYNG or the patient's caregiver may administer ENSPRYNG, if the HCP determines that it is appropriate. See ENSPRYNG " Instructions for Use " (IFU) for more detailed instructions on the preparation and administration of ENSPRYNG. Patients or caregivers should seek immediate medical attention if the patient develops symptoms of a serious allergic reaction and should not administer further doses until evaluated by a HCP [see Contraindications (4) and Warning and Precautions (5.4) ] . Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes. Do not warm ENSPRYNG in any other way. Inspect visually for particulate matter and discoloration prior to administration. ENSPRYNG solution should be clear and colorless to slightly yellow. Do not use ENSPRYNG if the solution is cloudy, discolored, or contains particles, or if any part of the prefilled syringe appears to be damaged. Instruct patients to inject the full amount in the syringe (1 mL), which provides 120 mg of ENSPRYNG, according to the directions provided in the IFU. Administer ENSPRYNG by subcutaneous injection in the abdomen or thigh. Rotate injection sites with each administration. Do not give injection into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. 2.4 Safety Monitoring During Treatment Liver Transaminases Monitor ALT and AST levels every 4 weeks for the first 3 months of treatment with ENSPRYNG, followed by every 3 months for one year, and thereafter as clinically necessary [see Warnings and Precautions (5.2) ]. If an ALT or AST elevation of greater than 5 times the ULN occurs, discontinue ENSPRYNG as follows: If associated with any bilirubin elevation, discontinue ENSPRYNG, and reinitiation is not recommended . If not associated with any bilirubin elevation above the ULN, when the ALT or AST level has returned to the normal range and following a benefit-risk assessment of the patient, treatment with ENSPRYNG can be restarted per the schedule in Table 2 . Table 2 Recommended Dosage for Restart of Treatment After Liver Transaminase Elevation Last Dose Administered Recommended Dosage for Restart of Treatment Less than 12 weeks Restart at a dosage of 120 mg by subcutaneous injection every 4 weeks. 12 weeks or longer Restart at a dose of 120 mg by subcutaneous injection at Weeks 0 "0 weeks" refers to time of the first administration after the missed dose. , 2, and 4, followed by a dosage of 120 mg every 4 weeks. If treatment is restarted, the liver parameters must be closely monitored, and if any subsequent increase in ALT/AST and/or bilirubin above the ULN is observed, ENSPRYNG should be discontinued, and another reinitiation is not recommended. Neutrophil Counts Monitor neutrophils 4 to 8 weeks after initiation of therapy and thereafter at regular clinically determined intervals. If the neutrophil count is below 1.0 × 10 9 /L and confirmed by repeat testing, ENSPRYNG should be interrupted until the neutrophil count is > 1.0 × 10 9 /L [see Warnings and Precautions (5.3) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions (5.1) ] Elevated Liver Enzymes [see Warnings and Precautions (5.2) ] Decreased Neutrophil Counts [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] The most common adverse reactions (incidence at least 15%) are nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety of ENSPRYNG was evaluated in two randomized, placebo-controlled clinical trials [Study 1 evaluated ENSPRYNG without concurrent immunosuppressive therapy (IST) and Study 2 evaluated ENSPRYNG with concurrent IST], which included 41 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 1 and 26 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 2 [see Clinical Studies (14) ] . In the double-blind, controlled period, the median exposure time on ENSPRYNG treatment was approximately 2 years in Study 1 and approximately 3 years in Study 2. The median exposure time on placebo treatment was approximately 1 year in both Study 1 and Study 2. Adverse reactions that occurred in Study 1 and Study 2 in more than 5% of patients treated with ENSPRYNG, and at a greater incidence than in patients who received placebo, are shown in Table 3 and Table 4 , respectively. The most common adverse reactions (15% or greater with ENSPRYNG in either) were nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea. Table 3 Adverse Reactions Occurring in 4 or More Patients Treated with ENSPRYNG and Greater Incidence than Placebo in Study 1 Adverse Reaction ENSPRYNG (N = 41) % PLACEBO (N = 23) % Rash 17 0 Arthralgia 17 0 Pain in extremity 15 9 Fatigue 15 4 Nausea 15 9 Nasopharyngitis 12 4 Pruritus 10 0 Depression 10 0 Cellulitis 10 0 Neutropenia 10 4 Blood creatine phosphokinase increased 10 4 Fall 10 4 Table 4 Adverse Reactions Occurring in 3 or More Patients Treated with ENSPRYNG and Greater Incidence than Placebo in Study 2 Adverse Reaction ENSPRYNG + IST (N = 26) % PLACEBO + IST (N = 26) % Nasopharyngitis 31 15 Headache 27 12 Upper respiratory tract infection 19 12 Gastritis 15 0 Arthralgia 12 0 Pharyngitis 12 8 Injection-Related Reactions In Study 1 and Study 2, injection-related reactions were reported in 9% of patients treated with ENSPRYNG compared with 8% in patients receiving placebo. These reactions in the ENSPRYNG-treated patients were predominantly mild to moderate in severity, and most occurred within 24 hours after the injection. The most commonly reported systemic symptom was diarrhea. The reported local injection site reactions were pruritus, injection site reaction, and skin mass. Infections In Study 1, the rate of patients with infections was 51 patients/100 patient-years (95% CI: 32, 78) in patients treated with ENSPRYNG compared with 108 patients/100 patient-years (95% CI: 52, 199) in patients receiving placebo. The rate of patients with serious infections was 5 patients/100 patient-years (95% CI: 1, 14) in patients treated with ENSPRYNG compared with 4 patients/100 patient-years (95% CI: 0, 21) in patients receiving placebo. In Study 2, the rate of patients with infections was 168 patients/100 patient-years (95% CI: 100, 265) in patients treated with ENSPRYNG compared with 143 patients/100 patient-years (95% CI: 83, 229) in patients treated with placebo. The rate of patients with serious infections was 4 patients/100 patient-years (95% CI: 1, 15) in patients treated with ENSPRYNG compared with 10 patients/100 patient-years (95% CI: 2, 28) in patients receiving placebo. Laboratory Abnormalities Decreased Neutrophil Count Of the patients treated with ENSPRYNG, 10% had neutrophils below 1 × 10 9 /L compared to 9% in placebo in Study 1. In Study 2, 15% patients had neutrophils below 1 × 10 9 /L compared to 4% in placebo. There was one patient in Study 1 treated with ENSPRYNG with neutrophil counts < 0.5 × 10 9 /L, and one patient in Study 2 discontinued ENSPRYNG because of neutropenia. Decreased Platelet Count In Study 1, a shift in platelet count decreases from normal at baseline to below the lower limit of normal (LLN) occurred in 26% of patients treated with ENSPRYNG compared to 5% of patients receiving placebo. In Study 2, decreases in platelet counts from normal at baseline to below the LLN occurred in 35% of patients treated with ENSPRYNG and in 17% of patients receiving placebo. None of the patients had a decrease in platelet count to less than 50 × 10 9 /L. Elevated Liver Enzymes In Study 1, increases from normal at baseline to above ULN in ALT or AST occurred in 43% and 25% of patients treated with ENSPRYNG, respectively, compared to 13% and 9% of patients receiving placebo. In Study 2, increases from normal at baseline to above the ULN in ALT or AST occurred in 8% and 8% of patients treated with ENSPRYNG, respectively, compared to 12% and 19% of patients receiving placebo. In Study 1 and Study 2 combined, elevations of ALT or AST greater than 3 times the ULN occurred in 3% of patients treated with ENSPRYNG, compared to no patients treated with placebo. These elevations were not associated with increases in total bilirubin. One patient receiving ENSPRYNG in Study 2 had an elevation of ALT above 5 times the ULN, which was observed 4 weeks after initiation of therapy, normalizing 78 days after discontinuation of ENSPRYNG. Lipid Abnormalities In Study 1 and Study 2, elevations in total cholesterol above 7.75 mmol/L (300 mg/dl) occurred in 12% and 15% of patients treated with ENSPRYNG, respectively, compared to no patients receiving placebo. Elevations in triglycerides above 3.42 mmol/L (300 mg/dl) occurred in 27% and 12% of patients treated with ENSPRYNG in Study 1 and Study 2, respectively, compared to 13% and 8% of patients receiving placebo. Fibrinogen Levels In Study 1, the median percent reduction in fibrinogen was 38% in patients treated with ENSPRYNG compared to 5% in patients receiving placebo. In Study 2, the median percent reduction in fibrinogen level was 33% in patients treated with ENSPRYNG compared to 0% in patients receiving placebo. Complement Levels In Study 1, the median percent reduction in the C3 and C4 components of complement was 23% and 50% in patients treated with ENSPRYNG, respectively, compared to 0% and 1% patients receiving placebo. In Study 2, the median percent reduction in the C3 and C4 components of complement was 20% and 53% in patients treated with ENSPRYNG, respectively, compared to 0% and 1% in patients receiving placebo. Body Weight In the pool of Studies 1 and 2, body weight increases of at least 7% from baseline occurred in 28% of patients treated with ENSPRYNG compared to 8% of patients receiving placebo. Body weight increases of at least 15% from baseline occurred in 4% of patients treated with ENSPRYNG compared to 4% of patients receiving placebo. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of anti-satralizumab-mwge antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In Study 1 and Study 2, anti-drug-antibodies (ADAs) were observed in 73% and 38% of patients receiving ENSPRYNG in the double-blind period, respectively. The ability of these ADAs to neutralize satralizumab-mwge binding is unknown. Patients with higher body weight and lower exposure were more likely to develop ADAs (irrespective of treatment with IST). Exposure was lower in ADA positive patients. Although anti-satralizumab-mwge antibody development was not found to affect the efficacy of ENSPRYNG in these patients, the available data are too limited to make definitive conclusions. Immunogenicity does not have a clinically-relevant impact on safety. Based on the available information, neither dose interruption nor modification is warranted in those patients who develop ADAs.

12.3 Pharmacokinetics The pharmacokinetics of ENSPRYNG have been characterized both in Japanese and Caucasian healthy volunteers, and in NMOSD patients. The pharmacokinetics in NMOSD patients using the recommended dose were characterized using population pharmacokinetic analysis methods based on a database of 154 patients. The concentration-time course of ENSPRYNG in patients with NMOSD was accurately described by a two-compartment population pharmacokinetic model with parallel linear and target-mediated (Michaelis-Menten) elimination and first-order subcutaneous absorption. ENSPRYNG clearance and volume parameters allometrically scaled by body weight (through power function with the fixed power coefficient of 0.75 and 1 for clearance and volume parameters, respectively). Body weight was shown to be a significant covariate, with clearance and V c for patients weighing 123 kg (97.5th percentile of the weight distribution) increased by 71.3% and 105%, respectively, compared to a patient weighing 60 kg. Steady state pharmacokinetics were achieved after the loading period (8 weeks) as follows [mean (±SD)]: C min : 19.7 (12.2) mcg/mL, C max : 31.5 (14.9) mcg/mL, and AUC: 737 (386) mcg.mL/day. Absorption The bioavailability of satralizumab-mwge was 85%. Distribution Satralizumab-mwge undergoes biphasic distribution. The central volume of distribution was 3.46 L and the peripheral volume of distribution was 2.07 L. The inter-compartmental clearance was 0.336 L/day. Elimination The total clearance of satralizumab-mwge is concentration-dependent. Linear clearance (accounting for approximately half of the total clearance at steady state using the recommended dose in NMOSD patients) is estimated to be 0.0601 L/day. The associated terminal t 1/2 is approximately 30 days (range 22 – 37 days) based on data pooled from Study 1 and Study 2. Metabolism The metabolism of satralizumab-mwge has not been directly studied, as antibodies are cleared principally by catabolism. Excretion Monoclonal antibodies, including satralizumab-mwge, are not eliminated via renal or hepatic pathways. Specific Populations Population pharmacokinetic analyses in patients with NMOSD showed that age, gender, and race did not meaningfully influence the pharmacokinetics of satralizumab-mwge. Patients with Renal or Hepatic Impairment No formal studies of the effect of renal impairment or hepatic impairment on the pharmacokinetics of satralizumab-mwge were conducted. Drug Interaction Studies No formal drug-drug interaction studies have been performed with ENSPRYNG. Based on population pharmacokinetic analyses of the available data, the impact of commonly used small molecule drugs on the pharmacokinetics of satralizumab-mwge remains inconclusive. Suppression of IL-6 signaling by treatment with ENSPRYNG, from the low baseline levels seen in Study 1 and Study 2, is expected to have a minor impact on exposure of concomitant medications metabolized by CYP450 enzymes. The clinical significance of this is unknown.