EPYSQLI- eculizumab-aagh_injection, solution

Eculizumab-aagh, the active ingredient in EPYSQLI, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab products inhibit terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction. In the placebo-controlled clinical study (PNH Study 1), eculizumab when administered as recommended reduced serum LDH levels from 2200 +/- 1034 U/L (mean +/- SD) at baseline to 700 +/- 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 +/- 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [ see Clinical Studies ( 14 In patients with PNH, aHUS, and gMG, free C5 concentrations of < 0. 5 mcg/mL was correlated with complete blockade of terminal complement activity. Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean +/- SD serum eculizumab maximum concentration (C max trough trough Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1,200 mg dose range, with inter-individual variability of 21% to 38%. Distribution The eculizumab volume of distribution for a typical 70 kg patient was 5 L to 8 L. Elimination The half-life of eculizumab was approximately 270 h to 414 h. Plasma exchange or infusion increased the clearance of eculizumab by approximately 250-fold and reduced the half-life to 1. Supplemental dosing is recommended when EPYSQLI is administered to patients receiving plasma exchange or infusion [ see Dosage and Administration ( 2. 5 Specific Populations Age, Sex, and Race: The pharmacokinetics of eculizumab were not affected by age (2 months to 85 years), sex, or race. Renal Impairment: Renal function did not affect the pharmacokinetics of eculizumab in PNH (creatinine clearance of 8 mL/min to 396 mL/min calculated using Cockcroft-Gault formula), aHUS (estimated glomerular filtration rate [eGFR] of 5 mL/min/1. 73 m 2 2 2 2 The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of eculizumab or of other eculizumab products. The immunogenicity of eculizumab has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro-chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS and gMG indications, as well as for additional patients with PNH. In the PNH population, antibodies to eculizumab were detected in 3/196 (2%) patients using the ELISA assay and in 5/161 (3%) patients using the ECL assay during the entire treatment period. In the aHUS population, antibodies to eculizumab were detected in 3/100 (3%) patients using the ECL assay during the entire treatment period. None of the 62 patients with gMG had antibodies to eculizumab detected following the 26-week active treatment. An ECL based neutralizing assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 5 patients with PNH and the 3 patients with aHUS with anti-eculizumab antibody positive samples using the ECL assay. Two of 161 patients with PNH (1. 2%) and 1 of 100 patients with aHUS (1%) had low positive values for neutralizing antibodies. No apparent correlation of antibody development to clinical response was observed.

EPYSQLI is a complement inhibitor indicated for: the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. 1 the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. 2 Limitation of Use the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive. 3 EPYSQLI is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. EPYSQLI is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Limitation of Use EPYSQLI is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). EPYSQLI is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive.

For intravenous infusion only PNH Dosage Regimen: ( 2. 2 aHUS Dosage Regimen: ( 2. 3 gMG Dosage Regimen: ( 2. 4 Vaccinate patients against meningococcal infection (serogroups A, C, W, Y, and B) according to current ACIP recommendations at least 2 weeks prior to initiation of EPYSQLI [ see Warnings and Precautions ( 5. 1 If urgent EPYSQLI therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe EPYSQLI must enroll in the EPYSQLI REMS [see Warnings and Precautions ( 5. 2 For patients 18 years of age and older, EPYSQLI therapy consists of: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points [ see Warnings and Precautions ( 5. 4 For patients 18 years of age and older, EPYSQLI therapy consists of: 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. For patients less than 18 years of age, administer EPYSQLI based upon body weight, according to the following schedule ( Table 1 Table 1: Dosing Recommendations in aHUS Patients Less Than 18 Years of Age Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly x 4 doses 1,200 mg at week 5; 30 kg to less than 40 kg 600 mg weekly x 2 doses 900 mg at week 3; 20 kg to less than 30 kg 600 mg weekly x 2 doses 600 mg at week 3; 10 kg to less than 20 kg 600 mg weekly x 1 dose 300 mg at week 2; 5 kg to less than 10 kg 300 mg weekly x 1 dose 300 mg at week 2; Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points. For adult patients with generalized myasthenia gravis, EPYSQLI therapy consists of: 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. Administer EPYSQLI at the recommended dosage regimen time points, or within two days of these time points. For adult and pediatric patients with aHUS, and adult patients with gMG, supplemental dosing of EPYSQLI is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) ( Table 2 Table 2: Supplemental Dose of EPYSQLI after PE/PI Type of Plasma Intervention Most Recent EPYSQLI Dose Supplemental EPYSQLI Dose with Each Plasma Intervention Timing of Supplemental EPYSQLI Dose Plasmapheresis or plasma exchange 300 mg 300 mg per each plasmapheresis or plasma exchange session Within 60 minutes after each plasmapheresis or plasma exchange >=600 mg 600 mg per each plasmapheresis or plasma exchange session Fresh frozen plasma infusion >=300 mg 300 mg per infusion of fresh frozen plasma 60 minutes prior to each infusion of fresh frozen plasma Dilute EPYSQLI to a final admixture concentration of 5 mg/mL using the following steps: Withdraw the required amount of EPYSQLI from the vial into a sterile syringe. Transfer the recommended dose to an infusion bag. Dilute EPYSQLI to a final concentration of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0. 9% Sodium Chloride Injection, USP; 0. 45% Sodium Chloride Injection, USP; or 5% Dextrose in Water Injection, USP to the infusion bag. The final admixed EPYSQLI 5 mg/mL infusion volume is 60 mL for 300 mg doses, 120 mL for 600 mg doses, 180 mL for 900 mg doses or 240 mL for 1,200 mg doses ( Table 3 Table 3: Preparation and Reconstitution of EPYSQLI EPYSQLI Dose Diluent Volume Final Volume 300 mg 30 mL 60 mL 600 mg 60 mL 120 mL 900 mg 90 mL 180 mL 1,200 mg 120 mL 240 mL Gently invert the infusion bag containing the diluted EPYSQLI solution to ensure thorough mixing of the product and diluent. Discard any unused portion left in a vial, as the product contains no preservatives. Prior to administration, the admixture should be allowed to adjust to room temperature [18°C to 25°C (64°F to 77°F)]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Only administer as an intravenous infusion. Do not administer as an intravenous push or bolus injection. Administer the EPYSQLI admixture by intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions of EPYSQLI are stable for 24 hours refrigerated at 2°C to 8°C (36°F to 46°F) and at room temperature. If an adverse reaction occurs during the administration of EPYSQLI, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours in adults. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion-related reaction.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [ see Warnings and Precautions ( 5. 1 Other Infections [ see Warnings and Precautions ( 5. 3 Monitoring Disease Manifestations after EPYSQLI Discontinuation [ see Warnings and Precautions ( 5. 4 Thrombosis Prevention and Management [ see Warnings and Precautions ( 5. 5 Infusion-Related Reactions [ see Warnings and Precautions ( 5. 6 The most frequently reported adverse reactions in the PNH randomized trial (>=10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea. 1 The most frequently reported adverse reactions in aHUS single arm prospective trials (>=20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia. 1 The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (>=10%) is: musculoskeletal pain. 1 To report SUSPECTED ADVERSE REACTIONS, contact Samsung Bioepis Co. at 1-800-806-0716 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Meningococcal infections are the most important adverse reactions experienced by patients receiving eculizumab. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period [ see Warnings and Precautions ( 5. 1 PNH The data described below reflect exposure to eculizumab in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. Eculizumab was studied in a placebo-controlled clinical study (PNH Study 1, in which 43 patients received eculizumab and 44, placebo); a single arm clinical study (PNH Study 2); and a long term extension study (E05-001). 182 patients were exposed for greater than one year. All patients received the recommended eculizumab dose regimen. Table 4 Table 4: Adverse Reactions Reported in 5% or More of Eculizumab Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study Reaction Eculizumab Placebo (N=43) (N=44) N (%) N (%) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving eculizumab and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving eculizumab experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with eculizumab in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). aHUS The safety of eculizumab therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (Studies C08-002A/B, C08-003A/B, and C10-004), one in pediatric and adolescent patients (Study C10-003), and one retrospective study (Study C09-001r). The data described below were derived from 78 adult and adolescent patients with aHUS in Studies C08-002A/B, C08-003A/B and C10-004. All patients received the recommended dosage of eculizumab. Median exposure was 67 weeks (range: 2-145 weeks). Table 5 Table 5: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total Number (%) of Patients C08-002A/B C08-003A/B C10-004 Total (N=17) (N=20) (N=41) (N=78) a. Vascular Disorders Hypertension a 10 (59) 9 (45) 7 (17) 26 (33) Hypotension 2 (12) 4 (20) 7 (17) 13 (17) Infections and Infestations Bronchitis 3 (18) 2 (10) 4 (10) 9 (12) Nasopharyngitis 3 (18) 11 (55) 7 (17) 21 (27) Gastroenteritis 3 (18) 4 (20) 2 (5) 9 (12) Upper respiratory tract infection 5 (29) 8 (40) 2 (5) 15 (19) Urinary tract infection 6 (35) 3 (15) 8 (20) 17 (22) Gastrointestinal Disorders Diarrhea 8 (47) 8 (40) 12 (32) 29 (37) Vomiting 8 (47) 9 (45) 6 (15) 23 (30) Nausea 5 (29) 8 (40) 5 (12) 18 (23) Abdominal pain 3 (18) 6 (30) 6 (15) 15 (19) Nervous System Disorders Headache 7 (41) 10 (50) 15 (37) 32 (41) Blood and Lymphatic System Disorders Anemia 6 (35) 7 (35) 7 (17) 20 (26) Leukopenia 4 (24) 3 (15) 5 (12) 12 (15) Psychiatric Disorders Insomnia 4 (24) 2 (10) 5 (12) 11 (14) Renal and Urinary Disorders Renal Impairment 5 (29) 3 (15) 6 (15) 14 (18) Proteinuria 2 (12) 1 (5) 5 (12) 8 (10) Respiratory, Thoracic and Mediastinal Disorders Cough 4 (24) 6 (30) 8 (20) 18 (23) General Disorders and Administration Site Conditions Fatigue 3 (18) 4 (20) 3 (7) 10 (13) Peripheral edema 5 (29) 4 (20) 9 (22) 18 (23) Pyrexia 4 (24) 5 (25) 7 (17) 16 (21) Asthenia 3 (18) 4 (20) 6 (15) 13 (17) Eye Disorder 5 (29) 2 (10) 8 (20) 15 (19) Metabolism and Nutrition Disorders Hypokalemia 3 (18) 2 (10) 4 (10) 9 (12) Neoplasms benign, malignant, and unspecified (including cysts and polyps) 1 (6) 6 (30) 1 (20) 8 (10) Skin and Subcutaneous Tissue Disorders Rash 2 (12) 3 (15) 6 (15) 11 (14) Pruritus 1 (6) 3 (15) 4 (10) 8 (10) Musculoskeletal and Connective Tissue Disorders Arthralgia 1 (6) 2 (10) 7 (17) 10 (13) Back pain 3 (18) 3 (15) 2 (5) 8 (10) In Studies C08-002A/B, C08-003A/B and C10-004 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued eculizumab due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningococcal meningitis. Study C10-003 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. Median exposure was 44 weeks (range: 1 dose-87 weeks). Table 6 Table 6: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003 1 month to <12 yrs (N=18) Total (N=22) Eye Disorders 3 (17) 3 (14) Gastrointestinal Disorders Abdominal pain 6 (33) 7 (32) Diarrhea 5 (28) 7 (32) Vomiting 4 (22) 6 (27) Dyspepsia 0 3 (14) General Disorders and Administration Site Conditions Pyrexia 9 (50) 11 (50) Infections and Infestations Upper respiratory tract infection 5 (28) 7 (32) Nasopharyngitis 3 (17) 6 (27) Rhinitis 4 (22) 4 (18) Urinary Tract infection 3 (17) 4 (18) Catheter site infection 3 (17) 3 (14) Musculoskeletal and Connective Tissue Disorders Muscle spasms 2 (11) 3 (14) Nervous System Disorders Headache 3 (17) 4 (18) Renal and Urinary Disorders 3 (17) 4 (18) Respiratory, Thoracic and Mediastinal Disorders Cough 7 (39) 8 (36) Oropharyngeal pain 1 (6) 3 (14) Skin and Subcutaneous Tissue Disorders Rash 4 (22) 4 (18) Vascular Disorders Hypertension 4 (22) 4 (18) In Study C10-003, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued eculizumab due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in Study C09-001r (N=30) revealed a safety profile that was similar to that which was observed in the two prospective studies. Study C09-001r included 19 pediatric patients less than 18 years of age. Overall, the safety of eculizumab in pediatric patients with aHUS enrolled in Study C09-001r appeared similar to that observed in adult patients. The most common (>=15%) adverse events occurring in pediatric patients are presented in Table 7 Table 7: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r Number (%) of Patients < 2 yrs (N=5) 2 to < 12 yrs (N=10) 12 to < 18 yrs (N=4) Total (N=19) a. General Disorders and Administration Site Conditions Pyrexia 4 (80) 4 (40) 1 (25) 9 (47) Gastrointestinal Disorders Diarrhea 1 (20) 4 (40) 1 (25) 6 (32) Vomiting 2 (40) 1 (10) 1 (25) 4 (21) Infections and Infestations Upper respiratory tract infection a 2 (40) 3 (30) 1 (25) 6 (32) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (60) 2 (20) 0 (0) 5 (26) Nasal congestion 2 (40) 2 (20) 0 (0) 4 (21) Cardiac Disorders Tachycardia 2 (40) 2 (20) 0 (0) 4 (21) Generalized Myasthenia Gravis (gMG) In a 26-week placebo-controlled trial evaluating the effect of eculizumab for the treatment of gMG (gMG Study 1), 62 patients received eculizumab at the recommended dosage regimen and 63 patients received placebo [see Clinical Studies ( 14. 3 Table 8 Table 8: Adverse Reactions Reported in 5% or More of Eculizumab-Treated Patients in gMG Study 1 and at a Greater Frequency than in Placebo-Treated Patients Eculizumab (N=62) N (%) Placebo (N=63) N (%) Gastrointestinal Disorders Abdominal pain 5 (8) 3 (5) General Disorders and Administration Site Conditions Peripheral edema 5 (8) 3 (5) Pyrexia 4 (7) 2 (3) Infections and Infestations Herpes simplex virus 5 (8) 1 (2) Injury, Poisoning, and Procedural Complications Contusion 5 (8) 2 (3) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 9 (15) 5 (8) The most common adverse reactions (>=10%) that occurred in eculizumab-treated patients in the long-term extension to gMG Study 1, Study ECU-MG-302, and that are not included in Table 8 The following adverse reactions have been identified during post-approval use of eculizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to eculizumab products exposure. Adverse Reactions from Postmarketing Spontaneous Reports Fatal or serious infections: Neisseria gonorrhoeae Neisseria meningitidis Neisseria sicca/subflava Neisseria spp Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with eculizumab products. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks.

EPYSQLI is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis see Warnings and Precautions ( 5. 1 EPYSQLI is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis 4.

Risk Summary Limited data on outcomes of pregnancies that have occurred following eculizumab use in pregnant women have not identified a concern for specific adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations see Data The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Fetal/Neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50. 3%) and retrospectively (49. 7%) collected data in more than 300 pregnant women with live births following exposure to eculizumab have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. Risk Summary Although limited published data does not report detectable levels of eculizumab in human milk, maternal IgG is known to be present in human milk. Available information is insufficient to inform the effect of eculizumab products on the breastfed infant. There are no data on the effects of eculizumab products on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EPYSQLI and any potential adverse effects on the breastfed child from EPYSQLI or from the underlying maternal condition. Safety and effectiveness of EPYSQLI for the treatment of PNH or gMG in pediatric patients have not been established. The safety and effectiveness of EPYSQLI for the treatment of aHUS have been established in pediatric patients. Use of EPYSQLI in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients [ see Adverse Reactions ( 6. 2 Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [ see Warnings and Precautions ( 5. 3 Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with another indication) were treated with eculizumab in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.

Concomitant use of eculizumab products with plasma exchange (PE), plasmapheresis (PP) or fresh frozen plasma infusion (PE/PI) treatment can reduce serum eculizumab product concentrations and requires a supplemental dose of EPYSQLI [see Dosage and Administration ( 2. 5 Concomitant use of eculizumab products with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of eculizumab products. Closely monitor for reduced effectiveness of EPYSQLI.

25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement) Daily TMA intervention rate ( defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day aHUS Resistant to PE/PI (Study C08-002A/B) Study C08-002A/B enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count <=150 x 10 9 Table 11 Table 11: Baseline Characteristics of Patients Enrolled in Study C08-002A/B Parameter C08-002A/B (N=17) Time from aHUS diagnosis until screening in months, median (min, max) 10 (0. 26, 236) Time from current clinical TMA manifestation until screening in months, median (min, max) <1 (<1, 4) Baseline platelet count (× 109/L), median (range) 118 (62, 161) Baseline LDH (U/L), median (range) 269 (134, 634) Patients in Study C08-002A/B received eculizumab for a minimum of 26 weeks. In Study C08-002A/B, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. The mean eGFR (+/- SD) increased from 23 +/- 15 mL/min/1. 73m 2 2 2 Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C08- 002A/B, mean platelet count (+/- SD) increased from 109 +/- 32 x10 9 9 9 9 Table 12 Table 12: Efficacy Results for Study C08-002A/B 1. Efficacy Parameter Study C08-002A/B at 26 wks 1 (N=17) Study C08-002A/B at 2 yrs 2 (N=17) Complete TMA response, n (%) 11 (65) 13 (77) eGFR improvement >=15 mL/min/1. 73 m 2 9 (53) 10 (59) Hematologic normalization, n (%) 13 (76) 15 (88) TMA event-free status, n (%) 15 (88) 15 (88) Daily TMA intervention rate, median (range) aHUS Sensitive to PE/PI (Study C08-003A/B) Study C08-003A/B enrolled patients undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first eculizumab dose. Patients on chronic dialysis were permitted to enroll in Study C08- 003A/B. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in Study C08- 003A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 37%-118%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 13 Table 13: Baseline Characteristics of Patients Enrolled in Study C08-003A/B Parameter Study C08-003A/B (N=20) Time from aHUS diagnosis until screening in months, median (min, max) 48 (0. 66, 286) Time from current clinical TMA manifestation until screening in months, median (min, max) 9 (1, 45) Baseline platelet count (× 109/L), median (range) 218 (105, 421) Baseline LDH (U/L), median (range) 200 (151, 391) Patients in Study C08-003A/B received eculizumab for a minimum of 26 weeks. In Study C08-003A/B, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). Renal function, as measured by eGFR, was maintained during eculizumab therapy. The mean eGFR (+/- SD) was 31 +/- 19 mL/min/1. 73m 2 2 2 Reduction in terminal complement activity was observed in all patients after the commencement of eculizumab. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (+/- SD) was 228 +/- 78 x 10 9 9 9 Table 14 Table 14: Efficacy Results for Study C08-003A/B 1. Efficacy Parameter Study C08-003A/B at 26 wks 1 (N=20) Study C08-003A/B at 2 yrs 2 (N=20) Complete TMA response, n (%) 5 (25) 11 (55) eGFR improvement >=15 mL/min/1. 73 m 2 1 (5) 8 (40) TMA Event-free status n (%) 16 (80) 19 (95) Daily TMA intervention rate, median (range) Hematologic normalization 4 3 Retrospective Study in Patients with aHUS (C09-001r) The efficacy results for the aHUS retrospective study (Study C09-001r) were generally consistent with results of the two prospective studies. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count (+/- SD) increased from 171 +/- 83 x10 9 9 9 A total of 19 pediatric patients (ages 2 months to 17 years) received eculizumab in Study C09-001r. The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children <2 years of age (n=5), 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10), and 38 weeks (range 1 to 69 weeks) for patients 12 to <18 years of age (n=4). Fifty-three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in Studies C08-002A/B and C08-003A/B ( Table 15 Table 15: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r 1. 2 Efficacy Parameter <2 yrs (N=5) 2 to <12 yrs (N=10) 12 to <18 yrs (N=4) Total (N=19) Complete TMA response, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Patients with eGFR improvement >= 15 mL/min/1. 73 m 2 2 2 (40) 6 (60) 1 (25) 9 (47) Platelet count normalization, n (%) 1 4 (80) 10 (100) 3 (75) 17 (89) Hematologic Normalization, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Daily TMA intervention rate, median (range) Adult Patients with aHUS (Study C10-004) Study C10-004 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrollment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in Study C10-004 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 16 Table 16: Baseline Characteristics of Patients Enrolled in Study C10-004 Parameter Study C10-004 (N=41) Time from aHUS diagnosis until start of study drug in months, median (range) 0. 03 en dash 311) Time from current clinical TMA manifestation until first study dose in months, median (range) 0. 03-19) Baseline platelet count (× 10 9 125 (16 en dash 332) Baseline LDH (U/L), median (range) 375 (131 en dash 3318) Patients in Study C10-004 received eculizumab for a minimum of 26 weeks. In Study C10-004, the median duration of eculizumab therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (+/- SD) increased from 17 +/- 12 mL/min/1. 73m 2 2 Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. In Study C10- 004, mean platelet count (+/- SD) increased from 119 +/- 66 x10 9 9 9 Table 17 Table 17: Efficacy Results for Study C10-004 Efficacy Parameter Study C10-004 (N=41) Complete TMA response, n (%), 23 (56) Patients with eGFR improvement >= 15 mL/min/1. 73m 2 22 (54) Hematologic Normalization, n (%) 36 (88) TMA Event-free Status, n (%) 37 (90) Daily TMA Intervention Rate, median (range) Pediatric and Adolescent Patients with aHUS (Study C10-003) Study C10-003 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level >=97 percentile for age without the need for chronic dialysis. The median patient age was 6. 5 (range: 5 months to 17 years). Patients enrolled in Study C10-003 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38%-121%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 18 Table 18: Baseline Characteristics of Patients Enrolled in Study C10-003 Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Time from aHUS diagnosis until start of study drug in months, median (range) 0. 03 en dash 58) 0. 03-191) Time from current clinical TMA manifestation until first study dose in months, median (range) 0. 03 en dash 4) 0. 03-4) Baseline platelet count (x 10 9 110 (19-146) 91 (19-146) Baseline LDH (U/L) median (range) 1510 (282-7164) 1244 (282-7164) Patients in Study C10-003 received eculizumab for a minimum of 26 weeks. In Study C10-003, the median duration of eculizumab therapy was approximately 44 weeks (range: 1 dose to 88 weeks). The mean eGFR (+/- SD) increased from 33 +/- 30 mL/min/1. 73m 2 2 Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. The mean platelet count (+/- SD) increased from 88 +/- 42 x10 9 9 9 Table 19 Table 19: Efficacy Results for Study C10-003 1. Efficacy Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Complete TMA response, n (%) 1 11 (61) 14 (64) eGFR improvement >=15 mL/min/ 1. 73 m 2 16 (89) 19 (86) Complete Hematologic Normalization, n (%) 14 (78) 18 (82) TMA Event-Free Status, n (%) 17 (94) 21 (95) Daily TMA Intervention rate, median (range) 0. 7) The efficacy of eculizumab for the treatment of gMG was established in gMG Study 1 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi-center trial that enrolled patients who met the following criteria at screening: Positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV, MG-Activities of Daily Living (MG-ADL) total score >=6, Failed treatment over 1 year or more with 2 or more immunosuppressive therapies (ISTs) either in combination or as monotherapy, or failed at least 1 IST and required chronic plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIg). A total of 62 patients were randomized to receive eculizumab treatment and 63 were randomized to receive placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group), gender [66% female (eculizumab) versus 65% female (placebo)], and duration of gMG [9. 9 (eculizumab) versus 9. 2 (placebo) years]. Over 95% of patients in each group were receiving acetylcholinesterase (AchE) inhibitors, and 98% were receiving immunosuppressant therapies (ISTs). Approximately 50% of each group had been previously treated with at least 3 ISTs. Eculizumab was administered according to the recommended dosage regimen [see Dosage and Administration ( 2. 4 The primary efficacy endpoint for gMG Study 1 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MGADL) total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0-24). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4. 2 points in the eculizumab-treated group compared with -2. 3 points in the placebo-treated group (p=0. A key secondary endpoint in gMG Study 1 was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness (total score 0-39). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in QMG total scores [-4. 6 points in the eculizumab-treated group compared with -1. 6 points in the placebo-treated group (p=0. The results of the analysis of the MG-ADL and QMG from gMG Study 1 are shown in Table 20 Table 20: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in gMG Study 1 SEM= Standard Error of the Mean; eculizumab-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms a b Efficacy Endpoints Eculizumab-LS Mean (N=62) (SEM) Placebo-LS Mean (N=63) (SEM) Eculizumab change relative to placebo en dash LS Mean Difference (95% CI) p-values MG-ADL -4. 006 a b QMG -4. 001 a b In gMG Study 1, a clinical response was defined in the MG-ADL total score as at least a 3-point improvement and in QMG total score as at least a 5-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was statistically significantly higher for eculizumab compared to placebo for both measures. For both endpoints, and also at higher response thresholds (>=4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and >=6-, 7-, 8-, 9-, or 10-point improvement on QMG), the proportion of clinical responders was consistently greater for eculizumab compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of eculizumab treatment.">NONCLINICAL TOXICOLOGY
Long-term animal carcinogenicity studies of eculizumab products have not been conducted. Genotoxicity studies have not been conducted with eculizumab products. Effects of eculizumab products upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility.
CLINICAL STUDIES
The safety and efficacy of eculizumab in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (PNH Study 1, NCT00122330); PNH patients were also treated with eculizumab in a single arm 52 week study (PNH Study 2, NCT00122304) and in a long- term extension study (E05-001, NCT00122317). Patients received meningococcal vaccination prior to receipt of eculizumab. In all studies, the dose of eculizumab was 600 mg study drug every 7 +/- 2 days for 4 weeks, followed by 900 mg 7 +/- 2 days later, then 900 mg every 14 +/- 2 days for the study duration. Eculizumab was administered as an intravenous infusion over 25 - 45 minutes. PNH Study 1: PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either eculizumab (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the "set-point") which would define each patient''s hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26 week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Major baseline characteristics were balanced (see Table 9 Table 9: PNH Study 1 Patient Baseline Characteristics Study 1 Parameter Placebo (N=44) Eculizumab (N=43) Mean age (SD) 38 (13) 42 (16) Gender - female (%) 29 (66) 23 (54) History of aplastic anemia or myelodysplastic syndrome (%) 12 (27) 8 (19) Patients with history of thrombosis (events) 8 (11) 9 (16) Concomitant anticoagulants (%) 20 (46) 24 (56) Concomitant steroids/immunosuppressant treatments (%) 16 (36) 14 (33) Packed RBC units transfused per patient in previous 12 months (median (Q1,Q3)) 17 (14, 25) 18 (12, 24) Mean Hgb level (g/dL) at setpoint (SD) 8 (1) 8 (1) Pre-treatment LDH levels (median, U/L) 2,234 2,032 Free hemoglobin at baseline (median, mg/dL) 46 41 Patients treated with eculizumab had significantly reduced (p< 0. 001) hemolysis resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 10 Table 10: PNH Study 1 Results Placebo (N=44) Eculizumab (N=43) Percentage of patients with stabilized hemoglobin levels 0 49 Packed RBC units transfused per patient (median) 10 0 (range) (2 - 21) (0 - 16) Transfusion avoidance (%) 0 51 LDH levels at end of study (median, U/L) 2,167 239 Free hemoglobin at end of study (median, mg/dL) 62 5 PNH Study 2 and Extension Study: PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received eculizumab over a 52-week period. Concomitant medications included anti- thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. 187 eculizumab- treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during eculizumab products therapy was not studied [ see Warnings and Precautions ( 5. 5 Five single-arm studies [four prospective: C08-002A/B (NCT00844545 and NCT00844844), C08- 003A/B (NCT00838513 and NCT00844428), C10-003 (NCT01193348), and C10-004 (NCT01194973); and one retrospective: C09-001r (NCT01770951)] evaluated the safety and efficacy of eculizumab for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of eculizumab in adult and adolescent patients was 900 mg every 7 +/- 2 days for 4 weeks, followed by 1,200 mg 7 +/- 2 days later, then 1,200 mg every 14 +/- 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in Study C09-001r and Study C10-003 was based on body weight [ see Dosage and Administration ( 2. 3 Endpoints related to TMA included the following: platelet count change from baseline hematologic normalization ( maintenance of normal platelet counts and LDH levels for at least four weeks) complete TMA response ( hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks TMA-event free status ( absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement) Daily TMA intervention rate ( defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day aHUS Resistant to PE/PI (Study C08-002A/B) Study C08-002A/B enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count <=150 x 10 9 Table 11 Table 11: Baseline Characteristics of Patients Enrolled in Study C08-002A/B Parameter C08-002A/B (N=17) Time from aHUS diagnosis until screening in months, median (min, max) 10 (0. 26, 236) Time from current clinical TMA manifestation until screening in months, median (min, max) <1 (<1, 4) Baseline platelet count (× 109/L), median (range) 118 (62, 161) Baseline LDH (U/L), median (range) 269 (134, 634) Patients in Study C08-002A/B received eculizumab for a minimum of 26 weeks. In Study C08-002A/B, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. The mean eGFR (+/- SD) increased from 23 +/- 15 mL/min/1. 73m 2 2 2 Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C08- 002A/B, mean platelet count (+/- SD) increased from 109 +/- 32 x10 9 9 9 9 Table 12 Table 12: Efficacy Results for Study C08-002A/B 1. Efficacy Parameter Study C08-002A/B at 26 wks 1 (N=17) Study C08-002A/B at 2 yrs 2 (N=17) Complete TMA response, n (%) 11 (65) 13 (77) eGFR improvement >=15 mL/min/1. 73 m 2 9 (53) 10 (59) Hematologic normalization, n (%) 13 (76) 15 (88) TMA event-free status, n (%) 15 (88) 15 (88) Daily TMA intervention rate, median (range) aHUS Sensitive to PE/PI (Study C08-003A/B) Study C08-003A/B enrolled patients undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first eculizumab dose. Patients on chronic dialysis were permitted to enroll in Study C08- 003A/B. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in Study C08- 003A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 37%-118%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 13 Table 13: Baseline Characteristics of Patients Enrolled in Study C08-003A/B Parameter Study C08-003A/B (N=20) Time from aHUS diagnosis until screening in months, median (min, max) 48 (0. 66, 286) Time from current clinical TMA manifestation until screening in months, median (min, max) 9 (1, 45) Baseline platelet count (× 109/L), median (range) 218 (105, 421) Baseline LDH (U/L), median (range) 200 (151, 391) Patients in Study C08-003A/B received eculizumab for a minimum of 26 weeks. In Study C08-003A/B, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). Renal function, as measured by eGFR, was maintained during eculizumab therapy. The mean eGFR (+/- SD) was 31 +/- 19 mL/min/1. 73m 2 2 2 Reduction in terminal complement activity was observed in all patients after the commencement of eculizumab. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (+/- SD) was 228 +/- 78 x 10 9 9 9 Table 14 Table 14: Efficacy Results for Study C08-003A/B 1. Efficacy Parameter Study C08-003A/B at 26 wks 1 (N=20) Study C08-003A/B at 2 yrs 2 (N=20) Complete TMA response, n (%) 5 (25) 11 (55) eGFR improvement >=15 mL/min/1. 73 m 2 1 (5) 8 (40) TMA Event-free status n (%) 16 (80) 19 (95) Daily TMA intervention rate, median (range) Hematologic normalization 4 3 Retrospective Study in Patients with aHUS (C09-001r) The efficacy results for the aHUS retrospective study (Study C09-001r) were generally consistent with results of the two prospective studies. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count (+/- SD) increased from 171 +/- 83 x10 9 9 9 A total of 19 pediatric patients (ages 2 months to 17 years) received eculizumab in Study C09-001r. The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children <2 years of age (n=5), 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10), and 38 weeks (range 1 to 69 weeks) for patients 12 to <18 years of age (n=4). Fifty-three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in Studies C08-002A/B and C08-003A/B ( Table 15 Table 15: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r 1. 2 Efficacy Parameter <2 yrs (N=5) 2 to <12 yrs (N=10) 12 to <18 yrs (N=4) Total (N=19) Complete TMA response, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Patients with eGFR improvement >= 15 mL/min/1. 73 m 2 2 2 (40) 6 (60) 1 (25) 9 (47) Platelet count normalization, n (%) 1 4 (80) 10 (100) 3 (75) 17 (89) Hematologic Normalization, n (%) 2 (40) 5 (50) 1 (25) 8 (42) Daily TMA intervention rate, median (range) Adult Patients with aHUS (Study C10-004) Study C10-004 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrollment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in Study C10-004 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 16 Table 16: Baseline Characteristics of Patients Enrolled in Study C10-004 Parameter Study C10-004 (N=41) Time from aHUS diagnosis until start of study drug in months, median (range) 0. 03 en dash 311) Time from current clinical TMA manifestation until first study dose in months, median (range) 0. 03-19) Baseline platelet count (× 10 9 125 (16 en dash 332) Baseline LDH (U/L), median (range) 375 (131 en dash 3318) Patients in Study C10-004 received eculizumab for a minimum of 26 weeks. In Study C10-004, the median duration of eculizumab therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (+/- SD) increased from 17 +/- 12 mL/min/1. 73m 2 2 Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. In Study C10- 004, mean platelet count (+/- SD) increased from 119 +/- 66 x10 9 9 9 Table 17 Table 17: Efficacy Results for Study C10-004 Efficacy Parameter Study C10-004 (N=41) Complete TMA response, n (%), 23 (56) Patients with eGFR improvement >= 15 mL/min/1. 73m 2 22 (54) Hematologic Normalization, n (%) 36 (88) TMA Event-free Status, n (%) 37 (90) Daily TMA Intervention Rate, median (range) Pediatric and Adolescent Patients with aHUS (Study C10-003) Study C10-003 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level >=97 percentile for age without the need for chronic dialysis. The median patient age was 6. 5 (range: 5 months to 17 years). Patients enrolled in Study C10-003 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38%-121%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 18 Table 18: Baseline Characteristics of Patients Enrolled in Study C10-003 Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Time from aHUS diagnosis until start of study drug in months, median (range) 0. 03 en dash 58) 0. 03-191) Time from current clinical TMA manifestation until first study dose in months, median (range) 0. 03 en dash 4) 0. 03-4) Baseline platelet count (x 10 9 110 (19-146) 91 (19-146) Baseline LDH (U/L) median (range) 1510 (282-7164) 1244 (282-7164) Patients in Study C10-003 received eculizumab for a minimum of 26 weeks. In Study C10-003, the median duration of eculizumab therapy was approximately 44 weeks (range: 1 dose to 88 weeks). The mean eGFR (+/- SD) increased from 33 +/- 30 mL/min/1. 73m 2 2 Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. The mean platelet count (+/- SD) increased from 88 +/- 42 x10 9 9 9 Table 19 Table 19: Efficacy Results for Study C10-003 1. Efficacy Parameter Patients 1 month to <12 years (N=18) All Patients (N=22) Complete TMA response, n (%) 1 11 (61) 14 (64) eGFR improvement >=15 mL/min/ 1. 73 m 2 16 (89) 19 (86) Complete Hematologic Normalization, n (%) 14 (78) 18 (82) TMA Event-Free Status, n (%) 17 (94) 21 (95) Daily TMA Intervention rate, median (range) 0. 7) The efficacy of eculizumab for the treatment of gMG was established in gMG Study 1 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi-center trial that enrolled patients who met the following criteria at screening: Positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV, MG-Activities of Daily Living (MG-ADL) total score >=6, Failed treatment over 1 year or more with 2 or more immunosuppressive therapies (ISTs) either in combination or as monotherapy, or failed at least 1 IST and required chronic plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIg). A total of 62 patients were randomized to receive eculizumab treatment and 63 were randomized to receive placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group), gender [66% female (eculizumab) versus 65% female (placebo)], and duration of gMG [9. 9 (eculizumab) versus 9. 2 (placebo) years]. Over 95% of patients in each group were receiving acetylcholinesterase (AchE) inhibitors, and 98% were receiving immunosuppressant therapies (ISTs). Approximately 50% of each group had been previously treated with at least 3 ISTs. Eculizumab was administered according to the recommended dosage regimen [see Dosage and Administration ( 2. 4 The primary efficacy endpoint for gMG Study 1 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MGADL) total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0-24). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4. 2 points in the eculizumab-treated group compared with -2. 3 points in the placebo-treated group (p=0. A key secondary endpoint in gMG Study 1 was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness (total score 0-39). A statistically significant difference favoring eculizumab was observed in the mean change from baseline to Week 26 in QMG total scores [-4. 6 points in the eculizumab-treated group compared with -1. 6 points in the placebo-treated group (p=0. The results of the analysis of the MG-ADL and QMG from gMG Study 1 are shown in Table 20 Table 20: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in gMG Study 1 SEM= Standard Error of the Mean; eculizumab-LSMean = least square mean for the treatment group; Placebo-LSMean = least square mean for the placebo group; LSMean-Difference (95% CI) = Difference in least square mean with 95% confidence interval; p-values (testing the null hypothesis that there is no difference between the two treatment arms a b Efficacy Endpoints Eculizumab-LS Mean (N=62) (SEM) Placebo-LS Mean (N=63) (SEM) Eculizumab change relative to placebo en dash LS Mean Difference (95% CI) p-values MG-ADL -4. 006 a b QMG -4. 001 a b In gMG Study 1, a clinical response was defined in the MG-ADL total score as at least a 3-point improvement and in QMG total score as at least a 5-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was statistically significantly higher for eculizumab compared to placebo for both measures. For both endpoints, and also at higher response thresholds (>=4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and >=6-, 7-, 8-, 9-, or 10-point improvement on QMG), the proportion of clinical responders was consistently greater for eculizumab compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of eculizumab treatment.

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