14 CLINICAL STUDIES

14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH)

The safety and efficacy of SOLIRIS 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 SOLIRIS 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 SOLIRIS. In all studies, the dose of SOLIRIS 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. SOLIRIS 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 SOLIRIS (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 11).

Table 11: PNH Study 1 Patient Baseline Characteristics
	Study 1
Parameter	Placebo (N=44)	SOLIRIS (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 SOLIRIS 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 12). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of SOLIRIS treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of SOLIRIS on thrombotic events could not be determined.

Table 12: PNH Study 1 Results
	Placebo (N=44)	SOLIRIS (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 SOLIRIS 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 SOLIRIS-treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total SOLIRIS exposure time ranging from 10 to 54 months. There were fewer thrombotic events with SOLIRIS 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 SOLIRIS therapy was not studied [see Warnings and Precautions (5.5)].

14.2 Atypical Hemolytic Uremic Syndrome (aHUS)

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 SOLIRIS for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of SOLIRIS or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of SOLIRIS in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg 7 ± 2 days later, then 1200 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)]. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints.

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 × 109/L, 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 28 (range: 17 to 68 years). Patients enrolled in Study C08-002A/B were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 70%-121%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 13 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-002A/B.

Table 13: 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 SOLIRIS for a minimum of 26 weeks. In Study C08-002A/B, the median duration of SOLIRIS therapy was approximately 100 weeks (range: 2 weeks to 145 weeks).

Renal function, as measured by eGFR, was improved and maintained during SOLIRIS therapy. The mean eGFR (± SD) increased from 23 ± 15 mL/min/1.73m2 at baseline to 56 ± 40 mL/min/1.73m2 by 26 weeks; this effect was maintained through 2 years (56 ± 30 mL/min/1.73m2). Four of the five patients who required dialysis at baseline were able to discontinue dialysis.

Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of SOLIRIS. SOLIRIS 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 ×109/L at baseline to 169 ± 72 ×109/L by one week; this effect was maintained through 26 weeks (210 ± 68 ×109/L), and 2 years (205 ± 46 ×109/L). When treatment was continued for more than 26 weeks, two additional patients achieved Hematologic Normalization as well as Complete TMA response. Hematologic Normalization and Complete TMA response were maintained by all responders. In Study C08-002A/B, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins.

Table 14 summarizes the efficacy results for Study C08-002A/B.

Table 14: Efficacy Results for Study C08-002A/B
Efficacy Parameter	Study C08-002A/B at 26 wks* (N=17)	Study C08-002A/B at 2 yrs† (N=17)
* At data cut-off (September 8, 2010). † At data cut-off (April 20, 2012).
Complete TMA response, n (%)	11 (65)	13 (77)
Median Duration of complete TMA response, weeks (range)	38 (25, 56)	99 (25, 139)
eGFR improvement ≥15 mL/min/1.73 m2, n (%)	9 (53)	10 (59)
Median duration of eGFR improvement, days (range)	251 (70, 392)	ND
Hematologic normalization, n (%) Median Duration of hematologic normalization, weeks (range)	13 (76) 37 (25, 62)	15 (88) 99 (25, 145)
TMA event-free status, n (%)	15 (88)	15 (88)
Daily TMA intervention rate, median (range)
Before eculizumab	0.82 (0.04, 1.52)	0.82 (0.04, 1.52)
On eculizumab treatment	0 (0, 0.31)	0 (0, 0.36)

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 SOLIRIS 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 15 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C08-003A/B.

Table 15: 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 SOLIRIS for a minimum of 26 weeks. In Study C08-003A/B, the median duration of SOLIRIS therapy was approximately 114 weeks (range: 26 to 129 weeks).

Renal function, as measured by eGFR, was maintained during SOLIRIS therapy. The mean eGFR (± SD) was 31 ± 19 mL/min/1.73m2 at baseline, and was maintained through 26 weeks (37 ± 21 mL/min/1.73m2) and 2 years (40 ± 18 mL/min/1.73m2). No patient required new dialysis with SOLIRIS.

Reduction in terminal complement activity was observed in all patients after the commencement of SOLIRIS. SOLIRIS reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (± SD) was 228 ± 78 × 109/L at baseline, 233 ± 69 × 109/L at week 26, and 224 ± 52 × 109/L at 2 years. When treatment was continued for more than 26 weeks, six additional patients achieved Complete TMA response. Complete TMA Response and Hematologic Normalization were maintained by all responders. In Study C08-003A/B, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins.

Table 16 summarizes the efficacy results for Study C08-003A/B.

Table 16: Efficacy Results for Study C08-003A/B
Efficacy Parameter	Study C08-003A/B at 26 wks* (N=20)	Study C08-003A/B at 2 yrs† (N=20)
* At data cut-off (September 8, 2010). † At data cut-off (April 20, 2012). ‡ In Study C08-003A/B, 85% of patients had normal platelet counts and 80% of patients had normal serum LDH levels at baseline, so hematologic normalization in this population reflects maintenance of normal parameters in the absence of PE/PI. § Calculated at each post-dose day of measurement (excluding Days 1 to 4) using a repeated measurement ANOVA model.
Complete TMA response, n (%)	5 (25)	11 (55)
Median duration of complete TMA response, weeks (range)	32 (12, 38)	68 (38, 109)
eGFR improvement ≥15 mL/min/1.73 m2, n (%)	1 (5)	8 (40)
TMA Event-free status n (%)	16 (80)	19 (95)
Daily TMA intervention rate, median (range)
Before eculizumab	0.23 (0.05, 1.07)	0.23 (0.05, 1.07)
On eculizumab treatment	0	0 (0, 0.01)
Hematologic normalization‡, n (%) Median duration of hematologic normalization, weeks (range)§	18 (90) 38 (22, 52)	18 (90) 114 (33, 125)

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. SOLIRIS 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 ×109/L at baseline to 233 ±109 ×109/L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 254 ± 79 ×109/L).

A total of 19 pediatric patients (ages 2 months to 17 years) received SOLIRIS in Study C09-001r. The median duration of SOLIRIS 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 17). No pediatric patient required new dialysis during treatment with SOLIRIS.

Table 17: Efficacy Results in Pediatric Patients Enrolled in Study C09-001r
Efficacy Parameter	<2 yrs (N=5)	2 to <12 yrs (N=10)	12 to <18 yrs (N=4)	Total (N=19)
* Of the 9 patients who experienced an eGFR improvement of at least 15 mL/min/1.73 m2, one received dialysis throughout the study period and another received SOLIRIS as prophylaxis following renal allograft transplantation. † Platelet count normalization was defined as a platelet count of at least 150,000 × 109/L on at least two consecutive measurements spanning a period of at least 4 weeks.
Complete TMA response, n (%)	2 (40)	5 (50)	1 (25)	8 (42)
Patients with eGFR improvement ≥ 15 mL/min/1.73 m2, n (%)*	2 (40)	6 (60)	1 (25)	9 (47)
Platelet count normalization, n (%)†	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)
Before eculizumab	1 (0, 2)	<1 (0.07, 1.46)	<1 (0, 1)	0.31 (0.00, 2.38)
On eculizumab treatment	<1 (0, <1)	0 (0, <1)	0 (0, <1)	0.00 (0.00, 0.08)

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 18 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-004.

Table 18: 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)	0.79 (0.03 – 311)
Time from current clinical TMA manifestation until first study dose in months, median (range)	0.52 (0.03-19)
Baseline platelet count (× 109/L), median (range)	125 (16 – 332)
Baseline LDH (U/L), median (range)	375 (131 – 3318)

Patients in Study C10-004 received SOLIRIS for a minimum of 26 weeks. In Study C10-004, the median duration of SOLIRIS therapy was approximately 50 weeks (range: 13 weeks to 86 weeks).

Renal function, as measured by eGFR, was improved during SOLIRIS therapy. The mean eGFR (± SD) increased from 17 ± 12 mL/min/1.73m2 at baseline to 47 ± 24 mL/min/1.73m2 by 26 weeks. Twenty of the 24 patients who required dialysis at study baseline were able to discontinue dialysis during SOLIRIS treatment.

Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of SOLIRIS. SOLIRIS reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In Study C10-004, mean platelet count (± SD) increased from 119 ± 66 ×109/L at baseline to 200 ± 84 ×109/L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 252 ± 70 ×109/L). In Study C10-004, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H.

Table 19 summarizes the efficacy results for Study C10-004.

Table 19: Efficacy Results for Study C10-004
Efficacy Parameter	Study C10-004 (N=41)
Complete TMA response, n (%),	23 (56)
95% CI	40,72
Median duration of complete TMA response, weeks (range)	42 (6, 75)
Patients with eGFR improvement ≥ 15 mL/min/1.73m2, n (%)	22 (54)
Hematologic Normalization, n (%)	36 (88)
Median duration of hematologic normalization, weeks (range)	46 (10, 75)
TMA Event-free Status, n (%)	37 (90)
Daily TMA Intervention Rate, median (range)
Before eculizumab	0.63 (0, 1.38)
On eculizumab treatment	0 (0, 0.58)

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 20 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in Study C10-003.

Table 20: 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)	0.51 (0.03 – 58)	0.56 (0.03-191)
Time from current clinical TMA manifestation until first study dose in months, median (range)	0.23 (0.03 – 4)	0.2 (0.03-4)
Baseline platelet count (× 109/L), median (range)	110 (19-146)	91 (19-146)
Baseline LDH (U/L) median (range)	1510 (282-7164)	1244 (282-7164)

Patients in Study C10-003 received SOLIRIS for a minimum of 26 weeks. In Study C10-003, the median duration of SOLIRIS therapy was approximately 44 weeks (range: 1 dose to 88 weeks).

Renal function, as measured by eGFR, was improved during SOLIRIS therapy. The mean eGFR (± SD) increased from 33 ± 30 mL/min/1.73m2 at baseline to 98 ± 44 mL/min/1.73m2 by 26 weeks. Among the 20 patients with a CKD stage ≥2 at baseline, 17 (85%) achieved a CKD improvement of ≥1 stage. Among the 16 patients ages 1 month to <12 years with a CKD stage ≥2 at baseline, 14 (88%) achieved a CKD improvement by ≥1 stage. Nine of the 11 patients who required dialysis at study baseline were able to discontinue dialysis during SOLIRIS treatment. Responses were observed across all ages from 5 months to 17 years of age.

Reduction in terminal complement activity was observed in all patients after commencement of SOLIRIS. SOLIRIS reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean platelet count (± SD) increased from 88 ± 42 ×109/L at baseline to 281 ± 123 ×109/L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 ×109/L). In Study C10-003, responses to SOLIRIS were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H.

Table 21 summarizes the efficacy results for Study C10-003.

Table 21: Efficacy Results for Study C10-003
Efficacy Parameter	Patients 1 month to <12 years (N=18)	All Patients (N=22)
* Through data cutoff (October 12, 2012).
Complete TMA response, n (%) 95% CI Median Duration of complete TMA response, weeks (range)*	11 (61) 36, 83 40 (14, 77)	14 (64) 41, 83 37 (14, 77)
eGFR improvement ≥15 mL/min/ 1.73∙m2∙n (%)	16 (89)	19 (86)
Complete Hematologic Normalization, n (%) Median Duration of complete hematologic normalization, weeks (range)	14 (78) 38 (14, 77)	18 (82) 38 (14, 77)
TMA Event-Free Status, n (%)	17 (94)	21 (95)
Daily TMA Intervention rate, median (range) Before eculizumab treatment On eculizumab treatment	0.2 (0, 1.7) 0 (0, 0.01)	0.4 (0, 1.7) 0 (0, 0.01)

14.3 Generalized Myasthenia Gravis (gMG)

The efficacy of SOLIRIS for the treatment of gMG was established in Study ECU-MG-301 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi-center trial that enrolled adult 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 SOLIRIS 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.

SOLIRIS was administered according to the recommended dosage regimen [see Dosage and Administration (2.4)].

The primary efficacy endpoint for Study ECU-MG-301 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) 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 4-point 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 SOLIRIS was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4.2 points in the SOLIRIS-treated group compared with -2.3 points in the placebo-treated group (p=0.006)].

A key secondary endpoint in Study ECU-MG-301 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 SOLIRIS was observed in the mean change from baseline to Week 26 in QMG total scores [-4.6 points in the SOLIRIS-treated group compared with -1.6 points in the placebo-treated group (p=0.001)].

The results of the analysis of the MG-ADL and QMG from Study ECU-MG-301 are shown in Table 22.

Table 22: Analysis of Change from Baseline to Week 26 in MG-ADL and QMG Total Scores in Study ECU-MG-301
Efficacy Endpoints	SOLIRIS-LS Mean (N=62) (SEM)	Placebo-LS Mean (N=63) (SEM)	SOLIRIS change relative to placebo – LS Mean Difference (95% CI)	p-values
SEM= Standard Error of the Mean; SOLIRIS-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
* in least square means at Week 26 using a repeated measure analysis; † in ranks at Week 26 using a worst rank analysis).
MG-ADL	-4.2 (0.49)	-2.3 (0.48)	-1.9 (-3.3, -0.6)	(0.006*; 0.014†)
QMG	-4.6 (0.60)	-1.6 (0.59)	-3.0 (-4.6, -1.3)	(0.001 *; 0.005 †)

In Study ECU-MG-301, 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 SOLIRIS 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 SOLIRIS compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of SOLIRIS treatment.

14.4 Neuromyelitis Optica Spectrum Disorder (NMOSD)

The efficacy of SOLIRIS for the treatment of NMOSD was established in NMOSD Study 1 (NCT01892345), a randomized, double-blind, placebo-controlled trial that enrolled 143 patients with NMOSD who were anti-AQP4 antibody positive and met the following criteria at screening:

History of at least 2 relapses in last 12 months or 3 relapses in the last 24 months, with at least 1 relapse in the 12 months prior to screening,
Expanded Disability Status Scale (EDSS) score ≤ 7 (consistent with the presence of at least limited ambulation with aid),
If on immunosuppressive therapy (IST), on a stable dose regimen,
The use of concurrent corticosteroids was limited to 20 mg per day or less,
Patients were excluded if they had been treated with rituximab or mitoxantrone within 3 months or with IVIg within 3 weeks prior to screening.

A total of 96 patients were randomized to receive SOLIRIS treatment and 47 were randomized to receive placebo.

The baseline demographic and disease characteristics were balanced between treatment groups. During the treatment phase of the trial, 76% percent of patients received concomitant IST, including chronic corticosteroids; 24% of patients did not receive concomitant IST or chronic corticosteroids during the treatment phase of the trial.

SOLIRIS was administered according to the recommended dosage regimen [see Dosage and Administration (2.4)].

The primary endpoint for NMOSD Study 1 was the time to the first adjudicated on-trial relapse. The time to the first adjudicated on-trial relapse was significantly longer in SOLIRIS-treated patients compared to placebo-treated patients (relative risk reduction 94%; hazard ratio 0.058; p < 0.0001) (Figure 1).

Figure 1: Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse – Full Analysis Set

Note: Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period. Abbreviations: CI = confidence interval

SOLIRIS-treated patients experienced similar improvement in time to first adjudicated on-trial relapse with or without concomitant treatment. SOLIRIS-treated patients had a 96% relative reduction in the adjudicated on-trial annualized relapse rate (ARR) compared to patients on placebo, as shown in Table 23.

Table 23: Adjudicated On-trial Annualized Relapse Rate – Full Analysis Set
Variable	Statistic	Placebo (N=47)	SOLIRIS (N=96)
ARR = annualized relapse rate
* Based on a Poisson regression adjusted for randomization strata and historical ARR in 24 months prior to screening.
Total number of relapses	Sum	21	3
Adjusted adjudicated ARR*	Rate	0.350	0.016
Treatment effect*	Rate ratio (eculizumab/placebo)	…	0.045
Treatment effect*	p-value	…	<0.0001

Compared to placebo-treated patients, SOLIRIS-treated patients had reduced annualized rates of hospitalizations (0.04 for SOLIRIS versus 0.31 for placebo), of corticosteroid administrations to treat acute relapses (0.07 for SOLIRIS versus 0.42 for placebo), and of plasma exchange treatments (0.02 for SOLIRIS versus 0.19 for placebo).