Ultomiris Dailymed

• See Full Prescribing Information for instructions on dosage, preparation, and administration. (2.1, 2.2, 2.3, 2.4, 2.5)
• Dilute ULTOMIRIS before use. (2.5)
• Only administer as an intravenous infusion through a 0.2 or 0.22 micron filter. (2.5)

2.1Important Dosage Information

ULTOMIRIS is intended to be administered only as an intravenous infusion in adult or pediatric patients one month of age and older.

2.2Recommended Vaccination and Prophylaxis for Meningococcal Infection

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 ULTOMIRIS [see Warnings and Precautions (5.1)].

If urgent ULTOMIRIS 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 ULTOMIRIS must enroll in the ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2)].

2.3Recommended Dosage for Intravenous Administration in Adult and Pediatric Patients with PNH or aHUS, and in Adult Patients with gMG or NMOSD

The recommended intravenous (IV) ULTOMIRIS loading and maintenance dosing in adult and pediatric patients, one month of age or older weighing 5 kg or greater, with PNH or aHUS, or in adult patients with gMG or NMOSD weighing 40 kg or greater, is based on the patient's body weight, as shown in Table 1, with maintenance doses administered every 4 or 8 weeks, starting 2 weeks after loading dose.

The IV dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but subsequent doses should be administered according to the original schedule.

Following a missed IV ULTOMIRIS dose, the patient should contact their health care provider immediately.

Table 1: IV Administration of ULTOMIRIS Weight-Based Dosing Regimen – PNH, aHUS, gMG, or NMOSDSee Table 4, Table 5, Table 7, and Table 8 for selection of the proper total volume and maximum infusion rate [see Dosage and Administration (2.5)]

Indications	Body Weight Range (kg)	Loading Dose (mg)See Table 2 for ULTOMIRIS treatment initiation instruction and timing of loading dose and maintenance dose	Maintenance Dose (mg) and Dosing Interval
PNH or aHUS	5 to less than 10	600	300	Every 4 weeks
	10 to less than 20	600	600
	20 to less than 30	900	2,100	Every 8 weeks
	30 to less than 40	1,200	2,700
PNH, aHUS, gMG, or NMOSD	40 to less than 60	2,400	3,000	Every 8 weeks
	60 to less than 100	2,700	3,300
	100 or greater	3,000	3,600

Refer to Table 2 for treatment initiation instructions in patients who are complement inhibitor treatment-naïve or switching treatment from eculizumab.

Table 2: IV Administration of ULTOMIRIS Treatment Initiation Instructions – PNH, aHUS, gMG, or NMOSD

Population	Weight-based ULTOMIRIS Loading Dose	Time of First ULTOMIRIS Weight-based Maintenance Dose
Not currently on ULTOMIRIS or eculizumab treatment	At treatment start	2 weeks after ULTOMIRIS loading dose
Currently treated with eculizumab	At time of next scheduled eculizumab dose	2 weeks after ULTOMIRIS loading dose

2.4Dosing Considerations

Supplemental Dose of ULTOMIRIS

Plasma exchange (PE), plasmapheresis (PP), and intravenous immunoglobulin (IVIg) have been shown to reduce ULTOMIRIS serum levels. A supplemental dose of ULTOMIRIS is required in the setting of PE, PP, or IVIg (Table 3).

Table 3: Supplemental Dose of ULTOMIRIS after PE, PP, or IVIgSee Table 6 and Table 9 for selection of the proper total volume and maximum infusion rate [see Dosage and Administration (2.5)]

Body Weight Range (kg)	Most Recent ULTOMIRIS Dose (mg)	Supplemental Dose (mg) following each PE or PP Intervention	Supplemental Dose (mg) following Completion of an IVIg Cycle
Abbreviations: IVIg = intravenous immunoglobulin; PE = plasma exchange; PP = plasmapheresis
40 to less than 60	2,400	1,200	600
	3,000	1,500
60 to less than 100	2,700	1,500	600
	3,300	1,800
100 or greater	3,000	1,500	600
	3,600	1,800
Timing of ULTOMIRIS Supplemental Dose		Within 4 hours following each PE or PP intervention	Within 4 hours following completion of an IVIg cycle

2.5Preparation and Administration

Preparation of ULTOMIRIS Vials for Intravenous Administration

Each vial of ULTOMIRIS is intended for single-dose only.

ULTOMIRIS vials are for intravenous administration by a healthcare provider and are intended for intravenous administration only.

Dilute before use.

Do not mix ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials) and 10 mg/mL (30 mL vial) concentrations together.

Use aseptic technique to prepare ULTOMIRIS as follows:

• 1.The number of vials to be diluted is determined based on the individual patient's weight and the prescribed dose [see Dosage and Administration (2.3)].
• 2.Prior to dilution, visually inspect the solution in the vials; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation.
• 3.Withdraw the calculated volume of ULTOMIRIS from the appropriate number of vials and dilute in an infusion bag using 0.9% Sodium Chloride Injection, USP to a final concentration of:
  • 50 mg/mL for the 3 mL and 11 mL vial sizes or
  • 5 mg/mL for the 30 mL vial size.

The product should be mixed gently. Do not shake. Protect from light. Do not freeze.

Refer to the following reference tables for IV preparation and minimum infusion duration:

•  
  • ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials): see Table 4 (loading doses), Table 5 (maintenance doses), and Table 6 (supplemental doses)
  • ULTOMIRIS 10 mg/mL (30 mL vial): see Table 7 (loading doses), Table 8 (maintenance doses), and Table 9 (supplemental doses)
• 4.Administer the prepared solution immediately following preparation.
• 5.If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2°C - 8°C (36°F - 46°F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within 6 hours if prepared with ULTOMIRIS 30 mL vials or within 4 hours if prepared with ULTOMIRIS 3 mL or 11 mL vials.

Intravenous Administration of ULTOMIRIS (Healthcare Providers)

Only administer as an intravenous infusion through a 0.2 or 0.22 micron filter.

Dilute ULTOMIRIS to a final concentration of:

•  
  • 50 mg/mL for the 3 mL and 11 mL vial sizes or
  • 5 mg/mL for the 30 mL vial size.

Prior to administration, allow the admixture to adjust to room temperature (18°C - 25°C, 64°F - 77°F). Do not heat the admixture 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.

After administration of ULTOMIRIS, flush the entire line with 0.9% Sodium Chloride Injection, USP.

Table 4: Loading Dose Reference Table for ULTOMIRIS 100 mg/mL (3 mL and 11 mL Vials)

Body Weight Range (kg)Body weight at time of treatment.	Loading Dose (mg)	ULTOMIRIS Volume (mL)	Volume of NaCl DiluentDilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL)	Total Volume (mL)	Minimum Infusion Time (hr)	Maximum Infusion Rate (mL/hr)
5 to less than 10For PNH and aHUS indications only.	600	6	6	12	1.4	9
10 to less than 20	600	6	6	12	0.8	15
20 to less than 30	900	9	9	18	0.6	30
30 to less than 40	1,200	12	12	24	0.5	48
40 to less than 60	2,400	24	24	48	0.8	60
60 to less than 100	2,700	27	27	54	0.6	90
100 or greater	3,000	30	30	60	0.4	150

Table 5: Maintenance Dose Reference Table for ULTOMIRIS 100 mg/mL (3 mL and 11 mL Vials)

Body Weight Range (kg)Body weight at time of treatment.	Maintenance Dose (mg)	ULTOMIRIS Volume (mL)	Volume of NaCl DiluentDilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL)	Total Volume (mL)	Minimum Infusion Time (hr)	Maximum Infusion Rate (mL/hr)
5 to less than 10For PNH and aHUS indications only.	300	3	3	6	0.8	8
10 to less than 20	600	6	6	12	0.8	15
20 to less than 30	2,100	21	21	42	1.3	33
30 to less than 40	2,700	27	27	54	1.1	50
40 to less than 60	3,000	30	30	60	0.9	67
60 to less than 100	3,300	33	33	66	0.7	95
100 or greater	3,600	36	36	72	0.5	144

Table 6: Supplemental Dose Reference Table for ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials)

Body Weight Range (kg)Body weight at time of treatment.	Supplemental Dose (mg)	ULTOMIRIS Volume (mL)	Volume of NaCl DiluentDilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL)	Total Volume (mL)	Minimum Infusion Time(hr)	Maximum Infusion Rate(mL/hr)
Note: Refer to Table 3 for selection of ravulizumab supplemental dose
40 to less than 60	600	6	6	12	0.25	48
	1,200	12	12	24	0.42	57
	1,500	15	15	30	0.5	60
60 to less than 100	600	6	6	12	0.20	60
	1,500	15	15	30	0.36	83
	1,800	18	18	36	0.42	86
100 or greater	600	6	6	12	0.17	71
	1,500	15	15	30	0.25	120
	1,800	18	18	36	0.28	129

Table 7: Loading Dose Reference Table for ULTOMIRIS 10 mg/mL (30 mL Vial)

Body Weight Range (kg)Body weight at time of treatment.	Loading Dose (mg)	ULTOMIRIS Volume (mL)	Volume of NaCl DiluentDilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL)	Total Volume (mL)	Minimum Infusion Time (hr)	Maximum Infusion Rate (mL/hr)
5 to less than 10For PNH and aHUS indications only.	600	60	60	120	3.8	32
10 to less than 20	600	60	60	120	1.9	64
20 to less than 30	900	90	90	180	1.5	120
30 to less than 40	1,200	120	120	240	1.3	185
40 to less than 60	2,400	240	240	480	1.9	253
60 to less than 100	2,700	270	270	540	1.7	318
100 or greater	3,000	300	300	600	1.8	334

Table 8: Maintenance Dose Reference Table for ULTOMIRIS 10 mg/mL (30 mL Vial)

Body Weight Range (kg)Body weight at time of treatment.	Maintenance Dose (mg)	ULTOMIRIS Volume (mL)	Volume of NaCl DiluentDilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL)	Total Volume (mL)	Minimum Infusion Time (hr)	Maximum Infusion Rate (mL/hr)
5 to less than 10For PNH and aHUS indications only.	300	30	30	60	1.9	32
10 to less than 20	600	60	60	120	1.9	64
20 to less than 30	2,100	210	210	420	3.3	128
30 to less than 40	2,700	270	270	540	2.8	193
40 to less than 60	3,000	300	300	600	2.3	261
60 to less than 100	3,300	330	330	660	2	330
100 or greater	3,600	360	360	720	2.2	328

Table 9: Supplemental Dose Reference Table for ULTOMIRIS 10 mg/mL (30 mL vial)

Body Weight Range (kg)Body weight at time of treatment.	Supplemental Dose (mg)	ULTOMIRIS Volume (mL)	Volume of NaCl DiluentDilute ULTOMIRIS only using 0.9% Sodium Chloride Injection, USP. (mL)	Total Volume (mL)	Minimum Infusion Time (hr)	Maximum Infusion Rate (mL/hr)
Note: Refer to Table 3 for selection of ravulizumab supplemental dose
40 to less than 60	600	60	60	120	0.5	240
	1,200	120	120	240	1	240
	1,500	150	150	300	1.2	250
60 to less than 100	600	60	60	120	0.4	300
	1,500	150	150	300	1	300
	1,800	180	180	360	1.1	327
100 or greater	600	60	60	120	0.4	300
	1,500	150	150	300	1	300
	1,800	180	180	360	1.1	327

If an adverse reaction occurs during the administration of ULTOMIRIS, the infusion may be slowed or stopped at the discretion of the physician. Monitor the patient for at least 1 hour following completion of the infusion for signs or symptoms of an infusion-related reaction.

14.1Paroxysmal Nocturnal Hemoglobinuria (PNH)

The safety and efficacy of ULTOMIRIS in adult patients with PNH was assessed in 2 open-label, randomized, active-controlled, non-inferiority Phase 3 studies: PNH Study 301 and PNH Study 302. Study 301 enrolled patients with PNH who were complement inhibitor naïve and had active hemolysis. Study 302 enrolled patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months. The safety and efficacy of ULTOMIRIS in pediatric patients with PNH was assessed in PNH Study 304, an open-label, Phase 3 study conducted in eculizumab-experienced and complement inhibitor treatment naïve pediatric patients with PNH.

In Study 301 and Study 302, adults with PNH were dosed with ULTOMIRIS administered intravenously in accordance with the weight-based dosing described in Section 2.3 (4 infusions of ULTOMIRIS over 26 weeks) above. Eculizumab was administered on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every 2 weeks (q2w) thereafter for a total of 26 weeks of treatment, according to the approved dosing regimen of eculizumab which was the standard-of-care for PNH at the time of the studies.

Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with ULTOMIRIS or eculizumab, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. Prophylactic treatment with appropriate antibiotics beyond 2 weeks after vaccination was at the discretion of the provider.

Study in Complement-Inhibitor Naïve Adult Patients with PNH

The Complement-Inhibitor Naïve Study [ALXN1210-PNH-301; NCT02946463] was a 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 246 patients naïve to complement inhibitor treatment prior to study entry.

Patients with PNH with flow cytometric confirmation of at least 5% PNH cells were randomized 1:1 to either intravenously administered ULTOMIRIS or eculizumab. The mean total PNH granulocyte clone size was 85%, the mean total PNH monocyte clone size was 88%, and the mean total PNH RBC clone size was 39%. Ninety-eight percent of patients had a documented PNH-associated condition diagnosed prior to enrollment on the trial: anemia (85%), hemoglobinuria (63%), history of aplastic anemia (32%), history of renal failure (12%), myelodysplastic syndrome (5%), pregnancy complications (3%), and other (16%). Major baseline characteristics were balanced between treatment groups. Table 22 provides the baseline characteristics for the patients enrolled in the complement-inhibitor naïve study.

Table 22: Baseline Characteristics in the Complement-Inhibitor Naïve Study

Parameter	Statistics	ULTOMIRIS (N=125)	Eculizumab(N=121)
Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; MAVE = major adverse vascular event; pRBC = packed red blood cell; SD = standard deviation
Age (years) at first infusion in study	Mean (SD)Min, max	44.8 (15.2)18, 83	46.2 (16.2)18, 86
Sex
  Male	n (%)	65 (52.0)	69 (57.0)
Race
  Asian	n (%)	72 (57.6)	57 (47.1)
  White		43 (34.4)	51 (42.1)
  Black or African American		2 (1.6)	4 (3.3)
  American Indian or Alaska Native		1 (0.8)	1 (0.8)
  Other		4 (3.2)	4 (3.3)
  Not reported		3 (2.4)	4 (3.3)
Pre-treatment LDH levels (U/L)	MedianMin, max	1513.5(378.0, 3759.5)	1445.0(423.5, 3139.5)
Units of pRBC/whole blood transfused within 12 months prior to first dose	MedianMin, max	6.0(1, 44)	6.0(1, 32)
Antithrombotic agents used within 28 days prior to first dose	n (%)	22 (17.6)	22 (18.2)
Patients with a history of MAVE	n (%)	17 (13.6)	25 (20.7)
Patients with a history of thrombosis	n (%)	17 (13.6)	20 (16.5)
Patients with concomitant anticoagulant treatment	n (%)	23 (18.4)	28 (23.1)

Efficacy was established based upon transfusion avoidance and hemolysis as directly measured by normalization of LDH levels. Transfusion avoidance was defined as patients who did not receive a transfusion and did not meet the protocol specified guidelines for transfusion from baseline up to Day 183. Supportive efficacy data included the percent change from baseline in LDH levels, the proportion of patients with breakthrough hemolysis defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥ 2 × ULN, after prior LDH reduction to < 1.5 × ULN on therapy and the proportion of patients with stabilized hemoglobin.

Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the complement-inhibitor naïve treatment population described in Table 23 below.

Table 23: Efficacy Results in the Complement-Inhibitor Naïve Study

	ULTOMIRIS (N=125)	Eculizumab(N=121)	Statistic for Comparison	Treatment Effect(95% CI)
For the transfusion avoidance endpoint, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI. For the lactate dehydrogenase normalization endpoint, the adjusted prevalence within each treatment is displayed. Abbreviations: LDH = lactate dehydrogenase; CI = confidence interval
Transfusion avoidance rate	73.6%	66.1%	Difference in rate	6.8(-4.66, 18.14)
LDH normalization	53.6%	49.4%	Odds ratio	1.19(0.80, 1.77)
LDH percent change	-76.84%	-76.02%	Difference in % change from baseline	-0.83(-5.21, 3.56)
Breakthrough hemolysis	4.0%	10.7%	Difference in rate	-6.7(-14.21, 0.18)
Hemoglobin stabilization	68.0%	64.5%	Difference in rate	2.9(-8.80, 14.64)

There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under- or over-estimation because patients were not blinded to treatment assignment.

Study in Eculizumab-Experienced Adult Patients with PNH

The study in eculizumab-experienced patients [ALXN1210-PNH-302; NCT03056040] was a 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 195 patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months.

Patients who demonstrated clinically stable disease after being treated with eculizumab for at least the prior 6 months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS administered intravenously. The mean total PNH granulocyte clone size was 83%, the mean total PNH monocyte clone size was 86%, and the mean total PNH RBC clone size was 60%. Ninety-five percent of patients had a documented PNH-associated condition diagnosed prior to enrollment in the trial: anemia (67%), hematuria or hemoglobinuria (49%), history of aplastic anemia (37%), history of renal failure (9%), myelodysplastic syndrome (5%), pregnancy complication (7%), and other (14%). Major baseline characteristics were balanced between the 2 treatment groups. Table 24 provides the baseline characteristics for the patients enrolled in the eculizumab-experienced study.

Table 24: Baseline Characteristics in Eculizumab-Experienced Adult Patients with PNH

Parameter	Statistics	ULTOMIRIS (N=97)	Eculizumab(N=98)
Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; MAVE = major adverse vascular event; pRBC = packed red blood cell; SD = standard deviation
Age (years) at first infusion in study	Mean (SD)Min, max	46.6 (14.41)18, 79	48.8 (13.97)23, 77
Race	n (%)
  White		50 (51.5)	61 (62.2)
  Asian		23 (23.7)	19 (19.4)
  Black or African American		5 (5.2)	3 (3.1)
  Other		2 (2.1)	1 (1.0)
  Not reported		13 (13.4)	13 (13.3)
  Unknown		3 (3.1)	1 (1.0)
  Multiple		1 (1.0)	0
Sex	n (%)
  Male		50 (51.5)	48 (49.0)
Pre-treatment LDH levels (U/L)	MedianMin, max	224.0135.0, 383.5	234.0100.0, 365.5
Units of pRBC/whole blood transfused within 12 months prior to first dose	MedianMin, max	4.0(1, 32)	2.5(2, 15)
Antithrombotic agents used within 28 days prior to first dose	n (%)	20 (20.6)	13 (13.3)
Patients with a history of MAVE	n (%)	28 (28.9)	22 (22.4)
Patients with a history of thrombosis	n (%)	27 (27.8)	21 (21.4)
Patients with concomitant anticoagulant treatment	n (%)	22 (22.7)	16 (16.3)

Efficacy was established based on hemolysis as measured by LDH percent change from baseline to Day 183 and supportive efficacy data was transfusion avoidance, proportion of patients with stabilized hemoglobin, and the proportion of patients with breakthrough hemolysis through Day 183.

Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the patients with PNH previously treated with eculizumab described in Table 25 below.

Table 25: Efficacy Results in the Eculizumab-Experienced Adult Patients with PNH Eculizumab-Experienced Study

	ULTOMIRIS N = 97	EculizumabN = 98	Statistic for Comparison	Treatment Effect(95% CI)
Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase
LDH percent change	-0.82%	8.4%	Difference in % change from baseline	9.2(-0.42, 18.8)
Breakthrough hemolysis	0%	5.1%	Difference in rate	5.1(-8.9, 19.0)
Transfusion avoidance	87.6 %	82.7%	Difference in rate	5.5(-4.3, 15.7)
Hemoglobin stabilization	76.3%	75.5%	Difference in rate	1.4(-10.4, 13.3)

There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under-or over-estimation because patients were not blinded to treatment assignment.

Study in Eculizumab-Experienced and Complement-Inhibitor Naïve Pediatric Patients with PNH

The pediatric study, ALXN1210-PNH-304 (NCT03406507), was a multi-center, open-label Phase 3 study conducted in eculizumab-experienced and complement inhibitor treatment-naïve pediatric patients with PNH. A total of 13 pediatric patients with PNH completed intravenously administered ULTOMIRIS treatment during the Primary Evaluation Period (26 weeks). Five of the 13 patients had never been treated with complement inhibitors and 8 patients were treated with eculizumab. Eleven of the thirteen patients were between 12 and 17 years of age at first infusion, with 2 patients under 12 years old (11 and 9 years old). Table 26 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-PNH-304.

Table 26: Baseline Characteristics for Pediatric Patients with PNH

Variable	Complement Inhibitor Treatment-naïve Patients(N = 5)	Eculizumab-Experienced Patients(N = 8)	All Patients(N = 13)
Note: Percentages were based on the total number of patients in each cohort, or overall.Abbreviations: LDH = lactate dehydrogenase; kg = kilogram; max = maximum; min = minimum; pRBC = packed red blood cells; SD = standard deviation
Sex, n (%)
  Male	4 (80.0)	1 (12.5)	5 (38.5)
  Female	1 (20.0)	7 (87.5)	8 (61.5)
Age at first infusion (years)
  Mean (SD)	14.4 (2.2)	14.4 (3.1)	14.4 (2.7)
  Median (min, max)	15.0 (11, 17)	15.0 (9, 17)	15.0 (9, 17)
Age at first infusion (years) category, n (%)
  < 12 years	1 (20.0)	1 (12.5)	2 (15.4)
  ≥ 12 years	4 (80.0)	7 (87.5)	11 (84.6)
Baseline weight (kg)
  Mean (SD)	56.3 (11.6)	56.3 (12.2)	56.3 (11.5)
  Median (min, max)	55.6 (39.5, 72.0)	55.5 (36.7, 69.0)	55.6 (36.7, 72.0)
Baseline weight (kg) category, n (%)
  ≥ 30 to < 40 kg	1 (20.0)	1 (12.5)	2 (15.4)
  ≥ 40 to < 60 kg	3 (60.0)	4 (50.0)	7 (53.8)
  ≥ 60 to < 100 kg	1 (20.0)	3 (37.5)	4 (30.8)
Units of pRBC/whole blood transfused within 12 months prior to first dose
  Median (min, max)	7.0 (3, 11)	2.0 (2, 2)	-
Pre-treatment LDH levels (U/L)
  Median (min, max)	588.5 (444, 2269.7)	251.5 (140.5, 487)	-

Based on body weight, patients received a loading dose of ULTOMIRIS on Day 1, followed by maintenance treatment on Day 15 and once every 8 weeks (q8w) thereafter for patients weighing ≥ 20 kg, or once every 4 weeks (q4w) for patients weighing < 20 kg. For patients who entered the study on eculizumab therapy, Day 1 of study treatment was planned to occur 2 weeks from the patient's last dose of eculizumab.

The weight-based dose regimen of ravulizumab-cwvz provided inhibition of terminal complement in all patients throughout the entire 26-week treatment period regardless of prior experience with eculizumab. Following initiation of ravulizumab-cwvz treatment, steady-state therapeutic serum concentrations of ravulizumab-cwvz were achieved after the first dose and maintained throughout the primary evaluation period in both cohorts. Three of 5 complement inhibitor treatment-naïve patients and 6 out of 8 eculizumab-experienced patients achieved hemoglobin stabilization by Week 26, respectively. Transfusion avoidance was reached for 11 out of 13 of patients during the 26-week Primary Evaluation Period. One patient experienced breakthrough hemolysis during the extension period. Table 27 presents secondary efficacy outcomes for the primary evaluation period.

Table 27: Efficacy Outcomes from the 26-Week Primary Evaluation Period of Pediatric Patient Study in PNH (ALXN1210-PNH-304)

Endpoint	Treatment Naïve(N = 5)	Eculizumab Experienced (N = 8)
Abbreviations: FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase
LDH percent change from baseline (%)95% CIs for the mean obtained from t-distribution were presented.	-47.9 (-113.4, 17.5)	4.7 (-36.7, 46.0)
Transfusion avoidance (%)95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.	60.0 (14.7, 94.7)	100.0 (63.1, 100.0)
Change in FACIT-Fatigue	3.4 (-4.2, 11.0)	1.3 (-3.1, 5.7)
Hemoglobin stabilization (%)	60.0 (14.7, 94.7)	75.0 (34.9, 96.8)
Breakthrough hemolysis (%)	0	0No patients experienced breakthrough hemolysis during the primary evaluation period. One patient experienced breakthrough hemolysis at 1.8 years during the extension period; however, at the time of the breakthrough hemolysis event the patient had adequate C5 inhibition (free C5 < 0.5 mcg/mL).

A clinically relevant improvement from baseline in fatigue as assessed by Pediatric FACIT-Fatigue (i.e., mean improvement of > 3 units for Pediatric FACIT Fatigue scores) was sustained throughout the primary evaluation period in the 5-complement inhibitor treatment naïve patients. A slight improvement was also observed in eculizumab-experienced patients. However, patient-reported fatigue may be an under- or over-estimation because patients were not blinded to treatment assignment.

The efficacy of ULTOMIRIS in pediatric patients with PNH is similar to that observed in adult patients with PNH enrolled in pivotal studies.

14.2Atypical Hemolytic Uremic Syndrome (aHUS)

The efficacy of ULTOMIRIS administered intravenously in patients with aHUS was assessed in 2 open-label, single-arm studies. Study ALXN1210-aHUS-311 enrolled adult patients who displayed signs of TMA. 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 or required dialysis.

Study ALXN1210-aHUS-312 enrolled pediatric patients who displayed signs of TMA. 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 level ≥ 97.5% percentile at screening or required dialysis. In both studies, enrollment criteria excluded patients presenting with TMA due to a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin C metabolism. Patients with confirmed diagnosis of STEC-HUS after enrollment were excluded from the efficacy evaluation.

Study in Adult Patients with aHUS

The adult study [ALXN1210-aHUS-311; NCT02949128] was conducted in patients who were naïve to complement inhibitor treatment prior to study entry. The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years. All patients received ULTOMIRIS administered intravenously according to their weight [see Dosage and Administration (2.3)].

A total of 56 patients with aHUS were evaluated for efficacy. Ninety-three percent of patients had extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 71.4% (n = 40) of patients had Stage 5 chronic kidney disease (CKD). Fourteen percent had a medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for > 3 days after childbirth (i.e., postpartum).

Table 28 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210-aHUS-311 that constituted the Full Analysis Set.

Table 28: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-311

Parameter	Statistics	ULTOMIRIS (N=56)
Note: Percentages are based on the total number of patients.Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum; SD = standard deviation
Age at time of first infusion (years)	Mean (SD)Min, max	42.2 (14.98)19.5, 76.6
Sex
  Female	n (%)	37 (66.1)
Race Patients can have multiple races selected.	n (%)
  White		29 (51.8)
  Asian		15 (26.8)
  Unknown		8 (14.3)
  Other		4 (7.1)
Platelets (109/L) blood[normal range 130 to 400 × 109/L]	nMedian (min,max)	5695.25 (18, 473)
Hemoglobin (g/L) blood[normal range 115 to 160 g/L (female), 130 to 175 g/L (male)]	nMedian (min,max)	5685.00 (60.5, 140)
LDH (U/L) serum[normal range 120 to 246 U/L]	nMedian (min,max)	56508.00 (229.5, 3249)
eGFR (mL/min/1.73 m2)[normal range ≥ 60 mL/min/1.73 m2]	n (%)Mean (SD)Median (min,max)	5515.86 (14.815)10.00 (4, 80)

The efficacy evaluation was based on Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet each Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.

Complete TMA Response was observed in 30 of the 56 patients (54%) during the 26-week Initial Evaluation Period as shown in Table 29.

Table 29: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-311)

	Total	Responder
		n	Proportion (95% CI)95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.
Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy
Complete TMA Response	56	30	0.54 (0.40, 0.67)
Components of Complete TMA Response
  Platelet count normalization	56	47	0.84 (0.72, 0.92)
  LDH normalization	56	43	0.77 (0.64, 0.87)
  ≥ 25% improvement in serum creatinine from baseline	56	33	0.59 (0.45, 0.72)
Hematologic normalization	56	41	0.73 (0.60, 0.84)

One additional patient had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period. Complete TMA Response was achieved at a median time of 86 days (range: 7 to 169 days). The median duration of Complete TMA Response was 7.97 months (range: 2.52 to 16.69 months). All responses were maintained through all available follow-up.

Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by estimated glomerular filtration rate (eGFR).

An increase in mean platelet count was observed after commencement of ULTOMIRIS treatment, increasing from 118.52 × 10⁹/L at baseline to 240.34 ×10⁹/L at Day 8 and remaining above 227 × 10⁹/L at all subsequent visits in the Initial Evaluation Period (26 weeks).

Renal function, as measured by eGFR, was improved or maintained during ULTOMIRIS therapy. The mean eGFR (+/- SD) increased from 15.86 (14.82) at baseline to 51.83 (39.16) by 26 weeks. In patients with Complete TMA Response, renal function continued to improve after the Complete TMA Response was achieved.

Seventeen of the 29 patients (59%) who required dialysis at study entry discontinued dialysis by the end of the available follow-up and 6 of 27 (22%) patients were off dialysis at baseline were on dialysis at last available follow-up.

Study in Pediatric Patients with aHUS

The Pediatric Study [ALXN1210-aHUS-312; NCT03131219] is a 26-week ongoing, multicenter, single-arm study conducted in 16 pediatric patients. All patients received ULTOMIRIS administered intravenously according to their weight [see Dosage and Administration (2.3)]

A total of 14 eculizumab-naïve patients with documented diagnosis of aHUS were enrolled and included in this interim analysis. The median age at the time of first infusion was 5.2 years (range 0.9, 17.3 years). The overall mean weight at Baseline was 19.8 kg; half of the patients were in the baseline weight category ≥ 10 to < 20 kg. The majority of patients (71%) had pretreatment extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 35.7% (n = 5) of patients had a CKD Stage 5. Seven percent had history of prior kidney transplant and 35.7% were on dialysis at study entry.

Table 30 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-aHUS-312.

Table 30: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-312

Parameter	Statistics	ULTOMIRIS (N = 14)
Note: Percentages are based on the total number of patients.Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum
Age at time of first infusion (years) category	n (%)
  Birth to < 2 years		2 (14.3)
  2 to < 6 years		7 (50.0)
  6 to < 12 years		4 (28.6)
  12 to < 18 years		1 (7.1)
Sex	n (%)
  Female		9 (64.3)
RacePatients can have multiple races selected.	n (%)
  White		7 (50.0)
  Asian		4 (28.6)
  Black or African American		2 (14.3)
  American Indian or Alaskan Native		1 (7.1)
  Unknown		1 (7.1)
Platelets (109/L) blood [normal range 229 to 533 × 109/L]	Median (min, max)	64.00 (14, 125)
Hemoglobin (g/L) blood [normal range 107 to 131 g/L]	Median (min, max)	74.25 (32, 106)
LDH (U/L) serum [normal range 165 to 395 U/L]	Median (min, max)	2077.00 (772, 4985)
eGFR (mL/min/1.73 m2) [normal range ≥ 60 mL/min/1.73 m2]	Mean (SD)Median (min, max)	28.4 (23.11)22.0 (10, 84)

Efficacy evaluation was based upon Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet all Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.

Complete TMA Response was observed in 10 of the 14 patients (71%) during the 26-week Initial Evaluation Period as shown in Table 31.

Table 31: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-312)

	Total	Responder
		n	Proportion (95% CI)95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.
Note: One patient withdrew from study after receiving 2 doses of ravulizumab-cwvz.Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy
Complete TMA Response	14	10	0.71 (0.42, 0.92)
Components of Complete TMA Response
  Platelet count normalization	14	13	0.93 (0.66, 0.99)
  LDH normalization	14	12	0.86 (0.57, 0.98)
  ≥ 25% improvement in serum creatinine from baseline	14	11	0.79 (0.49, 0.95)
Hematologic normalization	14	12	0.86 (0.57, 0.98)

Complete TMA Response during the Initial Evaluation Period was achieved at a median time of 30 days (range:15 to 88 days). The median duration of Complete TMA Response was 5.08 months (range: 3.08 to 5.54 months). All responses were maintained through all available follow-up.

Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by eGFR.

An increase in mean platelet count was observed after commencement of ULTOMIRIS treatment, increasing from 60.50 × 10⁹/L at baseline to 296.67 × 10⁹/L at Day 8 and remained above 296 × 10⁹/L at all subsequent visits in the Initial Evaluation Period (26 weeks). The mean eGFR (+/- SD) increased from 28.4 (23.11) at baseline to 108.0 (63.21) by 26 weeks.

Four of the 5 patients who required dialysis at study entry were able to discontinue dialysis after the first month in study and for the duration of ULTOMIRIS treatment. No patient started dialysis during the study.

14.3Generalized Myasthenia Gravis (gMG)

The efficacy of ULTOMIRIS for the treatment of gMG was demonstrated in a randomized, double-blind, placebo-controlled, multicenter study (ALXN1210-MG-306; NCT03920293). Patients were randomized 1:1 to either receive ULTOMIRIS (n=86) or placebo (n=89) for 26 weeks. ULTOMIRIS was administered intravenously according to the weight-based recommended dosage [see Dosage and Administration (2.3)].

Patients with gMG with a positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV, and Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score ≥ 6 were enrolled. Baseline and disease characteristics were similar between treatment groups (including age at first dose [mean of 58 years for ULTOMIRIS versus 53 years for placebo], gender [51% female for ULTOMIRIS versus 51% female for placebo], race as White, Asian, and Black or African American [78%, 17%, and 2% for ULTOMIRIS versus 69%, 18%, and 5% for placebo, respectively], and duration of MG since diagnosis [mean of 10 years, ranging from 0.5 to 39.5 years, for ULTOMIRIS versus mean of 10.0 years, ranging from 0.5 to 36.1 years, for placebo].

Over 80% of patients were receiving acetylcholinesterase inhibitors, 70% were receiving corticosteroids, and 68% were receiving non-steroidal immunosuppressants (ISTs) at study entry. Patients on concomitant medications to treat gMG were permitted to continue on therapy throughout the course of the study.

The primary efficacy endpoint was a comparison of the change from baseline between treatment groups in the 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 li 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. The total score ranges from 0 to 24, with the higher scores indicating more impairment.

The secondary endpoints, also assessed from baseline to Week 26, included the change in the Quantitative MG total score (QMG). The QMG is a 13-li categorical scale assessing muscle weakness. Each li is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total score ranges from 0 to 39, where higher scores indicate more severe impairment.

Other secondary endpoints included the proportion of patients with improvements of at least 5 and 3 points in the QMG and MG-ADL total scores, respectively.

Treatment with ULTOMIRIS demonstrated a statistically significant change in the MG-ADL and QMG total scores from baseline at Week 26 as compared to placebo (Table 32).

Table 32: Efficacy Results in Patients with gMG

Efficacy Endpoints: Change from Baseline at Week 26	Placebo(n = 89)LS Mean	ULTOMIRIS (n = 86)LS Mean	Treatment Effect(95% CI)	p-valuep-value calculated using mixed effect model for repeated measures
Abbreviations: CI = confidence interval, LS = least squares; MG-ADL = Myasthenia Gravis Activities of Daily Living profile; QMG = Quantitative Myasthenia Gravis score for disease severity
Primary Endpoint
MG-ADL	-1.4	-3.1	-1.6 (-2.6, -0.7)	< 0.001
Secondary Endpoint
QMG	-0.8	-2.8	-2.0 (-3.2, -0.8)	< 0.001

The proportion of QMG responders with at least a 5-point improvement at week 26 was greater for ULTOMIRIS (30.0%) compared to placebo (11.3%) p = 0.005. The proportion of MG-ADL responders with at least a 3-point improvement at week 26 was also greater for ULTOMIRIS (56.7%) compared to placebo (34.1%). The proportion of clinical responders 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) was consistently greater for ULTOMIRIS compared to placebo.

Figure 1: Change from Baseline in MG-ADL Total Score (A) and QMG Total Score (B) Through Week 26 of the Randomized Controlled Period of ALXN1210-MG-306 (Mean and 95% CI)

Note: *p<0.001 versus placebo

14.4Neuromyelitis Optica Spectrum Disorder (NMOSD)

The efficacy and safety of ULTOMIRIS in adult patients with anti-AQP4 antibody positive NMOSD was assessed in an open-label multicenter study, Study ALXN1210-NMO-307 (NCT04291262). Patients participating in Study ALXN1210-NMO-307 received ULTOMIRIS intravenously in the Primary Treatment Period that ended when the last enrolled patient completed (or discontinued prior to) 50 weeks on study, representing a median study duration of 73.5 weeks (minimum 13.7, maximum 117.7). Efficacy assessments were based on a comparison of patients in Study ALXN1210-NMO-307 with an external placebo control group from another study (Study ECU-NMO-301, NCT01892345) composed of a comparable population of adult patients with anti-AQP4 antibody positive NMOSD.

Study ALXN1210-NMO-307 enrolled 58 adult patients with NMOSD who had a positive serologic test for anti-AQP4 antibodies, at least 1 relapse in the last 12 months prior to the Screening Period, and an Expanded Disability Status Scale (EDSS) score ≤ 7. In the external placebo control group, eligibility criteria were similar except patients were required to have 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. Prior treatment with immunosuppressant therapies (ISTs) was not required for enrollment. However, patients on selected ISTs (i.e., corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, and tacrolimus) were permitted to continue on therapy, with a requirement for stable dosing until they reached Week 106 in the Study. Similar IST use was permitted in the external placebo control group.

ULTOMIRIS was administered intravenously according to the weight-based recommended dosage [see Dosage and Administration (2.3)].

The demographics were similar between the ULTOMIRIS treatment group from Study ALXN1210-NMO-307 and the placebo treatment group from Study ECU-NMO-301 (including age [median of 46.0 years for ULTOMIRIS versus 44.0 years for placebo] and sex [89.7% female for ULTOMIRIS versus 89.4% female for placebo]). The majority of patients were White or Asian. The median time from diagnosis to first dose was 0.9 years for ULTOMIRIS and 2.0 years for placebo. The median annualized relapse rate (ARR) in the last 24 months was 1.4 for ULTOMIRIS versus 1.9 for placebo, and the median number of historical relapses was 2 for ULTOMIRIS versus 4 for placebo. The median baseline EDSS score was 3.3 for ULTOMIRIS versus 4.0 for placebo. At baseline, 48% of patients in the ULTOMIRIS group received concomitant IST, including corticosteroids, versus 72% of subjects in the placebo group.

The primary endpoint of Study ALXN1210-NMO-307 was the time to first adjudicated on-trial relapse as determined by an independent adjudication committee. No adjudicated on-trial relapses were observed in ULTOMIRIS-treated patients during the Primary Treatment Period, representing a statistically significant difference between the ULTOMIRIS and placebo treatment arms in time to first adjudicated on-trial relapse (p < 0.0001). The hazard ratio (95% confidence interval [CI]) for ULTOMIRIS compared with placebo was 0.014 (0.000, 0.103), representing a 98.6% reduction in the risk of relapse (Figure 2). ULTOMIRIS-treated patients experienced similar improvement in time to first adjudicated on-trial relapse with or without concomitant treatment.

Figure 2: Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse in Study ALXN1210-NMO-307 and Comparative Placebo Arm of Study ECU-NMO-301

Note: The placebo group data were collected as part of Study ECU-NMO-301. Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period. If a patient in the placebo group was followed longer than any of the patients in the Ultomiris group, then that patient was censored at the longest Ultomiris follow-up time.