Ultomiris Drug Information

Generic name: RAVULIZUMAB

Complement Inhibitor [EPC]

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Uses of Ultomiris

Paroxysmal Nocturnal Hemoglobinuria ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH).

Atypical Hemolytic Uremic Syndrome ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Limitations of Use: ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

Generalized Myasthenia Gravis ULTOMIRIS is indicated for the treatment of adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive.

Neuromyelitis Optica Spectrum Disorder ULTOMIRIS is indicated for the treatment of adult patients with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody-positive.

Dosage & Administration of Ultomiris

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

Recommended 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. 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.

Recommended 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 NMOSD See Table 4 and Table 5 for selection of the proper total volume and maximum infusion rate Refer to Table 2 for treatment initiation instructions in patients who are complement inhibitor treatment-naïve or switching treatment from eculizumab.

Dosing 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 IVIg See Table 6 for selection of the proper total volume and maximum infusion rate

Preparation 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.

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. 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. The product should be mixed gently.

Do not shake. Protect from light. Do not freeze.

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 4 hours.

Intravenous Administration of ULTOMIRIS (Healthcare Providers) Only administer as an intravenous infusion through a 0.2 or 0.22 micron filter. 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 Table 5: Maintenance Dose Reference Table for ULTOMIRIS Table 6: Supplemental Dose Reference Table for ULTOMIRIS 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.

Table 1: IV Administration of ULTOMIRIS Weight-Based Dosing Regimen – PNH, aHUS, gMG, or NMOSD See Table 4 and Table 5 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	Every 4 weeks
	20 to less than 30	900	2,100	Every 8 weeks
	30 to less than 40	1,200	2,700	Every 8 weeks
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

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

Table 3: Supplemental Dose of ULTOMIRIS after PE, PP, or IVIg See Table 6 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
40 to less than 60	3,000	1,500	600
60 to less than 100	2,700	1,500	600
60 to less than 100	3,300	1,800	600
100 or greater	3,000	1,500	600
100 or greater	3,600	1,800	600
Timing of ULTOMIRIS Supplemental Dose		Within 4 hours following each PE or PP intervention	Within 4 hours following completion of an IVIg cycle

Table 4: Loading Dose Reference Table for ULTOMIRIS
Body Weight Range (kg) Body weight at time of treatment.	Loading Dose (mg)	ULTOMIRIS Volume (mL)	Volume of NaCl Diluent Dilute 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 10 For 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
Body Weight Range (kg) Body weight at time of treatment.	Maintenance Dose (mg)	ULTOMIRIS Volume (mL)	Volume of NaCl Diluent Dilute 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 10 For 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
Body Weight Range (kg) Body weight at time of treatment.	Supplemental Dose (mg)	ULTOMIRIS Volume (mL)	Volume of NaCl Diluent Dilute 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

Side Effects of Ultomiris

Clinical Trial Experience

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. Paroxysmal Nocturnal Hemoglobinuria (PNH) Adult Population with PNH Treated with ULTOMIRIS The data described below reflect exposure of 441 adult patients with PNH in Phase 3 studies who received ULTOMIRIS (n = 222) or eculizumab (n = 219) at the recommended dosing regimens with median treatment duration of 6 months for ULTOMIRIS and 6 months for eculizumab. The most frequent adverse reactions (≥ 10%) with ULTOMIRIS were upper respiratory tract infection and headache.

Table 7 describes adverse reactions that occurred at a rate of 5% or more among patients treated with ULTOMIRIS in PNH studies. Serious adverse reactions were reported in 15 (6.8%) patients with PNH receiving ULTOMIRIS. The serious adverse reactions in patients treated with ULTOMIRIS included hyperthermia and pyrexia.

No serious adverse reaction was reported in more than 1 patient treated with ULTOMIRIS. One fatal case of sepsis was identified in a patient treated with ULTOMIRIS. Pediatric Population with PNH Treated with ULTOMIRIS In pediatric patients with PNH (aged 9 to 17 years old) included in the pediatric PNH Phase 3 study, the safety profile appeared similar to that observed in adult patients with PNH and in pediatric and adult patients with aHUS.

The most common adverse reactions (> 20%) were upper respiratory tract infection, anemia, abdominal pain, and headache. Table 8 describes the adverse reactions that occurred at a rate of 10% or more among pediatric patients treated with ULTOMIRIS in Study ALXN1210-PNH-304. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS.

The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia, and abdominal pain. Four patients died during the ALXN1210-aHUS-311 study. The cause of death was sepsis in 2 patients and intracranial hemorrhage in 1 patient.

The fourth patient, who was excluded from the trial after a diagnosis of STEC-HUS, died due to pretreatment cerebral arterial thrombosis. Table 11: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients from Birth to 16 Years of Age with aHUS in Study Clinically relevant adverse reactions in < 10% of patients include viral infection. Table 12 describes adverse reactions that occurred at a rate of 5% or more and at greater frequency than placebo.

Table 12: Adverse Reactions Reported in ≥ 5% and at Greater Frequency than Placebo in ULTOMIRIS-Treated Adult Patients with gMG in Study ALXN1210-MG-306 8 3 Neuromyelitis Optica Spectrum Disorder (NMOSD) The safety of ULTOMIRIS has been evaluated in 58 adult patients with NMOSD who received at least one dose of ULTOMIRIS. In Study ALXN1210-NMO-307, an open-label multicenter trial, the most frequent adverse reactions (≥10%) with ULTOMIRIS were COVID-19, headache, back pain, urinary tract infection and arthralgia. Serious adverse reactions were reported in 8 (13.8%) patients with NMOSD receiving ULTOMIRIS.

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 ULTOMIRIS exposure. Adverse Reactions from Postmarketing Spontaneous Reports Anaphylaxis 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 another C5 complement inhibitor. These events occurred within 3 to 27 days after starting treatment.

The median time to resolution (or return to baseline) was approximately 3 weeks.

Table 7: Adverse Reactions Reported in 5% or More of ULTOMIRIS-Treated Patients in Complement Inhibitor-Naïve and Eculizumab-Experienced Adult Patients with PNH
Body System Adverse Reaction	Number of Patients
Body System Adverse Reaction	ULTOMIRIS (N=222) n (%)	Eculizumab (N=219) n (%)
Gastrointestinal disorders
Diarrhea	19 (9)	12 (5)
Nausea	19 (9)	19 (9)
Abdominal pain	13 (6)	16 (7)
General disorders and administration site conditions
Pyrexia	15 (7)	18 (8)
Infections and infestations
Upper respiratory tract infection Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, viral upper respiratory tract infection, rhinitis, respiratory tract infection, rhinorrhea, pharyngitis, and upper respiratory tract inflammation	86 (39)	86 (39)
Musculoskeletal and connective tissue disorders
Pain in extremity	14 (6)	11 (5)
Arthralgia	11 (5)	12 (5)
Nervous system disorders
Headache	71 (32)	57 (26)
Dizziness	12 (5)	14 (6)

Table 9: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-311
Body System Adverse Reaction	ALXN1210-aHUS-311 (N=58)
Body System Adverse Reaction	All Grades Graded per CTCAE v5.0. (n=53) n (%)	≥ Grade 3 (n=14) n (%)
Blood and lymphatic system disorders
Anemia	8 (14)	0 (0)
Gastrointestinal disorders
Diarrhea	18 (31)	2 (3)
Nausea	15 (26)	2 (3)
Vomiting	15 (26)	2 (3)
Constipation	8 (14)	1 (2)
Abdominal pain	7 (12)	1 (2)
General disorders and administration site conditions
Pyrexia	11 (19)	1 (2)
Edema peripheral	10 (17)	0 (0)
Fatigue	8 (14)	0 (0)
Infections and infestations
Upper respiratory tract infection Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain.	15 (26)	0 (0)
Urinary tract infection	10 (17)	5 (9)
Gastrointestinal infection Grouped term includes gastroenteritis, gastrointestinal infection, enterocolitis infectious, infectious colitis, and enterocolitis.	8 (14)	2 (3)
Metabolism and nutrition disorders
Hypokalemia	6 (10)	1 (2)
Musculoskeletal and connective tissue disorders
Arthralgia	13 (22)	0 (0)
Back pain	7 (12)	1 (2)
Muscle spasms	6 (10)	0 (0)
Pain in extremity	6 (10)	0 (0)
Nervous system disorders
Headache	23 (40)	1 (2)
Psychiatric disorders
Anxiety	8 (14)	1 (2)
Respiratory, thoracic and mediastinal disorders
Cough	10 (17)	0 (0)
Dyspnea	10 (17)	1 (2)
Skin and subcutaneous tissue disorders
Alopecia	6 (10)	0 (0)
Dry skin	6 (10)	0 (0)
Vascular disorders
Hypertension	14 (24)	7 (12)

Table 10: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-312
Body System Adverse Reaction	ALXN1210-aHUS-312 (N=16)
Body System Adverse Reaction	All Grades Graded per CTCAE v5.0. (n=16) n (%)	≥ Grade 3 (n=6) n (%)
Blood and lymphatic system disorders
Anemia	2 (13)	1 (6)
Lymphadenopathy	2 (13)	0 (0)
Gastrointestinal disorders
Diarrhea	6 (38)	0 (0)
Constipation	4 (25)	0 (0)
Vomiting	4 (25)	1 (6)
Abdominal pain	3 (19)	0 (0)
Nausea	2 (13)	0 (0)
General disorders and administration site conditions
Pyrexia	8 (50)	0 (0)
Infections and infestations
Upper respiratory tract infection Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain.	7 (44)	1 (6)
Gastroenteritis viral	2 (13)	2 (13)
Pneumonia	2 (13)	1 (6)
Tonsillitis	2 (13)	0 (0)
Injury, poisoning and procedural complications
Contusion	3 (19)	0 (0)
Investigations
Vitamin D decreased	3 (19)	0 (0)
Metabolism and nutrition disorders
Decreased appetite	2 (13)	0 (0)
Iron deficiency	2 (13)	0 (0)
Musculoskeletal and connective tissue disorders
Myalgia	3 (19)	0 (0)
Pain in extremity	2 (13)	0 (0)
Nervous system disorders
Headache	5 (31)	0 (0)
Respiratory, thoracic and mediastinal disorders
Cough	3 (19)	0 (0)
Dyspnea	2 (13)	0 (0)
Skin and subcutaneous tissue disorders
Rash	3 (19)	0 (0)
Vascular disorders
Hypertension	4 (25)	1 (6)
Hypotension	2 (13)	0 (0)

Table 11: Adverse Reactions Reported in ≥ 10% of ULTOMIRIS-Treated Patients from Birth to 16 Years of Age with aHUS in Study ALXN1210-aHUS-312
Body System Adverse Reaction	ALXN1210-aHUS-312
	Age 0 to < 2 (N=2)	Age 2 to < 12 (N=12)	Age 12 to 16 (N=1)	Total (N=15)
	n (%)	n (%)	n (%)	n (%)
Blood and lymphatic system disorders
Lymphadenopathy	0 (0)	2 (17)	0 (0)	2 (13)
Gastrointestinal disorders
Diarrhea	1 (50)	3 (25)	1 (100)	5 (33)
Constipation	0 (0)	4 (33)	0 (0)	4 (27)
Vomiting	0 (0)	3 (25)	0 (0)	3 (20)
Abdominal pain	0 (0)	2 (17)	0 (0)	2 (13)
General disorders and administration site conditions
Pyrexia	1 (50)	5 (42)	1 (100)	7 (47)
Infections and infestations
Upper respiratory tract infection Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain	1 (50)	6 (50)	0 (0)	7 (47)
Gastroenteritis viral	0 (0)	2 (17)	0 (0)	2 (13)
Tonsillitis	1 (50)	1 (8)	0 (0)	2 (13)
Injury, poisoning and procedural complications
Contusion	0 (0)	2 (17)	0 (0)	2 (13)
Investigations
Vitamin D decreased	0 (0)	2 (17)	1 (100)	3 (20)
Metabolism and nutrition disorders
Decreased appetite	1 (50)	1 (8)	0 (0)	2 (13)
Iron deficiency	0 (0)	2 (17)	0 (0)	2 (13)
Musculoskeletal and connective tissue disorders
Myalgia	1 (50)	1 (8)	0 (0)	2 (13)
Pain in extremity	0 (0)	2 (17)	0 (0)	2 (13)
Nervous system disorders
Headache	0 (0)	4 (33)	0 (0)	4 (27)
Respiratory, thoracic and mediastinal disorders
Cough	0 (0)	3 (25)	0 (0)	3 (20)
Dyspnea	1 (50)	1 (8)	0 (0)	2 (13)
Skin and subcutaneous tissue disorders
Rash	1 (50)	2 (17)	0 (0)	3 (20)
Vascular disorders
Hypertension	1 (50)	3 (25)	0 (0)	4 (27)
Hypotension	0 (0)	2 (17)	0 (0)	2 (13)

Table 12: Adverse Reactions Reported in ≥ 5% and at Greater Frequency than Placebo in ULTOMIRIS-Treated Adult Patients with gMG in Study ALXN1210-MG-306
Body System Adverse Reaction	Number of Patients
Body System Adverse Reaction	ULTOMIRIS (N=86) n (%)	Placebo (N=89) n (%)
Gastrointestinal Disorders
Diarrhea	13 (15)	11 (12)
Abdominal pain	5 (6)	0
Infections and Infestations
Upper respiratory tract infection	12 (14)	7 (8)
Urinary tract infection	5 (6)	4 (4)
Musculoskeletal and Connective Tissue Disorders
Back Pain	7 (8)	5 (6)
Nervous System Disorders
Dizziness	8 (9)	3 (3)

Table 13: Adverse Reactions Reported in ≥ 5% in ULTOMIRIS-Treated Adult Patients with NMOSD in Study ALXN1210-NMO-307
Body System Adverse Reaction	ULTOMIRIS (N=58) n (%)
Blood and Lymphatic System Disorder
Lymphadenopathy	3 (5)
Gastrointestinal Disorders
Constipation	4 (7)
Vomiting	4 (7)
Diarrhea	3 (5)
Gastroesophageal reflux disease	3 (5)
General Disorders and Administration Site Reactions
Pyrexia	5 (9)
Chills	3 (5)
Fatigue	3 (5)
Malaise	3 (5)
Non-cardiac chest pain	3 (5)
Vaccination site pain	3 (5)
Infections and Infestations
COVID-19	14 (24)
Urinary tract infection	6 (10)
Cystitis	5 (9)
Upper respiratory tract infection	5 (9)
Nasopharyngitis	3 (5)
Sinusitis	3 (5)
Injury, Poisoning and Procedural Complications
Infusion related reaction	4 (7)
Musculoskeletal and Connective Tissue Disorders
Back pain	7 (12)
Arthralgia	6 (10)
Myalgia	3 (5)
Nervous System Disorders
Headache	14 (24)
Dizziness	4 (7)
Migraine	3 (5)
Respiratory, thoracic and mediastinal disorders
Cough	3 (5)

Warnings & Cautions for Ultomiris

Serious Meningococcal Infections ULTOMIRIS, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of ULTOMIRIS treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection.

Complete or update meningococcal vaccination (for serogroups A, C, W, Y and B) at least 2 weeks prior to administration of the first dose of ULTOMIRIS, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of ULTOMIRIS therapy. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information.

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 meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including ULTOMIRIS. The benefits and risks of treatment with ULTOMIRIS, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis.

Vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur.

Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated.

ULTOMIRIS is available only through a restricted program under a REMS.

Notable requirements of the ULTOMIRIS and SOLIRIS REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials.

Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of ULTOMIRIS. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of ULTOMIRIS. Healthcare settings and pharmacies that dispense ULTOMIRIS must be certified in the REMS and must verify prescribers are certified.

Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 8 months following treatment with ULTOMIRIS. Further information is available at www.UltSolREMS.com or 1-888-765-4747.

Other Infections

Serious infections with Neisseria species (other than Neisseria meningitidis ), including disseminated gonococcal infections, have been reported. ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).

Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving ULTOMIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.

Monitoring Disease

Manifestations after ULTOMIRIS Discontinuation Treatment Discontinuation for PNH After discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated lactate dehydrogenase (LDH) along with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions. If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS.

Treatment Discontinuation for aHUS ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized. There are no specific data on ULTOMIRIS discontinuation.

After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months. TMA complications post-discontinuation can be identified if any of the following is observed: Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure. In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment; an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment.

If TMA complications occur after ULTOMIRIS discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Thromboembolic Event Management

The effect of withdrawal of anticoagulant therapy during ULTOMIRIS treatment has not been established. Therefore, treatment with ULTOMIRIS should not alter anticoagulant management.

Infusion-Related Reactions Administration of ULTOMIRIS may result in systemic infusion-related reactions, including anaphylaxis and hypersensitivity reactions. In clinical trials, infusion-related reactions occurred in approximately 1 to 7% of patients treated with ULTOMIRIS. These events included lower back pain, abdominal pain, muscle spasms, drop in blood pressure, elevation in blood pressure, rigors, limb discomfort, drug hypersensitivity (allergic reaction), and dysgeusia (bad taste).

These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS infusion and institute appropriate supportive measures.

Drug Interactions with Ultomiris

Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins Concomitant use of ULTOMIRIS with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and requires a supplemental dose of ULTOMIRIS.

Neonatal Fc Receptor Blockers

Concomitant use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers (e.g., efgartigimod) may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely monitor for reduced effectiveness of ULTOMIRIS.

Pregnancy Safety for Ultomiris

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ULTOMIRIS during pregnancy. Healthcare providers and patients may call 1-833-793-0563 or go to www.UltomirisPregnancyStudy.com to enroll in or to obtain information about the registry. Risk Summary There are no available data on ULTOMIRIS use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There are risks to the mother and fetus associated with untreated PNH and aHUS in pregnancy (see Clinical Considerations ). Animal studies using a mouse analogue of the ravulizumab-cwvz molecule (murine anti-mouse complement component 5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 0.8-2.2 times the human dose (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. In the U.S. general population, the estimated background risk of major birth defects 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.

In pregnancy, aHUS is associated with adverse maternal outcomes, including preeclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 1-2.2 times (loading dose) and 0.8-1.8 times (maintenance dose) the recommended human ULTOMIRIS 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, 2 cases of retinal dysplasia and 1 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.

Human IgG are known to cross the human placental barrier, and thus ULTOMIRIS may potentially cause terminal complement inhibition in fetal circulation.

Pediatric Use of Ultomiris

Pediatric Use The safety and effectiveness of ULTOMIRIS for the treatment of PNH have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, efficacy and safety data in pediatric patients aged 9 to 17 years. The safety and efficacy for the treatment of pediatric and adult patients with PNH appear similar.

Use of ULTOMIRIS in pediatric patients with PNH aged less than 9 years and body weight < 30 kg is based on extrapolation of pharmacokinetic / pharmacodynamic (PK/PD), and efficacy and safety data from aHUS and PNH clinical studies. The safety and efficacy of ULTOMIRIS for the treatment of aHUS appear similar in pediatric and adult patients. The safety and effectiveness of ULTOMIRIS for the treatment of gMG or NMOSD in pediatric patients have not been established.

Contraindications for Ultomiris

ULTOMIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection.

Clinical Studies of Ultomiris

Atypical 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 × 10 9 /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 × 10 9 /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 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. 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 25 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210-aHUS-311 that constituted the Full Analysis Set. Table 25: Demographics and Baseline Characteristics in Study ALXN.00 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.

Table 26: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period ALXN 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). Renal function, as measured by eGFR, was improved or maintained during Ultomiris therapy.

The mean eGFR (+/- SD) increased from 15.86 at baseline to 51.83 by 26 weeks. In patients with Complete TMA Response, renal function continued to improve after the Complete TMA Response was achieved. Study in Pediatric Patients with aHUS The Pediatric Study is a 26-week ongoing, multicenter, single-arm study conducted in 16 pediatric patients.

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 27 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-aHUS-312. Table 28: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period ALXN 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).

The mean eGFR (+/- SD) increased from 28.4 at baseline to 108.0 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.

Generalized 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.

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, gender, race as White, Asian, and Black or African American, and duration of MG since diagnosis. 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 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. 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-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. 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 29). 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 (≥ or 8-point improvement on MG-ADL, and ≥ 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 Figure 1

Neuromyelitis 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. 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. 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 and sex ). 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 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). 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.

Figure 2

Table 19: 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)	Median Min, 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	Median Min, 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)

Table 20: 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)

Table 21: 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	n (%)	50 (51.5)	48 (49.0)
Pre-treatment LDH levels (U/L)	Median Min, max	224.0 135.0, 383.5	234.0 100.0, 365.5
Units of pRBC/whole blood transfused within 12 months prior to first dose	Median Min, 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)

Table 22: Efficacy Results in the Eculizumab-Experienced Adult Patients with PNH Eculizumab-Experienced Study
	Ultomiris N = 97	Eculizumab N = 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)

Table 23: 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)	-

Table 24: 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	0 No 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).

Table 25: 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 (10 9 /L) blood [normal range 130 to 400 × 10 9 /L]	n Median (min,max)	56 95.25 (18, 473)
Hemoglobin (g/L) blood [normal range 115 to 160 g/L (female), 130 to 175 g/L (male)]	n Median (min,max)	56 85.00 (60.5, 140)
LDH (U/L) serum [normal range 120 to 246 U/L]	n Median (min,max)	56 508.00 (229.5, 3249)
eGFR (mL/min/1.73 m 2 ) [normal range ≥ 60 mL/min/1.73 m 2 ]	n (%) Mean (SD) Median (min,max)	55 15.86 (14.815) 10.00 (4, 80)

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

Table 27: 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)
Race Patients 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 (10 9 /L) blood [normal range 229 to 533 × 10 9 /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 m 2 ) [normal range ≥ 60 mL/min/1.73 m 2 ]	Mean (SD) Median (min, max)	28.4 (23.11) 22.0 (10, 84)

Table 28: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-312)
	Total	Responder
	Total	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)

Table 29: 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-value p-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

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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