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ULTOMIRIS pediatric efficacy and safety

ULTOMIRIS, the first and only long-acting complement inhibitor for atypical-HUS, provided immediate, complete, and sustained complement inhibition in adult and pediatric patients 1 month and older.1

For treatment of atypical-HUS in adult and pediatric patients 1 month of age and older. Not indicated in STEC‑HUS.1

Immediate complement inhibition

ULTOMIRIS provided immediate, complete, and sustained complement inhibition1-3

A total of 14 pediatric patients with atypical-HUS who were eculizumab naïve were evaluated for efficacy. The study consisted of a 26-week initial evaluation period, followed by an extension period up to 4.5 years, with an interim analysis at 50 weeks.

Immediate

100% demonstrated
C5 inhibition

14 of 14 pediatric patients in a 26-week study demonstrated complete C5 inhibition after the first infusion of ULTOMIRISa

Complete

71% achieved complete
TMA response

10 of 14 pediatric patients (Cl: 42%-92%) met the composite endpoints of complete TMA responseb with ULTOMIRIS by 26 weeks, which was maintained through 50 weeks

Sustained

C5 inhibition was sustained
for 4 or 8 weeks, with
the possibility to live
dialysis-free

aAs measured by free C5 serum concentration of <0.5 mcg/mL.1

bComplete TMA response was defined as normalization of hematological parameters (platelet count and LDH) and ≥25% improvement in serum creatinine from baseline during the 26-week initial evaluation period. Patients had to meet all criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart and any measurement in between.1

CI=confidence interval, defined as 95%; LDH=lactate dehydrogenase; TMA=thrombotic microangiopathy.

Complete TMA response

Nearly 3 out of 4 pediatric patients (n=10/14) taking ULTOMIRIS achieved complete TMA response, which was maintained by all patients at Week 501,3,c


Complete TMA response

Children

26 weeks
71%
n=10/14
(95% Cl: 42%-92%)
50 weeks
94%
n=17/18

cComplete TMA response was defined as normalization of hematological parameters (platelet count and LDH) and ≥25% improvement in serum creatinine from baseline during the 26-week initial evaluation period. Patients had to meet all criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart and any measurement in between.1 Patients that did not have a response were censored at the date of last visit or study discontinuation at the time when the analysis was performed.2

BL=baseline; LDH=lactate dehydrogenase; TMA=thrombotic microangiopathy.


Components of complete TMA response1,3,d


Platelet count normalization

Children

week 26
93%
n=13/14
(95% Cl: 66%-99%)
week 50
94%
n=17/18

LDH normalization

Children

week 26
86%
n=12/14
(95% Cl: 57%-98%)
week 50
94%
n=17/18

≥25% Improvement in serum creatinine from baseline

Children

week 26
79%
n=11/14
(95% Cl: 49%-95%)
week 50
94%
n=17/18

Hematologic normalization

Children

week 26
86%
n=12/14
(95% Cl: 57%-98%)
week 50
94%
n=17/18

dComplete TMA response during the 26-week initial evaluation period was summarized by number and proportion of complete TMA responders (with 2-sided 95% confidence interval). Statistical analysis was not performed on 50-week data.

CI=confidence interval, defined as 95%; LDH=lactate dehydrogenase; TMA=thrombotic microangiopathy.


99.6% of all free C5 serum samples in pediatric patients showed complete inhibition of C5 throughout the 6-month study period with ULTOMIRIS2,e

eAs measured by free C5 serum concentration of <0.5 mcg/mL.1

Changes in CKD stage

ULTOMIRIS offers 4 or 8 weeks of sustained C5 inhibition and an opportunity to discontinue dialysis in pediatric patients1,3

Patients with chronic kidney disease (CKD) Stage 5 cannot worsen and may not be able to improve2

CKD stage shift from baseline to end of initial evaluation period (full analysis set)2,f
Post-baseline CKD stage at Day 183 (N=13)g
Baseline CKD
stage
1
n (%)
2
n (%)
3A
n (%)
3B
n (%)
4
n (%)
5
n (%)
1 (n=0)
0
0
0
0
0
0
2 (n=2)
1 (7.7)
0
0
0
0
0
3A (n=1)
1 (7.7)
0
0
0
0
0
3B (n=0)
0
0
0
0
0
0
4 (n=6)
3 (23.1)
1 (7.7)
1 (7.7)
0
1 (7.7)
0
5 (n=5)
3 (23.1)
1 (7.7)
0
0
0
1 (7.7)
Total (n=14)
8 (61.5)
2 (15.4)
1 (7.7)
0
1 (7.7)
1 (7.7)
Swipe to view full table ↔

fGreen shading indicates improvement vs baseline; orange shading indicates worsening vs baseline. CKD stage classified based on the National Kidney Foundation CKD Stage (eGFR values were: Stage 1: ≥90; Stage 2: 60 to 89; Stage 3A: 45 to 59; Stage 3B: 30 to 44; Stage 4: 15 to 29; Stage 5: <15 [including dialysis]). The baseline was derived based on last available eGFR before starting treatment. Patients with both baseline and at least 1 value at post-baseline visits were included in the summary. Percentages based on number of patients with non-missing data at both baseline and post-baseline visit.

gThe percentages for the post-baseline CKD stage at Day 183 are based on 13 patients with available data.

CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate.

Discontinuing dialysis may be possible

80% of pediatric patients (n=4/5) who required dialysis at study entry discontinued dialysis after the first month in the study.1

No patient started dialysis during the study1

100% of pediatric patients (n=6/6) discontinued dialysis
by Week 50.3

Study design

ULTOMIRIS was evaluated in a 26-week study in pediatric patients with atypical-HUS, followed by an ongoing 4.5-year extension study1,3

Pivotal study and extension study1,3



hULTOMIRIS weight-based dosing regimen.

Select inclusion criteria:

  • Platelet count ≤150 x 109 cells/L
  • Evidence of hemolysis (eg, elevated serum LDH, serum creatinine ≥97.5%, or required dialysis)

Select exclusion criteria:

  • Patients with TMA due to ADAMTS13 deficiency, STEC‑HUS, and genetic defect in cobalamin C metabolism

Pivotal study

  • The pivotal study was conducted in 16 pediatric patients. A total of 14 eculizumab-naïve patients with documented diagnosis of atypical-HUS were enrolled and included in the interim 26-week analysis.

Extension study

  • Pediatric patients with atypical-HUS in the 26-week initial evaluation period could enter an ongoing 4.5-year extension period.
  • Long-term extension data are from an interim analysis with 18 patients at Week 50.

ADAMTS13=a disintegrin and matalloproteinase with a thrombospondin type 1 motif member 13; LDH=lactate dehydrogenase; STEC=Shiga toxin–producing E coli; TMA=thrombotic microangiopathy.

Select baseline characteristics1,2

Select demographics and baseline characteristics (N=14)
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
Female, n (%)
9 (64.3)
Race, n (%)i
White
7 (50.0)
Asian
4 (28.6)
Black or African American
2 (14.3)
American Indian or Alaskan Native
1 (7.1)
Unknown or other
1 (7.1)
Stage 5 CKD assessed by eGFR, n (%)
5 (35.7)
History of prior kidney transplant, n (%)
1 (7)
Extra-renal signs or symptoms of atypical-HUS at baseline, n (%)
10 (71)
Mean platelet count [normal range 229 to 533 x 109/L]
60.50 x 109/L
Mean LDH in serum [normal range 165 to 395 U/L]
2324.11 U/L
Mean eGFR [normal range ≥60 mL/min/1.73 m2]
28.4 mL/min/1.73 m2
Median hemoglobin [normal range 107 to 131 g/L]
74.25 g/L

iPatients can have multiple races selected.

CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate; LDH=lactate dehydrogenase.

Study endpoints2

Primary endpoint

Composite endpoint of complete TMA response:

  • Platelet count normalizationj
  • Serum LDH normalizationj
  • ≥25% improvement in serum creatinine from baseline

Patients had to meet all criteria for the primary endpoint of a complete TMA response at 2 separate assessments obtained at least 4 weeks (28 days) apart and any measurement in between.

jIncludes ≥150 x 109 cells/L for platelet count and ≤246 U/L for LDH.


Select secondary endpoints

  • Time to complete TMA response and complete TMA response status over time
  • Dialysis requirement and CKD stage as evaluated by eGFR
  • Hemoglobin response
  • Change from baseline in quality of life

CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate; LDH=lactate dehydrogenase; TMA=thrombotic microangiopathy.

Safety profile

Adverse reactions reported in ≥10% of ULTOMIRIS-treated pediatric patients with atypical-HUS at Week 261

Pediatric patients (N=16)
Body system Adverse reaction
All gradesk
(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 infectionl
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
Confusion
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)
  • The most frequent adverse reactions reported in ≥20% of pediatric patients treated with ULTOMIRIS were upper respiratory tract infection, diarrhea, constipation, vomiting, headache, hypertension, and pyrexia.
  • Clinically relevant adverse reactions in <10% of patients included viral infection.
  • Serious adverse reactions were reported in 42 adult and pediatric patients (57%) with atypical-HUS 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.

kGraded per CTCAE v5.0.

lGrouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain.

CTCAE=Common Terminology Criteria for Adverse Events.


Safety in pediatric patients at 50 weeks3,m

Event type
Overall (n=21)
n (%)
Events
Any AE
21 (100)
986
Any SAE
14 (66.7)
66
TEAE resulting in drug discontinuation
1 (4.8)
920
TESAE resulting in drug discontinuation
1 (4.8)
3
TEAE resulting in study discontinuation
1 (4.8)
2
TESAE resulting in study discontinuation
1 (4.8)
3
TEAE during study drug infusion
4 (19.0)
3
TESAE during study drug infusion
0 (0)
0
Treatment-related AEs
10 (47.6)
3
Meningococcal infections
0 (0)
0
Deaths
3 (5.2)
3

Most frequent treatment-emergent adverse events3

Adverse event
Overall (n=21)
n (%)
Events
Pyrexia
10 (47.6)
22
Nasopharyngitis
7 (33.3)
13
Diarrhea
7 (33.3)
10
Vomiting
7 (33.3)
25
Headache
7 (33.3)
19
Abdominal pain
6 (28.6)
11
Hypertension
6 (28.6)
8
Cough
5 (23.8)
6
Rash
4 (19.0)
5
Rhinorrhea
4 (19.0)
4
Myalgia
4 (19.0)
7
Constipation
4 (19.0)
8
Nausea
4 (19.0)
9

mSafety outcomes at the last available follow-up with ULTOMIRIS.

AE=adverse event; SAE=serious adverse event; TEAE=treatment-emergent adverse event; TESAE=treatment-emergent serious adverse event.


This way to adult efficacy data

Read the efficacy and safety data for ULTOMIRIS studied in adult patients with atypical-HUS.

Explore adult data

Tools for the journey

Find additional resources and support information to help get your patients started on ULTOMIRIS.

VIEW resources
References:
  1. ULTOMIRIS Prescribing information. Alexion Pharmaceuticals, Inc.
  2. Data on file [ALXN1210-aHUS-312CSR].
  3. Ariceta G, et al. Kidney Int. 2021;100(1):225-237.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING

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WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

Life-threatening meningococcal infections/sepsis have occurred in patients treated with ULTOMIRIS. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
  • Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a meningococcal infection. See Warnings and Precautions for additional guidance on the management of the risk of meningococcal infection.
  • Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.

Because of the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS REMS.

CONTRAINDICATIONS

  • Patients with unresolved Neisseria meningitidis infection.
  • Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection.

WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections

Life-threatening meningococcal infections have occurred in patients treated with ULTOMIRIS. The use of ULTOMIRIS increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.

Vaccinate or revaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Immunize patients without history of meningococcal vaccination at least 2 weeks prior to the first dose of ULTOMIRIS. Patients who initiate ULTOMIRIS treatment less than 2 weeks after receiving meningococcal vaccine(s) must receive appropriate prophylactic antibiotics until 2 weeks after vaccination.

The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established. Consider discontinuation of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection.

ULTOMIRIS REMS
Due to the risk of meningococcal infections, ULTOMIRIS is available only through a restricted program under a REMS called ULTOMIRIS REMS.

Under the ULTOMIRIS REMS, prescribers must enroll in the program. Prescribers must counsel patients about the risk of meningococcal infection/sepsis, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccines.

Additional information on the REMS requirements is available at www.ultomirisrems.com or 1-888-765-4747.

Other Infections
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 guidelines. If ULTOMIRIS is administered to patients with active systemic infections, monitor closely for worsening infection.

Monitoring Disease Manifestations after ULTOMIRIS Discontinuation
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; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment. If TMA complications occur after discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

Thromboembolic Event Management
The effect of withdrawal of anticoagulant therapy during treatment with ULTOMIRIS has not been established. Treatment should not alter anticoagulant management.

Infusion-Related Reactions
Intravenous or subcutaneous 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% of patients treated with ULTOMIRIS. These events included lower back pain, drop in blood pressure, elevation in blood pressure, limb discomfort, drug hypersensitivity (allergic reaction), dysgeusia (bad taste), and drowsiness. 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.

Injection Site Reactions-Subcutaneous administration
27% (23/84) of patients treated with subcutaneous administration of ULTOMIRIS experienced injection site reactions which included application site rash, device allergy, infusion site pain, infusion site reaction, injection site bruising, injection site erythema, injection site hematoma, injection site induration, injection site inflammation, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, injection site urticaria, medical device site bruise, medical device site erythema, medical device site hematoma, medical device site induration, medical device site pruritus, medical device site rash, and medical device site reaction.

Allergies to Acrylic Adhesives
The on-body injector of ULTOMIRIS uses acrylic adhesive. For patients with a known allergy to acrylic adhesive, use of this product may result in an allergic reaction. Premedication can be considered, and supportive measures should be instituted if signs of allergy appear.

ADVERSE REACTIONS
Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia. 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. In clinical studies, clinically relevant adverse reactions in <10% of patients include viral tonsillitis in adults and viral infection in pediatric patients and in 3% of adult patients include infusion-related reactions.

Adverse Reactions for Subcutaneous Administration of ULTOMIRIS

Most common adverse reactions (≥10%) with ULTOMIRIS subcutaneous administration via On Body Injector in adult patients with PNH were local injection site reactions, diarrhea, and headache.

DRUG INTERACTIONS

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.

INDICATION
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).

Limitation of Use:
ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC‑HUS).

Subcutaneous Use in Adult Patients with aHUS
Subcutaneous administration of ULTOMIRIS is not approved for use in pediatric patients.

Please see accompanying full Prescribing Information for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening meningococcal infections/sepsis.

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Healthcare Professionals:
Answers to your questions are
a phone call away! Connect
with a live representative.
833-551-2539

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