ULTOMIRIS adult 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 56 adult patients with atypical-HUS who were naïve to complement inhibitor treatment prior to study entry 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 52 weeks.
56 of 56 adult patients in a 26-week study demonstrated complete C5 inhibition after the first infusion of ULTOMIRISa
30 of 56 adult patients (CI: 40%-67%) met the composite endpoint of complete TMA responseb with ULTOMIRIS by 26 weeks, which was maintained through 52 weeks
for 8 weeks, with the
possibility to live
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
The majority of adult patients taking ULTOMIRIS achieved complete TMA response, which was maintained at 52 weeks1,3,c
Complete TMA response
(95% Cl: 40%-67%)
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
dPatient achieved initial complete TMA response measurement at day 169; however confirmatory measurement was not achieved until the extension period (day 239).3
BL=baseline; LDH=lactate dehydrogenase; TMA=thrombotic microangiopathy.
Components of complete TMA response1,3,e
Platelet count normalization
(95% Cl: 72%-92%)
(95% Cl: 64%-87%)
≥25% Improvement in serum creatinine from baseline
(95% Cl: 45%-72%)
(95% Cl: 60%-84%)
eComplete 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 52-week data.3
CI=confidence interval; defined as 95%; LDH=lactate dehydrogenase; TMA=thrombotic microangiopathy.
fAs measured by free C5 serum concentration of <0.5 mcg/mL.1
Changes in CKD stage
ULTOMIRIS offers sustained C5 inhibition and an opportunity to discontinue dialysis in adult patients1
Patients with chronic kidney disease (CKD) Stage 5 cannot worsen and may not be able to improve2
gGreen shading indicates improvement vs baseline; pink 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.4
CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate.
Discontinuing dialysis may be possible
6 of 27 patients who were off dialysis at baseline were on dialysis at 26 weeks1
ULTOMIRIS was evaluated in a 26-week study in adults with atypical-HUS, followed by an ongoing 4.5-year extension study1
Pivotal study and extension study1,3
hULTOMIRIS weight-based loading dose: ≥40 to <60 kg=2400 mg; ≥60 to <100 kg=2700 mg; ≥100 kg=3000 mg.
iULTOMIRIS weight-based maintenance dosing: ≥40 to <60 kg=3000 mg; ≥60 to <100 kg=3300 mg; ≥100 kg=3600 mg.
Select inclusion criteria:
- Platelet count ≤150 x 109 cells/L
- Evidence of hemolysis (eg, elevated serum LDH, serum creatinine >ULN, or required dialysis)
Select exclusion criteria:
- Patients with TMA due to ADAMTS13 deficiency, STEC‑HUS, and genetic defect in cobalamin C metabolism
- A total of 56 patients who were naïve to complement inhibitor treatment prior to study entry were evaluated for efficacy. The study consisted of a 26-week initial evaluation period.
- Adult 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 at Week 52.
ADAMTS13=a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13; LDH=lactate dehydrogenase; STEC=Shiga toxin–producing E coli; TMA=thrombotic microangiopathy; ULN=upper limit of normal.
Select baseline characteristics1,2
jPatients can have multiple races selected.
kPercentage of patients who had received ICU-level care prior to the start of screening based on the total number of patients who had any ER visits or hospitalizations due to atypical-HUS prior to the start of screening.2
CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate; LDH=lactate dehydrogenase; TMA=thrombotic microangiopathy.
Composite endpoint of complete TMA response:
- Platelet count normalizationl
- Serum LDH normalizationl
- ≥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.
lIncludes ≥150 x 109 cells/L for platelet count and ≤246 U/L for LDH.2
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.
Adverse reactions reported in ≥10% of ULTOMIRIS-treated adult patients with atypical-HUS at Week 261
- The most frequent adverse reactions reported in ≥20% of adult patients treated with ULTOMIRIS were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension, and arthralgia
- Clinically relevant adverse reactions in <10% of patients included viral tonsillitis
- 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
- Four patients died during the adult atypical-HUS study. Patient deaths were determined by study investigators as unrelated to study drug; the cause of death was sepsis in two patients and intracranial hemorrhage in one patient. The fourth patient, who was excluded from the trial after a diagnosis of STEC‑HUS, died due to pretreatment cerebral arterial thrombosis
mGraded per CTCAE v5.0.
nGrouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain.
oGrouped term includes gastroenteritis, gastrointestinal infection, enterocolitis infection, infectious colitis, and enterocolitis.
CTCAE=Common Terminology Criteria for Adverse Events; STEC=Shiga toxin–producing E coli.
Safety in adult patients at 52 weeks (N=58)3,p
- At the last available follow-up, all patients experienced one or more AEs; 20 patients (34.5%) experienced treatment-related AEs, most often headache, diarrhea, and vomiting
- A total of 33 patients (56.9%) experienced serious AEs, most often hypertension and pneumonia (5.2%)
pSafety 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.
- ULTOMIRIS. Prescribing information. Alexion Pharmaceuticals, Inc.
- Data on file [ALXN1210-aHUS-311CSR (Initial Analysis)].
- Barbour T, et al. Kidney Int Rep. 2021;6(6):1603-1613.
- Data on file [ALXN1210-aHUS-311CSR (52-week)].
IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING
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.
- 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.
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.
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.
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.
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.
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.
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.