ULTOMIRIS, the standard of care for adults with PNH, is now FDA approved for children. Learn More.

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PNH Treatment

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Study Design

ULTOMIRIS efficacy was evaluated in the largest ever clinical trial program of adult and pediatric patients with PNH1,2,4

Adult naïve study
Adult switch study
Pediatric study

Complement inhibitor-naïve study

This pivotal, phase 3, open-label, randomized, active-controlled, multicenter, noninferiority study included a broad, clinically diverse patient population of adults (≥18 years of age) with PNH who were complement inhibitor-naïve (Study 301)1,2,6,a,b

Complement inhibitor-naïve study design data
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aPopulation included male and female patients ≥18 years of age in 25 countries with diagnosis of PNH confirmed by red and white blood cell (granulocyte or monocyte) clone sizes of ≥5%.

b98% of patients had a documented PNH-associated condition diagnosed prior to enrollment in the trial: anemia (85%), hemoglobinuria (63%), history of aplastic anemia (32%), history of renal failure (12%), myelodysplastic syndrome (5%), pregnancy complications (3%), and other (16%).

cULTOMIRIS weight-based loading dosing: ≥40 to <60 kg=2400 mg; ≥60 to <100 kg=2700 mg; ≥100 kg=3000 mg.

dULTOMIRIS weight-based maintenance dosing: ≥40 to <60 kg=3000 mg; ≥60 to <100 kg=3300 mg; ≥100 kg=3600 mg.

eEculizumab induction dose=600 mg.

fEculizumab maintenance dose=900 mg.

Coprimary endpoints1,2

  • Transfusion avoidanceg
  • LDH normalization

Secondary endpoints2

  • Percent change from baseline in LDH levels
  • Change in fatigue (FACIT-Fatigue)h
  • Proportion of patients with breakthrough hemolysisi
  • MAVEsj
  • Proportion of patients with stabilized hemoglobink
  • Disease characteristics were similar between study arms2
  • Median pretreatment LDH levels were approximately 6x the upper limit of normal (246 U/L)1,2
  • Patients had received a median of 6 units of transfused packed RBCs or whole blood in the 12 months immediately preceding the study1
Baseline characteristics1,2
ULTOMIRIS
(n=125)
ECULIZUMAB (n=121)
Pretreatment LDH levels,
median U/L (min, max)
1513.5
(378.0, 3759.5)
1445.0
(423.5, 3139.5)
Transfusion units in preceding
12 months, median (min, max)
6.0 (1, 44)
6.0 (1, 32)
Antithrombotic agents use in
preceding 28 days, n (%)
22 (17.6)
22 (18.2)
Concomitant anticoagulant
treatment, n (%)
23 (18.4)
28 (23.1)
History of MAVEs, n (%)
17 (13.6)
25 (20.7)
History of thrombosis
17 (13.6)
20 (16.5)
Over one-third of patients had a history of bone marrow failure disorders, including aplastic anemia (32%) and myelodysplastic syndrome (5%)1

gTransfusion avoidance was considered as achieved only by the patients who did not receive a transfusion and did not meet the protocol-specified guidelines for transfusion from baseline to Day 183.

hFACIT-Fatigue scores can range from 0 to 52, with higher scores indicating less fatigue.

iBreakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥2 x ULN, after prior LDH reduction to <1.5 x ULN on therapy.

jMAVEs included both thromboembolisms (thrombophlebitis/deep vein thrombosis, renal vein thrombosis, renal arterial thrombosis, mesenteric/visceral vein thrombosis, mesenteric/visceral arterial thrombosis, hepatic/portal vein thrombosis, dermal thrombosis, acute peripheral vascular disease occlusion, cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, and pulmonary embolus) and nonthromboembolisms (amputation [nontraumatic, nondiabetic], myocardial infarction, transient ischemic attack, unstable angina, gangrene [nontraumatic, nondiabetic], and specified if other).

kStabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion.

FACIT=Functional Assessment of Chronic Illness Therapy; LDH=lactate dehydrogenase; MAVE=major adverse vascular event; Q8W=every 8 weeks; RBC=red blood cell; ULN=upper limit of normal.

Eculizumab-to-ULTOMIRIS switch study

This pivotal, phase 3, open-label, randomized, active-controlled, multicenter, noninferiority study included a broad, clinically diverse patient population of adults (≥18 years of age) with PNH who were clinically stable on eculizumab for ≥6 months (Study 302)1,3,6,a,b

Eculizumab-to-ULTOMIRIS switch study design data
Swipe to see more

aPopulation included male and female patients ≥18 years of age in 11 countries with diagnosis of PNH confirmed by red and white blood cell (granulocyte or monocyte) clone sizes of ≥5%.

b95% of patients had a documented PNH-associated condition diagnosed prior to enrollment in the trial: anemia (67%), hematuria or hemoglobinuria (49%), history of aplastic anemia (37%), history of renal failure (9%), myelodysplastic syndrome (5%), pregnancy complication (7%), and other (14%).

cULTOMIRIS weight-based loading dosing: ≥40 to <60 kg=2400 mg; ≥60 to <100 kg=2700 mg; ≥100 kg=3000 mg.

dULTOMIRIS weight-based maintenance dosing: ≥40 to <60 kg=3000 mg; ≥60 to <100 kg=3300 mg; ≥100 kg=3600 mg.
eEculizumab maintenance dose=900 mg.

Primary endpoint1,3

  • LDH percent change from baseline

Secondary endpoints1,3

  • Proportion of patients with breakthrough hemolysisf
  • Change in fatigue (FACIT-Fatigue)g
  • Transfusion avoidanceh
  • Proportion of patients with stabilized hemoglobini
  • Disease characteristics were similar between study arms2
  • Median pretreatment LDH levels were below the upper limit of normal (246 U/L)1,3
  • Patients had received a median 4 (ULTOMIRIS arm) and 2.5 (eculizumab arm) units of transfused packed RBCs or whole blood in the 12 months immediately preceding the study1
Baseline characteristics1,3
ULTOMIRIS
(n=97)
Eculizumab
(n=98)
Pretreatment LDH levels,
median U/L (min, max)
224.0
(135.0, 383.5)
234.0
(100.0, 365.5)
Transfusion units in preceding
12 months, median (min, max)
4.0 (1, 32)
2.5 (2, 15)
Antithrombotic agents use in
preceding 28 days, n (%)
20 (20.6)
13 (13.3)
Concomitant anticoagulant
treatment, n (%)
22 (22.7)
16 (16.3)
History of MAVEs, n (%)
28 (28.9)
22 (22.4)
History of thrombosis
27 (27.8)
21 (21.4)
Over one-third of patients had a history of bone marrow failure disorders, including aplastic anemia (37%) and myelodysplastic syndrome (5%)1

fBreakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL], MAVE [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 x ULN after prior reduction of LDH to <1.5 x ULN on treatment.

gFACIT-Fatigue scores can range from 0 to 52, with higher scores indicating less fatigue.

hTransfusion avoidance was defined as the proportion of patients who remained transfusion free and did not require a transfusion per protocol-specified guidelines.

iStabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion.

FACIT=Functional Assessment of Chronic Illness Therapy; LDH=lactate dehydrogenase; MAVE=major adverse vascular event; Q8W=every 8 weeks; RBC=red blood cell; ULN=upper limit of normal.

Pediatric study

ULTOMIRIS was studied in a clinically diverse population of children and adolescents with PNH1,6,a

Study design1,6

  • The phase 3 open-label, multicenter, 26-week pediatric study (N=13 in the interim analysis) included both:
    • Eculizumab-experienced patients (n=8)
    • Complement inhibitor-naïve patients (n=5)
  • Most patients were between 12 and 17 years of age (n=11); the youngest patient was 9 years old
  • The study adhered to the recommended weight-based dosing regimen, consisting of a loading dose followed 2 weeks later by maintenance doses every 4 or 8 weeks (depending on body weight)

Endpoints6

Primary:

Change in pharmacokinetic (serum concentrations)/pharmacodynamic (free C5 concentrations) parameters

Select secondary:
  • Percent change from baseline in LDH levels
  • Transfusion avoidanceb
  • Change in fatigue (FACIT-Fatigue)
  • Proportion of patients with stabilized hemoglobinc
  • Proportion of patients with breakthrough hemolysisd

aThe patient population included male and female patients. Reported PNH-associated conditions at baseline included anemia, hematuria or hemoglobinuria, aplastic anemia, and renal failure.
bTransfusion avoidance was defined as the proportion of patients who remained transfusion free and did not require a transfusion through Day 183 (Week 26).
cStabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion through Day 183 (Week 26).
dBreakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia, MAVE [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH. For patients who entered the study naïve to complement inhibitor treatment, elevated LDH was defined as ≥2 × ULN after prior LDH reduction to <1.5 × ULN on therapy. For patients who entered the study stabilized on eculizumab treatment, elevated LDH was defined as ≥2 × ULN.
FACIT=Functional Assessment of Chronic Illness Therapy; LDH=lactate dehydrogenase; MAVE=major adverse vascular event; ULN=upper limit of normal.

Efficacy

ULTOMIRIS every 8 weeksa demonstrated robust and sustained efficacy across all endpoints vs eculizumab in noninferiority studies of adult patients with PNH1-3

The efficacy and safety of ULTOMIRIS in pediatric patients with PNH appeared similar to that observed in pivotal studies of adult patients with PNH1

aStarting 2 weeks after the initial loading dose, maintenance doses are administered every 8 weeks for adults and every 4 or 8 weeks for pediatric patients (depending on body weight).

Adult naïve study
Adult switch study
Pediatric study

Complement inhibitor-naïve study

Efficacy across primary and select secondary endpoints through 52 weeks of treatment with ULTOMIRIS every 8 weeks1,2,4,a

Complement inhibitor-naïve study efficacy data
Swipe to see more

aStarting 2 weeks after the initial loading dose, maintenance doses are administered every 8 weeks for adults and every 4 or 8 weeks for pediatric patients (depending on body weight).

bFull analysis set (all patients who received ≥1 dose of study drug and had ≥1 efficacy assessment after the first infusion).

cExtension set (all patients who entered the extension period).

dFor the LDH normalization endpoint during the randomized treatment period, the adjusted prevalence within each treatment is displayed.

eTreatment differences (95% CIs) are based on estimated differences in percent with 95% CI.

fBreakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥2 x ULN, after prior LDH reduction to <1.5 × ULN on therapy.

gMAVEs included both thromboembolisms (thrombophlebitis/deep vein thrombosis, renal vein thrombosis, renal arterial thrombosis, mesenteric/visceral vein thrombosis, mesenteric/visceral arterial thrombosis, hepatic/portal vein thrombosis, dermal thrombosis, acute peripheral vascular disease occlusion, cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, and pulmonary embolus) and nonthromboembolisms (amputation [nontraumatic, nondiabetic], myocardial infarction, transient ischemic attack, unstable angina, gangrene [nontraumatic, nondiabetic], and specified if other).

LDH=lactate dehydrogenase; MAVE=major adverse vascular event.

  • ULTOMIRIS was noninferior to eculizumab across all endpoints during the randomized treatment period (Week 0 to Week 26), including LDH normalization, transfusion avoidance, and hemoglobin stabilization1,2
  • Among patients taking ULTOMIRIS in the randomized period, the prevalence of breakthrough hemolysis was 4.0%, and the prevalence of MAVE was 1.6%1,2,4
  • Efficacy in these measures was maintained through Week 52 of the extension period, during which all patients received ULTOMIRIS4

Eculizumab-to-ULTOMIRIS switch study

Efficacy across primary and select secondary endpoints through 52 weeks of treatment with ULTOMIRIS every 8 weeks1,3,5,a

Eculizumab-to-ULTOMIRIS switch study efficacy data
Swipe to see more

aStarting 2 weeks after the initial loading dose, maintenance doses are administered every 8 weeks for adults and every 4 or 8 weeks for pediatric patients (depending on body weight).

bFull analysis set (all patients who received ≥1 dose of study drug and had ≥1 efficacy assessment after the first infusion).

cExtension set (all patients who entered the extension period).

dBreakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL], MAVE [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 x ULN after prior reduction of LDH to <1.5 x ULN on treatment.

eA MAVE was defined as thrombophlebitis/deep vein thrombosis, pulmonary embolus, myocardial infarction, transient ischemic attack, unstable angina, renal vein thrombosis, acute peripheral vascular occlusion, mesenteric/visceral vein thrombosis or infarction, mesenteric/visceral arterial thrombosis or infarction, hepatic/portal vein thrombosis (Budd-Chiari syndrome), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, renal arterial thrombosis, gangrene (nontraumatic, nondiabetic), amputation (nontraumatic, nondiabetic), dermal thrombosis, and specified if other.

LDH=lactate dehydrogenase; MAVE=major adverse vascular event; ULN=upper limit of normal.

  • ULTOMIRIS was noninferior to eculizumab across all endpoints during the randomized treatment period (Week 0 to Week 26), including LDH mean % change from baseline, transfusion avoidance, and hemoglobin stabilization1,3
  • Among patients taking ULTOMIRIS in the randomized period, there were no breakthrough hemolysis events or MAVEs1,3,5
  • Efficacy in these measures was maintained through Week 52 of the extension period, during which all patients received ULTOMIRIS5

Pediatric study

Primary endpoint1

Pediatric study efficacy data

of patients experienced
free C5 levels ≥0.5 μg/mLa
(n=0/13)

Efficacy across select secondary endpoints1

84.6%

of patients were
transfusion free
(n=11/13)b,c

69.2%

of patients had stable
hemoglobin levels
(n=9/13)c,d

0%

of patients experienced
breakthrough hemolysis
(n=0/13)e,f

a0.5 μg/mL is the free C5 level threshold correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in clinical studies.

bTransfusion avoidance was achieved in 60% of complement inhibitor-naïve patients (n=3/5; 95% CI, 14.7 to 94.7) and 100% of eculizumab-experienced patients (n=8/8; 95% CI, 63.1 to 100.0).

c95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.

dHemoglobin stabilization was achieved in 60% of complement inhibitor-naïve patients (n=3/5; 95% CI, 14.7 to 94.7) and 75% of eculizumab-experienced patients (n=6/8; 95% CI, 34.9 to 96.8).

eBreakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia, MAVE [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH. For patients who entered the study naïve to complement inhibitor treatment, elevated LDH was defined as ≥2 × ULN after prior LDH reduction to <1.5 × ULN on therapy. For patients who entered the study stabilized on eculizumab treatment, elevated LDH was defined as ≥2 × ULN.

fNo patients experienced breakthrough hemolysis during the primary evaluation period. One patient experienced breakthrough hemolysis at 1.8 years during the extension period.

LDH=lactate dehydrogenase; MAVE=major adverse vascular event; ULN=upper limit of normal.

LDH

LDH control with ULTOMIRIS

LDH is an established biomarker of intravascular hemolysis and PNH disease activity, with LDH levels ≥1.5 x ULN being associated with increased disease activity7,8,17

Adult naïve study
Adult switch study
Pediatric study

Complement inhibitor-naïve study

ULTOMIRIS provided rapid and sustained control of LDH,a resulting in low rates of breakthrough hemolysis and MAVEs4

Mean LDH levels in complement inhibitor-naïve adult patients4,b

Complement inhibitor-naïve study LDH data
Swipe to see more

aIn patients receiving ULTOMIRIS, LDH levels rapidly fell below 1.5 x ULN by Week 2, normalized by Week 4, and were maintained below 1.5 x ULN through Week 52.

bError bars represent 95% CI.

cNumber of patients may be lower than number enrolled at time point because of exclusion of samples having serum potassium ≥6 mmol/L and LDH ≥2 x ULN, missing samples (because of site error or for any other reason), or patient discontinuations during the extension.

dLDH levels were not measured for patients in the ULTOMIRIS to ULTOMIRIS group on Days 197 and 225.

ULTOMIRIS treatment caused mean LDH levels to1,2,4:

  • • Rapidly fall below this 1.5 x ULN threshold by Week 2
  • • Normalize by Week 4
  • • Be maintained below 1.5 x ULN through Week 52
Through 1 year of ULTOMIRIS treatment4,6

~95%

(n=118/124)

of patients were free of breakthrough hemolysis eventse

98%

(n=122/124)

of patients were free of MAVEs
Through 2 years of ULTOMIRIS treatment6

In a post-hoc analysis, incidence of MAVEs and thromboembolism was reduced compared to the 2 years preceding complement inhibitor treatmentf

eBreakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥2 x ULN, after prior LDH reduction to <1.5 x ULN on therapy.

fBased on post-hoc analysis comparing the proportion of patients (N=244) experiencing a MAVE or thromboembolism in the 2 years prior to enrollment in the pivotal complement inhibitor-naïve study (Study 301) to the proportion after receiving ULTOMIRIS during 2 years of the study. Thromboembolisms included thrombophlebitis/deep vein thrombosis, renal vein thrombosis, renal arterial thrombosis, mesenteric/visceral vein thrombosis, mesenteric/visceral arterial thrombosis, hepatic/portal vein thrombosis, dermal thrombosis, acute peripheral vascular disease occlusion, cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, and pulmonary embolus. MAVEs included both thromboembolisms and nonthromboembolisms (amputation [nontraumatic, nondiabetic], myocardial infarction, transient ischemic attack, unstable angina, gangrene [nontraumatic, nondiabetic], and specified if other). MAVEs reported during the 2 years of treatment with ULTOMIRIS were all thromboembolisms.

BL=baseline; LDH=lactate dehydrogenase; MAVE=major adverse vascular event; ULN=upper limit of normal.

Eculizumab-to-ULTOMIRIS switch study

ULTOMIRIS maintained LDH levels below 1.5 x ULN for at least 52 weeks of treatment, resulting in low rates of breakthrough hemolysis and MAVEs5

Mean LDH levels in eculizumab-experienced adult patients5,a

Eculizumab-to-ULTOMIRIS switch study LDH data
Swipe to see more

aError bars represent 95% CI.

Through 1 year of ULTOMIRIS treatment5

~97%

(n=93/96)

of patients were free of breakthrough hemolysis eventsb

99%

(n=95/96)

of patients were free of MAVEsc

bBreakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL], MAVE [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 x ULN after prior reduction of LDH to <1.5 x ULN on treatment.

cA MAVE was defined as thrombophlebitis/deep vein thrombosis, pulmonary embolus, myocardial infarction, transient ischemic attack, unstable angina, renal vein thrombosis, acute peripheral vascular occlusion, mesenteric/visceral vein thrombosis or infarction, mesenteric/visceral arterial thrombosis or infarction, hepatic/portal vein thrombosis (Budd-Chiari syndrome), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, renal arterial thrombosis, gangrene (nontraumatic, nondiabetic), amputation (nontraumatic, nondiabetic), dermal thrombosis, and specified if other.

BL=baseline; LDH=lactate dehydrogenase; MAVE=major adverse vascular event; ULN=upper limit of normal.

Pediatric study

Pediatric study LDH data

Control of intravascular hemolysis in pediatric patients1,a

Reduction of LDH levels
in complement inhibitor-naïve patients

(-47.9% [-113.4, 17.5] mean [95% CI]
change from baseline; n=5)

Maintenance of LDH levels
in eculizumab-experienced patients

(4.7% [-36.7, 46.0] mean [95% CI]
change from baseline; n=8)

a95% CIs for the mean obtained from t-distribution.
LDH=lactate dehydrogenase; ULN=upper limit of normal.

FACIT-Fatigue

Reduced fatigue with ULTOMIRIS

Fatigue was measured with the FACIT-Fatigue instrument.2,3,6 FACIT-Fatigue scores can range from 0 to 52, with higher scores indicating less fatigue31

Adult naïve study
Adult switch study
Pediatric study

Complement inhibitor-naïve study

ULTOMIRIS improved and maintained FACIT-Fatigue scores in complement inhibitor-naïve adult patients2,4,6

Mean FACIT-Fatigue score6,a

Complement inhibitor-naïve study FACIT-Fatigue data
Swipe to see more

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

bMean FACIT-Fatigue score for the general population was determined through assessment of 2,426 adults (n=1,074 male; n=1,352 female; mean age [SD]: 49.8 [17.4] years) in Germany between March 2015 and May 2015.

BL=baseline; FACIT=Functional Assessment of Chronic Illness Therapy.

  • ULTOMIRIS provided a 7.07-point mean change in FACIT-Fatigue score at the end of the randomized period (95% CI 5.55, 8.60; Pinf<0.0001 vs eculizumab)2,a
    • This improvement in mean FACIT-Fatigue score was maintained through Week 52 of treatment4,6,a
  • FACIT-Fatigue scores can range from 0 to 52, with higher scores indicating less fatigue31
    • The mean FACIT-Fatigue score for the general population has been estimated to be 43.5 (SD: 8.3)31,b

Eculizumab-to-ULTOMIRIS switch study

ULTOMIRIS maintained FACIT-Fatigue scores in eculizumab-experienced patients3,5,6

Mean FACIT-Fatigue score in eculizumab-experienced adult patients6,a

Eculizumab-to-ULTOMIRIS switch study FACIT-Fatigue data
Swipe to see more

aThere was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-Fatigue instrument. Patient-reported fatigue may be an underestimation or overestimation because patients were not blinded to treatment assignment.
BL=baseline; FACIT=Functional Assessment of Chronic Illness Therapy.

  • ULTOMIRIS provided a 2.0-point mean change in FACIT-Fatigue score at the end of the randomized period (95% CI 0.6, 3.4; Pinf <0.0001 vs eculizumab)3,a
    • The mean FACIT-Fatigue score was maintained through Week 52 of treatment5,6,a
  • FACIT-Fatigue scores can range from 0 to 52, with higher scores indicating less fatigue31
    • The mean FACIT-Fatigue score for the general population has been estimated to be 43.5 (SD: 8.3)31,b

bMean FACIT-Fatigue score for the general population was determined through assessment of 2,426 adults (n=1,074 male; n=1,352 female; mean age [SD]: 49.8 [17.4] years) in Germany between March 2015 and May 2015.

Pediatric study

FACIT-Fatigue scores1,a
  • All (n=5/5) complement inhibitor-naïve patients had a clinically relevant decrease in fatigue over the 26-week studyb
  • A slight improvement was also observed in eculizumab-experienced patients (n=8)

aPatient-reported fatigue may be an underestimation or overestimation because patients were not blinded to treatment assignment.

bA clinically relevant decrease in fatigue was defined as a mean improvement of >3 units for Pediatric FACIT-Fatigue scores.
FACIT=Functional Assessment of Chronic Illness Therapy.

Safety

The safety of ULTOMIRIS was assessed in the largest phase 3 PNH clinical trial program to date1,2,4

C5 inhibitors have an established safety profile in more than 30,000 patients who have been treated with ULTOMIRIS and eculizumab to date6

Adult studies
Pediatric study

Safety profile of ULTOMIRIS in studies of adult patients with PNH1,a,b

The adult safety population (N=441) included patients from 2 clinical trials: 1 trial of patients who were naïve to complement inhibitor treatment (n=246) and 1 trial of patients who were clinically stable on eculizumab (n=195). Patients were randomized 1:1 to receive ULTOMIRIS or eculizumab for 26 weeks.

Adverse events reported in 5% or more of ULTOMIRIS-treated adult patients during the 26-week randomized period1

System organ class (preferred term)
Number (%) of patients
Eculizumab (n=219)
ULTOMIRIS (n=222)
Gastrointestinal disorders
Diarrhea
12 (5)
19 (9)
Nausea
19 (9)
19 (9)
Abdominal pain
16 (7)
13 (6)
General disorders and administration site conditions
Pyrexia
18 (8)
15 (7)
Infections and infestations
Upper respiratory tract infectionc
86 (39)
86 (39)
Musculoskeletal and connective tissue disorders
Pain in extremity
11 (5)
14 (6)
Arthralgia
12 (5)
11 (5)
Nervous system disorders
Headache
57 (26)
71 (32)
Dizziness
14 (6)
12 (5)

cIncludes the preferred terms nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, viral upper respiratory tract infection, rhinitis, respiratory tract infection, rhinorrhea, pharyngitis, and upper respiratory tract inflammation.

In the 26-week randomized period of the adult PNH clinical studies1-3:

  • The most frequent adverse reactions (≥10%) with ULTOMIRIS were upper respiratory tract infection and headache
  • Serious adverse reactions were reported in 15 (6.8%) patients 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
  • One patient receiving ULTOMIRIS discontinued treatment

No new safety signals were reported through 2 years of ULTOMIRIS treatment6

ULTOMIRIS safety outcomes reported from Week 27 to 2 years of treatment in the safety population (N=434)

Number (%) of patients
Any TEAEd
391 (90.1)
TEAE considered as a MAVE
6 (1.4)e
Most common TEAEs (occurring in ≥10% of patients)
Upper respiratory tract infection
80 (18.4)
Nasopharyngitis
70 (16.1)
Headache
56 (12.9)
Pyrexia
44 (10.1)
Any serious adverse event (SAE)
86 (19.8)
SAE leading to study drug discontinuation
3 (0.7)f
Death
4 (0.9)g

aThe complement inhibitor-naïve study (ALXN1210-PNH-301; NCT02946463) was a 26-week, multicenter, open-label, randomized, active-controlled, noninferiority, phase 3 study with an extension period. Patients (N=246) naïve to complement inhibitor treatment prior to study entry were randomized 1:1 to receive ULTOMIRIS or eculizumab. At the end of the randomized period, patients (N=243) entered the extension period, during which all received ULTOMIRIS.

bThe ULTOMIRIS switch study (ALXN1210-PNH-302; NCT03056040) was a 26-week, multicenter, open-label, randomized, active-controlled, noninferiority, phase 3 study with an extension period. Patients (N=195) who were clinically stable after having been treated with eculizumab for at least the past 6 months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS. At the end of the randomized period, patients (N=191) entered the extension period during which all received ULTOMIRIS.

dTEAEs are AEs with a start date and start time on or after the date and time of the first infusion of ULTOMIRIS.

eEight MAVEs were recorded; 1 patient had 2 events of pulmonary embolism, 1 patient had 2 events of cerebral infarction. The other MAVEs included thrombophlebitis, deep vein thrombosis, jugular vein thrombosis, and peripheral artery thrombosis. Six events were considered to be unrelated to treatment, and 2 events were unlikely related to treatment. None of these events led to change in dose.

fThe 3 recorded discontinuations were due to acute myeloid leukemia, myelodysplastic syndrome, and lung adenocarcinoma.

gFour deaths unrelated to ULTOMIRIS were reported and were due to pulmonary sepsis, acute myeloid leukemia, lung adenocarcinoma, and lung neoplasm malignant. The 2 deaths leading to study drug discontinuation were due to acute myeloid leukemia and lung adenocarcinoma.

AE=adverse event; MAVE=major adverse vascular event; REMS=Risk Evaluation and Mitigation Strategy; SAE=serious adverse event; TEAE=treatment-emergent adverse event.

Safety profile of ULTOMIRIS in studies of pediatric patients with PNH1

The most common adverse reactions (>20%) in pediatric patients with PNH were upper respiratory tract infection, anemia, abdominal pain, and headache.

Adverse events reported in 10% or more of ULTOMIRIS-treated pediatric patients during the 26-week randomized period1

Body system Adverse reaction
Number (%) of patients (N=13)
Blood and lymphatic system disorders
Anemiaa
3 (23)
Gastrointestinal disorders
Abdominal pain
3 (23)
Constipation
2 (15)
General disorders and administration site conditions
Pyrexia
2 (15)
Infections and infestations
Upper respiratory tract infectionb
7 (54)
Musculoskeletal and connective tissue disorders
Pain in extremity
2 (15)
Nervous system disorders
Headache
3 (23)

aGrouped term includes: anemia and iron deficiency anemia.

bGrouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, and viral upper respiratory tract infection.

Fewer infusions

ULTOMIRIS has weight-based dosing with
6 to 7 infusions per year.1,a

SEE THE DIFFERENCE

aStarting 2 weeks after the initial loading dose, maintenance doses are administered every 8 weeks for adults and every 4 or 8 weeks for pediatric patients (depending on body weight).

Ordering ULTOMIRIS

Alexion’s customer operations representatives will work with your office, distributor, or insurance-designated supplier to ensure timely delivery of ULTOMIRIS to your patients.

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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.

ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program. Enrollment in the ULTOMIRIS REMS program and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.

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

Risk and Prevention

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. If ULTOMIRIS must be initiated immediately in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide 2 weeks of antibacterial drug prophylaxis. In clinical studies, 59 adult patients with PNH were treated with ULTOMIRIS less than 2 weeks after meningococcal vaccination. All of these patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established. In PNH clinical studies in adult patients, 3 out of 261 PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ULTOMIRIS; all 3 had been vaccinated. These 3 patients recovered while continuing treatment with ULTOMIRIS. Consider discontinuation of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection.

REMS
Under the ULTOMIRIS REMS, prescribers must enroll in the program due to the risk of meningococcal infections. 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.

Other Infections
Patients may have increased susceptibility to encapsulated bacteria infections, especially 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
After discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH along with sudden decrease in PNH clone size or hemoglobin, or re-appearance 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.

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
Administration of ULTOMIRIS may result in infusion-related reactions. In clinical trials, 4 out of 309 patients treated with ULTOMIRIS experienced infusion-related reactions (lower back pain, drop in blood pressure, elevation in blood pressure and limb discomfort) during ULTOMIRIS administration which did not require discontinuation. Interrupt infusion and institute supportive measures if signs of cardiovascular instability or respiratory compromise occur.

ADVERSE REACTIONS
Adverse reactions reported in 5% or more of patients treated with ULTOMIRIS vs. Eculizumab was Upper respiratory tract infection (39% vs. 39%), Headache (32% vs. 26%), Diarrhea (9% vs. 5%), Nausea (9% vs. 9%), Pyrexia (7% vs. 8%), Pain in extremity (6% vs. 5%), Abdominal pain (6% vs. 7%), Dizziness (5% vs. 6%), Arthralgia (5% vs. 5%). Serious adverse reactions were reported in 15 (6.8%) patients 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.

Adverse reactions reported in 10% or more of pediatric patients treated with ULTOMIRIS who were treatment-naïve vs. Eculizumab-experienced was Anemia (20% vs. 25%), Abdominal pain (0% vs. 38%), Constipation (0% vs. 25%), Pyrexia (20% vs. 13%), Upper respiratory tract infection (20% vs. 75%), Pain in extremity (0% vs. 25%), Headache (20% vs. 25%).

INDICATION

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

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

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