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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
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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
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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
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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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INDICATION & IMPORTANT SAFETY INFORMATION

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WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

ULTOMIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)] Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.

  • Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria.
  • Patients receiving ULTOMIRIS are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious 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 [see Warnings and Precautions (5.2)].

CONTRAINDICATIONS

  • Initiation in patients with unresolved serious Neisseria meningitidis infection.

WARNINGS AND PRECAUTIONS
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.

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 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 those associated with 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 serious 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 they 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 REMS
Due to the risk of serious meningococcal infections, ULTOMIRIS is available only through a restricted program called ULTOMIRIS REMS.

Under the REMS, prescribers must enroll in the REMS, counsel patients about the risk of meningococcal infection, provide patients with the REMS educational materials, 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.  Antibacterial drug prophylaxis must be prescribed if treatment must be started urgently and the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of ULTOMIRIS.  Patients must receive counseling about the need to receive meningococcal vaccines and to take antibiotics as directed, signs and symptoms of meningococcal infection, and be instructed to carry the Patient Safety Card at all times during and for 8 months following ULTOMIRIS treatment.

Further information is available at www.ultomirisrems.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 devseloping 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 
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
Intravenous 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, 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.

ADVERSE REACTIONS
Adverse reactions reported in ≥10% or more of patients with PNH 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. In clinical studies, clinically relevant adverse reactions in 1% of adult patients include infusion-related reactions. Adverse reactions reported in ≥10% 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%).

Adverse reactions reported in 20% of pediatric patients treated with ULTOMIRIS were diarrhea, constipation, vomiting, pyrexia, upper respiratory tract infection, decreased vitamin D, headache, cough, rash, and hypertension.

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 paroxysmal nocturnal hemoglobinuria (PNH).

To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

Alexion Connect

Healthcare Professionals:
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833-551-2539

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Alexion Connect

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

Alexion Connect