Ultomiris: Package Insert and Label Information (Page 4 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal carcinogenicity studies of ravulizumab-cwvz have not been conducted.

Genotoxicity studies have not been conducted with ravulizumab-cwvz.

Effects of ravulizumab-cwvz upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.

14 CLINICAL STUDIES

14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH)

The safety and efficacy of ULTOMIRIS in adult patients with PNH was assessed in two open-label, randomized, active-controlled, non-inferiority Phase 3 studies: PNH Study 301 and PNH Study 302. Study 301 enrolled patients with PNH who were complement inhibitor naïve and had active hemolysis. Study 302 enrolled patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months. The safety and efficacy of ULTOMIRIS in pediatric patients with PNH was assessed in PNH Study 304, open-label, Phase 3 study conducted in eculizumab-experienced and complement inhibitor treatment naïve pediatric patients with PNH.

In both adult studies, ULTOMIRIS was dosed intravenously in accordance with the weight-based dosing described in Section 2.2 (4 infusions of ULTOMIRIS over 26 weeks) above. Eculizumab was administered on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every 2 weeks (q2w) thereafter for a total of 26 weeks of treatment, according to the approved dosing regimen of eculizumab which was the standard-of-care for PNH at the time of the studies.

Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with ULTOMIRIS or eculizumab, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. Prophylactic treatment with appropriate antibiotics beyond 2 weeks after vaccination was at the discretion of the provider.

Study in Complement-Inhibitor Naïve Adult Patients with PNH

The Complement-Inhibitor Naïve Study [ALXN1210-PNH-301; NCT02946463] was a 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 246 patients naïve to complement inhibitor treatment prior to study entry.

Patients with PNH with flow cytometric confirmation of at least 5% PNH cells were randomized 1:1 to either ULTOMIRIS or eculizumab. The mean total PNH granulocyte clone size was 85%, the mean total PNH monocyte clone size was 88%, and the mean total PNH RBC clone size was 39%. Ninety-eight percent of patients had a documented PNH-associated condition diagnosed prior to enrollment on 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%). Major baseline characteristics were balanced between treatment groups. Table 19 provides the baseline characteristics for the patients enrolled in the complement-inhibitor naïve study.

Table 19: Baseline Characteristics in the Complement-Inhibitor Naïve Study
Parameter Statistics ULTOMIRIS(N=125) Eculizumab(N=121)
*
MAVE = major adverse vascular event
Age (years) at first infusion in study Mean (SD)Min, max 44.8 (15.2)18, 83 46.2 (16.2)18, 86
Sex
Male n (%) 65 (52.0) 69 (57.0)
Race n (%)
Asian 72 (57.6) 57 (47.1)
White 43 (34.4) 51 (42.1)
Black or African American 2 ( 1.6) 4 ( 3.3)
American Indian or Alaska Native 1 ( 0.8) 1 ( 0.8)
Other 4 ( 3.2) 4 ( 3.3)
Not reported 3 ( 2.4) 4 ( 3.3)
Pre-treatment LDH levels (U/L) MedianMin, max 1513.5(378.0, 3759.5) 1445.0(423.5, 3139.5)
Units of pRBC/whole blood transfused within 12 months prior to first dose MedianMin, max 6.0(1, 44) 6.0(1, 32)
Antithrombotic agents used within 28 days prior to first dose n (%) 22 (17.6) 22 (18.2)
Patients with a history of MAVE * n (%) 17 (13.6) 25 (20.7)
Patients with a history of thrombosis n (%) 17 (13.6) 20 (16.5)
Patients with concomitant anticoagulant treatment n (%) 23 (18.4) 28 (23.1)

Efficacy was established based upon transfusion avoidance and hemolysis as directly measured by normalization of LDH levels. Transfusion avoidance was defined as patients who did not receive a transfusion and did not meet the protocol specified guidelines for transfusion from baseline up to Day 183. Supportive efficacy data included the percent change from baseline in LDH levels, the proportion of patients with breakthrough hemolysis defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥2 × ULN, after prior LDH reduction to < 1.5 × ULN on therapy and the proportion of patients with stabilized hemoglobin.

Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the complement-inhibitor naïve treatment population described in Table 20 below.

Table 20: Efficacy Results in the Complement-Inhibitor Naïve Study
ULTOMIRIS(N=125) Eculizumab(N=121) Statistic for Comparison Treatment Effect(95% CI)
Note: LDH = lactate dehydrogenase; CI = confidence interval For the transfusion avoidance endpoint, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI. For the lactate dehydrogenase normalization endpoint, the adjusted prevalence within each treatment is displayed.
Transfusion avoidance rate 73.6% 66.1% Difference in rate 6.8(-4.66, 18.14)
LDH normalization 53.6% 49.4% Odds ratio 1.19(0.80, 1.77)
LDH percent change -76.84% -76.02% Difference in % change from baseline -0.83(-5.21, 3.56)
Breakthrough hemolysis 4.0% 10.7% Difference in rate -6.7(-14.21, 0.18)
Hemoglobin stabilization 68.0% 64.5% Difference in rate 2.9(-8.80, 14.64)

There 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 under-or over-estimation, because patients were not blinded to treatment assignment.

Study in Eculizumab-Experienced Adult Patients with PNH

The study in eculizumab-experienced patients [ALXN1210-PNH-302; NCT03056040] was a 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 195 patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months.

Patients who demonstrated clinically stable disease after being treated with eculizumab for at least the prior 6 months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS. The mean total PNH granulocyte clone size was 83%, the mean total PNH monocyte clone size was 86%, and the mean total PNH RBC clone size was 60%. Ninety five percent 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%). Major baseline characteristics were balanced between the two treatment groups. Table 21 provides the baseline characteristics for the patients enrolled in the eculizumab-experienced study.

Table 21: Baseline Characteristics in Eculizumab-Experienced Adult Patients with PNH
Parameter Statistics ULTOMIRIS(N=97) Eculizumab(N=98)
*
MAVE = major adverse vascular event
Age (years) at first infusion in study Mean (SD)Min, max 46.6 (14.41)18, 79 48.8 (13.97)23, 77
Race n (%)
White 50 (51.5) 61 (62.2)
Asian 23 (23.7) 19 (19.4)
Black or African American 5 (5.2) 3 (3.1)
Other 2 (2.1) 1 (1.0)
Not reported 13 (13.4) 13 (13.3)
Unknown 3 (3.1) 1 (1.0)
Multiple 1 (1.0) 0
Sex n (%)
Male 50 (51.5) 48 (49.0)
Pre-treatment LDH levels (U/L) MedianMin, max 224.0135.0, 383.5 234.0100.0, 365.5
Units of pRBC/whole blood transfused within 12 months prior to first dose MedianMin, max 4.0(1, 32) 2.5(2, 15)
Antithrombotic agents used within 28 days prior to first dose n (%) 20 (20.6) 13 (13.3)
Patients with a history of MAVE * n (%) 28 (28.9) 22 (22.4)
Patients with a history of thrombosis n (%) 27 (27.8) 21 (21.4)
Patients with concomitant anticoagulant treatment n (%) 22 (22.7) 16 (16.3)

Efficacy was established based on hemolysis as measured by LDH percent change from baseline to Day 183 and supportive efficacy data was transfusion avoidance, proportion of patients with stabilized hemoglobin, and the proportion of patients with breakthrough hemolysis through Day 183.

Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the patients with PNH previously treated with eculizumab described in Table 22 below.

Table 22: Efficacy Results in the Eculizumab-Experienced Adult Patients with PNH Eculizumab-Experienced Study
ULTOMIRISN = 97 EculizumabN = 98 Statistic for Comparison Treatment Effect(95% CI)
Note: CI = confidence interval
LDH percent change -0.82% 8.4% Difference in % change from baseline 9.2(-0.42, 18.8)
Breakthrough hemolysis 0% 5.1% Difference in rate 5.1(-8.9, 19.0)
Transfusion avoidance 87.6 % 82.7% Difference in rate 5.5(-4.3, 15.7)
Hemoglobin stabilization 76.3% 75.5% Difference in rate 1.4(-10.4, 13.3)

There 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 under-or over-estimation, because patients were not blinded to treatment assignment.

Study in Eculizumab-Experienced and Complement-Inhibitor Naïve Pediatric Patients with PNH

The pediatric study, ALXN1210-PNH-304, was a multi-center, open-label Phase 3 study conducted in eculizumab-experienced and complement inhibitor treatment-naïve pediatric patients with PNH. A total of 13 pediatric patients with PNH completed ULTOMIRIS treatment during the Primary Evaluation Period (26 weeks). Five of the 13 patients had never been treated with complement inhibitors and 8 patients were treated with eculizumab. Eleven of the thirteen patients were between 12 and 17 years of age at first infusion, with 2 patients under 12 years old (11 and 9 years old). Table 23 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-PNH-304.

Table 23: Baseline Characteristics for Pediatric Patients with PNH
Variable Complement Inhibitor Treatment-naïve Patients(N = 5) Eculizumab-Experienced Patients(N = 8) All Patients(N = 13)
Note: Percentages were based on the total number of patients in each cohort, or overall.kg = kilogram; max = maximum; min = minimum; SD = standard deviation.
Sex, n (%)
Male 4 (80.0) 1 (12.5) 5 (38.5)
Female 1 (20.0) 7 (87.5) 8 (61.5)
Age at first infusion (years)
Mean (SD) 14.4 (2.2) 14.4 (3.1) 14.4 (2.7)
Median (min, max) 15.0 (11, 17) 15.0 (9, 17) 15.0 (9, 17)
Age at first infusion (years) category, n (%)
<12 years 1 (20.0) 1 (12.5) 2 (15.4)
≥12 years 4 (80.0) 7 (87.5) 11 (84.6)
Baseline weight (kg)
Mean (SD) 56.3 (11.6) 56.3 (12.2) 56.3 (11.5)
Median (min, max) 55.6 (39.5, 72.0) 55.5 (36.7, 69.0) 55.6 (36.7, 72.0)
Baseline weight (kg) category, n (%)
≥30 to <40 kg 1 (20.0) 1 (12.5) 2 (15.4)
≥40 to <60 kg 3 (60.0) 4 (50.0) 7 (53.8)
≥60 to <100 kg 1 (20.0) 3 (37.5) 4 (30.8)
Units of pRBC/whole blood transfused within 12 months prior to first dose
Median (min, max) 7.0 (3, 11) 2.0 (2, 2)
Pre-treatment LDH levels (U/L)
Median (min, max) 588.5 (444, 2269.7) 251.5 (140.5, 487)

Based on body weight, patients received a loading dose of ULTOMIRIS on Day 1, followed by maintenance treatment on Day 15 and once every 8 weeks (q8w) thereafter for patients weighing ≥20 kg, or once every 4 weeks (q4w) for patients weighing < 20 kg. For patients who entered the study on eculizumab therapy, Day 1 of study treatment was planned to occur 2 weeks from the patient’s last dose of eculizumab.

The weight-based dose regimen of ravulizumab-cwvz provided inhibition of terminal complement in all patients throughout the entire 26-week treatment period regardless of prior experience with eculizumab. Following initiation of ravulizumab-cwvz treatment, steady-state therapeutic serum concentrations of ravulizumab-cwvz were achieved after the first dose and maintained throughout the primary evaluation period in both cohorts. Three of 5 complement inhibitor treatment-naïve patients and 6 out of 8 eculizumab-experienced patients achieved hemoglobin stabilization by Week 26, respectively. Transfusion avoidance was reached for 11 out of 13 of patients during the 26-week Primary Evaluation Period. One patient experienced breakthrough hemolysis during the extension period. Table 24 presents secondary efficacy outcomes for the primary evaluation period.

Table 24: Efficacy Outcomes from the 26-Week Primary Evaluation Period of Pediatric Patient Study in PNH (ALXN1210-PNH-304)
End Point Treatment Naïve(N = 5) Eculizumab Experienced (N = 8)
LDH = lactate dehydrogenase
*
95% CIs for the mean obtained from t-distribution were presented.
95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.
No patients experienced breakthrough hemolysis during the primary evaluation period. One patient experienced breakthrough hemolysis at 1.8 years during the extension period; however, at the time of the BTH event the patient had adequate C5 inhibition (free C5 < 0.5 µg/mL).
LDH- Percent Change from Baseline (%)* -47.9 (-113.4, 17.5) 4.7 (-36.7, 46.0)
Transfusion Avoidance (%) 60.0 (14.7, 94.7) 100.0 (63.1, 100.0)
Change in FACIT-Fatigue * 3.4 (-4.2, 11.0) 1.3 (-3.1, 5.7)
Hemoglobin Stabilization (%) 60.0 (14.7, 94.7) 75.0 (34.9, 96.8)
Breakthrough Hemolysis (%) 0 0

A clinically relevant improvement from baseline in fatigue as assessed by Pediatric FACIT-Fatigue (i.e., mean improvement of > 3 units for Pediatric FACIT Fatigue scores) was sustained throughout the primary evaluation period in the 5-complement inhibitor treatment naïve patients. A slight improvement was also observed in eculizumab-experienced patients. However, patient-reported fatigue may be an under-or over-estimation, because patients were not blinded to treatment assignment.

The efficacy of ULTOMIRIS in pediatric patients with PNH is similar to that observed in adult patients with PNH enrolled in pivotal studies.

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