Ultomiris: Package Insert and Label Information (Page 5 of 7)

14.2 Atypical Hemolytic Uremic Syndrome (aHUS)

The efficacy of ULTOMIRIS in patients with aHUS was assessed in 2 open-label, single-arm studies. Study ALXN1210-aHUS-311 enrolled adult patients who displayed signs of TMA. In order to qualify for enrollment, patients were required to have a platelet count ≤150 × 109 /L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal or required dialysis.

Study ALXN1210-aHUS-312 enrolled pediatric patients who displayed signs of TMA. In order to qualify for enrollment, patients were required to have a platelet count ≤150 × 109 /L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine level ≥97.5% percentile at screening or required dialysis. In both studies, enrollment criteria excluded patients presenting with TMA due to a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin C metabolism. Patients with confirmed diagnosis of STEC-HUS after enrollment were excluded from the efficacy evaluation.

Study in Adult Patients with aHUS

The adult study [ALXN1210-aHUS-311; NCT02949128] was conducted in patients who were naïve to complement inhibitor treatment prior to study entry. The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years.

A total of 56 patients with aHUS were evaluated for efficacy. Ninety-three percent of patients had extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 71.4% (n = 40) of patients had Stage 5 chronic kidney disease (CKD). Fourteen percent had a medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for > 3 days after childbirth (ie, postpartum).

Table 25 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210-aHUS-311 that constituted the Full Analysis Set.

Table 25: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-311
Parameter Statistics ULTOMIRIS(N=56)
Note: Percentages are based on the total number of patients.eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum.
*
Patients can have multiple races selected.
Age at time of first infusion (years) Mean (SD)Min, max 42.2 (14.98)19.5, 76.6
Sex
Female n (%) 37 (66.1)
Race * n (%)
White 29 (51.8)
Asian 15 (26.8)
Unknown 8 (14.3)
Other 4 (7.1)
Platelets (109 /L) blood[normal range 130 to 400 × 109 /L] nMedian (min,max) 5695.25 (18, 473)
Hemoglobin (g/L) blood[normal range 115 to 160 g/L (female), 130 to 175 g/L (male)] nMedian (min,max) 5685.00 (60.5, 140)
LDH (U/L) serum[normal range 120 to 246 U/L] nMedian (min,max) 56508.00 (229.5, 3249)
eGFR (mL/min/1.73 m2)[normal range ≥60 mL/min/1.73 m2 ] n (%)Mean (SD)Median (min,max) 5515.86 (14.815)10.00 (4, 80)

The efficacy evaluation was based on Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥25% improvement in serum creatinine from baseline. Patients had to meet each Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.

Complete TMA Response was observed in 30 of the 56 patients (54%) during the 26-week Initial Evaluation Period as shown in Table 26.

Table 26: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-311)
Total Responder
n Proportion (95% CI)*
CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.
*
95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.
Complete TMA Response 56 30 0.54 (0.40, 0.67)
Components of Complete TMA Response
Platelet count normalization 56 47 0.84 (0.72, 0.92)
LDH normalization 56 43 0.77 (0.64, 0.87)
≥25% improvement in serum creatinine from baseline 56 33 0.59 (0.45, 0.72)
Hematologic normalization 56 41 0.73 (0.60, 0.84)

One additional patient had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period. Complete TMA Response was achieved at a median time of 86 days (range: 7 to 169 days). The median duration of Complete TMA Response was 7.97 months (range: 2.52 to 16.69 months). All responses were maintained through all available follow-up.

Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by estimated glomerular filtration rate (eGFR).

An increase in mean platelet count was observed after commencement of ULTOMIRIS, increasing from 118.52 × 109 /L at baseline to 240.34 ×109 /L at Day 8 and remaining above 227 × 109 /L at all subsequent visits in the Initial Evaluation Period (26 weeks).

Renal function, as measured by eGFR, was improved or maintained during ULTOMIRIS therapy. The mean eGFR (+/- SD) increased from 15.86 (14.82) at baseline to 51.83 (39.16) by 26 weeks. In patients with Complete TMA Response, renal function continued to improve after the Complete TMA Response was achieved.

Seventeen of the 29 patients (59%) who required dialysis at study entry discontinued dialysis by the end of the available follow-up and 6 of 27 (22%) patients were off dialysis at baseline were on dialysis at last available follow-up.

Study in Pediatric Patients with aHUS

The Pediatric Study [ALXN1210-aHUS-312; NCT03131219] is a 26-week ongoing, multicenter, single-arm study conducted in 16 pediatric patients.

A total of 14 eculizumab-naïve patients with documented diagnosis of aHUS were enrolled and included in this interim analysis. The median age at the time of first infusion was 5.2 years (range 0.9, 17.3 years). The overall mean weight at Baseline was 19.8 kg; half of the patients were in the baseline weight category ≥10 to <20 kg. The majority of patients (71%) had pretreatment extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 35.7% (n = 5) of patients had a CKD Stage 5. Seven percent had history of prior kidney transplant and 35.7% were on dialysis at study entry.

Table 27 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-aHUS-312.

Table 27: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-312
Parameter Statistics ULTOMIRIS(N = 14)
Note: Percentages are based on the total number of patients.eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum.
*
Patients can have multiple races selected.
Age at time of first infusion (years) category n (%)
Birth to < 2 years 2 (14.3)
2 to < 6 years 7 (50.0)
6 to < 12 years 4 (28.6)
12 to < 18 years 1 (7.1)
Sex n (%)
Female 9 (64.3)
Race * n (%)
White 7 (50.0)
Asian 4 (28.6)
Black or African American 2 (14.3)
American Indian or Alaskan Native 1 (7.1)
Unknown 1 (7.1)
Platelets (109 /L) blood [normal range 229 to 533 × 109 /L] Median (min, max) 64.00 (14, 125)
Hemoglobin (g/L) blood [normal range 107 to 131 g/L] Median (min, max) 74.25 (32, 106)
LDH (U/L) serum [normal range 165 to 395 U/L] Median (min, max) 2077.00 (772, 4985)
eGFR (mL/min/1.73 m2) [normal range ≥60 mL/min/1.73 m2 ] Mean (SD)Median (min, max) 28.4 (23.11)22.0 (10, 84)

Efficacy evaluation was based upon Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥25% improvement in serum creatinine from baseline. Patients had to meet all Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.

Complete TMA Response was observed in 10 of the 14 patients (71%) during the 26-week Initial Evaluation Period as shown in Table 28.

Table 28: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-312)
Total Responder
n Proportion (95% CI)*
Note: 1 patient withdrew from study after receiving 2 doses of ravulizumab-cwvz. CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy.
*
95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.
Complete TMA Response 14 10 0.71 (0.42, 0.92)
Components of Complete TMA Response
Platelet count normalization 14 13 0.93 (0.66, 0.99)
LDH normalization 14 12 0.86 (0.57, 0.98)
≥25% improvement in serum creatinine from baseline 14 11 0.79 (0.49, 0.95)
Hematologic normalization 14 12 0.86 (0.57, 0.98)

Complete TMA Response during the Initial Evaluation Period was achieved at a median time of 30 days (range:15 to 88 days). The median duration of Complete TMA Response was 5.08 months (range: 3.08 to 5.54 months). All responses were maintained through all available follow-up.

Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by eGFR.

An increase in mean platelet count was observed after commencement of ULTOMIRIS, increasing from 60.50 × 109 /L at baseline to 296.67 × 109 /L at Day 8 and remained above 296 × 109 /L at all subsequent visits in the Initial Evaluation Period (26 weeks). The mean eGFR (+/- SD) increased from 28.4 (23.11) at baseline to 108.0 (63.21) by 26 weeks.

Four of the 5 patients who required dialysis at study entry were able to discontinue dialysis after the first month in study and for the duration of ULTOMIRIS treatment. No patient started dialysis during the study.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2022. All Rights Reserved.