Phase 3 Study of Subcutaneous Versus Intravenous Ravulizumab in Eculizumab-Experienced Adult Patients with PNH: Primary Analysis and 1-Year Follow-Up

Abstract

Introduction: This study compared the pharmacokinetics (PK) of the ravulizumab on-body delivery system for subcutaneous (SUBQ) administration with intravenous (IV) ravulizumab in eculizumab-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH).

Methods: Patients with PNH received SUBQ ravulizumab (n = 90) or IV ravulizumab (n = 46) during the 10-week randomized treatment period; all patients then received SUBQ ravulizumab during an extension period (< 172 weeks; data cutoff 1 year). Primary endpoint was day 71 serum ravulizumab trough concentration (Ctrough). Secondary endpoints were ravulizumab Ctrough and free C5 over time. Efficacy endpoints included change in lactate dehydrogenase (LDH), breakthrough hemolysis (BTH), transfusion avoidance, stabilized hemoglobin, and Treatment Administration Satisfaction Questionnaire (TASQ) score. Safety, including adverse events (AEs) and adverse device effects (ADEs), was assessed until data cutoff.

Results: SUBQ ravulizumab demonstrated PK non-inferiority with IV ravulizumab (day 71 SUBQ/IV geometric least-squares means ratio 1.257 [90% confidence interval 1.160-1.361; p < 0.0001]). Through 1 year of SUBQ administration, ravulizumab Ctrough values were > 175 μg/mL (PK threshold) and free C5 < 0.5 μg/mL (PD threshold). Efficacy endpoints remained stable: mean (standard deviation, SD) LDH percentage change was 0.9% (20.5%); BTH events, 5/128 patients (3.9%); 83.6% achieved transfusion avoidance; 79.7% achieved stabilized hemoglobin. Total TASQ score showed improved satisfaction with SUBQ ravulizumab compared with IV eculizumab (mean [SD] change at SUBQ day 351, - 69.3 [80.1]). The most common AEs during SUBQ treatment (excluding ADEs) were headache (14.1%), COVID-19 (14.1%), and pyrexia (10.9%); the most common ADE unrelated to a device product issue was injection site reaction (4.7%). Although many patients had ≥ 1 device issue-related ADE, full SUBQ dose administration was achieved in 99.9% of attempts.

Conclusions: SUBQ ravulizumab provides an additional treatment choice for patients with PNH. Patients may switch to SUBQ ravulizumab from IV eculizumab or ravulizumab without loss of efficacy.

Trial registration: NCT03748823.

Keywords: Non-inferiority; Paroxysmal nocturnal hemoglobinuria; Quality of life; Ravulizumab; Subcutaneous.

© 2022. The Author(s).

Figures

Fig. 1

Schematic of study design and treatment formulations received during the randomized treatment period and SUBQ treatment. aPatients on eculizumab ≥ 3 months. bThe ravulizumab IV loading dose was 2400 mg for patients weighing ≥ 40 kg to < 60 kg and 2700 mg for patients weighing ≥ 60 kg to < 100 kg. cThe ravulizumab IV maintenance dose was 3000 mg for patients weighing ≥ 40 kg to < 60 kg and 3300 mg for patients weighing ≥ 60 kg to < 100 kg. dThe ravulizumab SUBQ maintenance dose was 490 mg (administered via two ravulizumab OBDS for SUBQ administration devices) for all patients (≥ 40 kg to < 100 kg). D day, IV intravenous, OBDS on-body delivery system, SUBQ subcutaneous

Fig. 2

Serum ravulizumab concentration (mean [SD]) over time during a the randomized treatment period (PK analysis set) and b the SUBQ treatment period (SUBQ treated full analysis set). BL was defined as the last assessment from the central laboratory prior to first dose of study drug. Circle = postdose sample; square = predose sample. The SUBQ group had samples collected predose at days 1, 15, 57, 64, and 71, and postdose at day 1. The IV group had samples collected predose at days 1, 15 and 71, postdose at days 1 and 15, and any time at day 57. SUBQBL was defined as the last assessment from the central laboratory prior to first dose of SUBQ treatment. BL baseline, IV intravenous, PK pharmacokinetics, SD standard deviation, SUBQ subcutaneous, SUBQBL subcutaneous baseline

Fig. 3

LDH (U/L) mean (95% CI) values during the randomized treatment period by a male and b female (full analysis set) and during the SUBQ treatment period by c male and d female (SUBQ treated full analysis set). BL was defined as the last assessment from the central laboratory prior to first dose of study drug. SUBQBL was defined as the last assessment from the central laboratory prior to first dose of SUBQ treatment (SUBQ/SUBQ group = day 15 and IV/SUBQ group = day 71 predose). Dotted horizontal lines indicate the ULN; ULN for male = 281 U/L; ULN for female = 330 U/L. Outliers were responsible for wide confidence intervals at some timepoints. One male patient with LDH > 1.5 times ULN on SUBQ day 295 had a BTH event that day; median LDH for all male patients at day 295 was 258 U/L. One female patient with LDH > 1.5 times ULN on SUBQ day 337 had high LDH values throughout; median LDH for all female patients at SUBQ day 337 was 224 U/L. BL baseline, CI confidence interval, IV intravenous, LDH lactate dehydrogenase, SUBQ subcutaneous, SUBQBL subcutaneous baseline, ULN upper limit of normal

Fig. 4

FACIT-Fatigue subscale score mean (95% CI) values during a the randomized treatment period (full analysis set) and b the SUBQ treatment period by treatment group (SUBQ treated full analysis set). BL was defined as the last assessment prior to first dose of study drug. Patients enrolled in the study were clinically stable on IV eculizumab prior to study entry. SUBQBL was defined as the last assessment prior to first dose of SUBQ treatment. FACIT subscale score ranges from 0 to 52, with a higher score indicating less fatigue. The mean FACIT-Fatigue score for the general population is 43.5 [21, 22]. BL baseline, CI confidence interval, FACIT-Fatigue Functional Assessment of Chronic Illness Therapy-Fatigue, IV intravenous, SUBQ subcutaneous, SUBQBL subcutaneous baseline

Fig. 5

EORTC QLQ-C30 global health status score mean (95% CI) values during a the randomized treatment period (full analysis set) and b the SUBQ treatment period by treatment group (SUBQ treated full analysis set). BL was defined as the last assessment prior to first dose of study drug. Patients enrolled in the study were clinically stable on IV eculizumab prior to study entry. SUBQBL was defined as the last assessment prior to first dose of SUBQ treatment. Each subscale has a range of 0–100%, with a high score representing a higher response level. The mean EORTC QLQ-C30 global health status score for the general population is 75.9 [23]. BL baseline, CI confidence interval, EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, IV intravenous, SUBQ subcutaneous, SUBQBL subcutaneous baseline

Fig. 6

Mean (95% CI) total TASQ score during a the randomized treatment period (full analysis set) and b the SUBQ treatment period (SUBQ-treated full analysis set). BL was defined as the last non-missing value prior to the first dose of study drug. At BL and on day 15, the TASQ-IV was completed for the SUBQ group. SUBQBL was defined as the last assessment prior to first dose of SUBQ treatment. Patients enrolled in the study were clinically stable on IV eculizumab prior to study entry. The TASQ-IV questionnaire was completed at SUBQBL, which is study day 15 for the SUBQ ravulizumab group and study day 71 for the IV ravulizumab group. BL baseline, CI confidence interval, IV intravenous, SD standard deviation, SUBQ subcutaneous, SUBQBL subcutaneous baseline, TASQ Treatment Administration Satisfaction Questionnaire