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Ravulizumab shows noninferiority versus eculizumab in adult patients with paroxysmal nocturnal haemoglobinuria naive to complement inhibitors

Ravulizumab (ALXN1210) is a C5 inhibitor with high C5 affinity and a half-life 3-4 times longer than eculizumab. It provides immediate, complete, and sustained C5 inhibition with extended dosing intervals. Jong-Wook Lee et al. presented the results of a noninferiority study of ravulizumab versus eculizumab. Ravulizumab met the primary objective of statistically significant noninferiority versus eculizumab on both primary endpoints: the proportion of patients who remain transfusion-free and LDH normalization. Safety was similar in both groups.

Eculizumab is currently the only approved medication for management of paroxysmal nocturnal haemoglobinuria (PNH). Some patients experience loss of C5 inhibition during the approved every-2-week dosing interval, which may result in breakthrough haemolysis, PNH-related symptoms, and thrombotic risk. The goal of the study is to compare the efficacy and safety of ravulizumab with that of eculizumab in adult PNH patients.

In this global, phase III, randomized, open-label, noninferiority, multicenter study, complement inhibitor-naive PNH patients with ≥1 PNH-related sign/symptom and LDH level ≥1.5 x ULN (upper limit of normal) at screening were stratified by transfusion history (0, 1-14, or >14 units of red blood cells 1 year before study) and screening LDH level (1.5- <3 x ULN or ≥3 x ULN), and randomised 1:1 to receive ravulizumab (loading/maintenance dose [day 1/day 15 and q8w thereafter] as follows: ≥40-<60 kg body weight [2,400/3,000 mg]; ≥60-<100 kg [2,700/3,300mg]; ≥100 kg [3,000/3,600 mg]), or eculizumab at approved dosing regimen through day 183 (primary evaluation period).

Primary efficacy endpoints included transfusion avoidance (TA; proportion of patients who remain transfusion-free) and LDH normalisation (LDH ULN=246 U/L) from days 29-183. Noninferiority was declared if the lower bound of the 95% CI for difference in proportion of patients with TA receiving ravulizumab versus eculizumab was >–20% and lower bound of the 95% CI for odds ratio for LDH normalisation between ravulizumab versus eculizumab was >0.39. Key secondary endpoints were percentage change in LDH from baseline, change from baseline in FACIT-Fatigue score, and proportion of patients with breakthrough haemolysis (BTH) and stabilized haemoglobin (Hb) level. Pharmacodynamic effects were measured by change in free C5.

All 125 ravulizumab patients and 119/121 eculizumab patients completed 26 weeks of treatment. Ravulizumab met the primary objective of statistically significant noninferiority versus eculizumab on both primary endpoints and all 4 key secondary endpoints, with trends favouring ravulizumab over eculizumab for all 6 endpoints. Ravulizumab was noninferior to eculizumab in proportion of patients achieving TA (73.6% versus 66.1%; difference 6.8% [95% CI -4.7% to 18.1%]) and LDH normalisation (53.6% versus 49.4%, OR 1.19 [0.80, 1.77]). Point estimates favoured ravulizumab in percentage change in least squares mean LDH levels (76.8% versus 76.0% reduction from baseline), change in FACIT-Fatigue score (7.1 versus 6.4 point improvement from baseline), and percentage of patients with BTH (4.0% versus 10.7%) and Hb stabilisation (68.0% versus 64.5%). Immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5μg/mL) was observed by end of first infusion of ravulizumab.

Most frequently reported treatment-emergent adverse event (AE) was headache (36.0%/33.1% in patients receiving ravulizumab/eculizumab). Serious AEs were experienced by 8.8%/7.4% in the ravulizumab/eculizumab groups. Major adverse vascular events occurred in 3 patients (ravulizumab, 2; eculizumab, 1). There were no meningococcal infections.

In conclusion, the largest study of PNH patients q8w ravulizumab achieved statistically significant noninferiority to q2w eculizumab on all primary and key secondary endpoints, with an efficacy profile consistent with immediate, complete, and sustained inhibition of free C5. Safety was similar in both groups.



Jong-Wook L, Rottinghaus ST, Lily Wong L, et al. Results from a phase 3, multicenter, noniferiority study of ravulizumab (ALXN1210) versus eculizumab in adult patients with PNH naive to compliment inhibitors. Presented at EHA 2018; Abstract 2603.

Spreker Jong-Wook Lee

Jong Wook Lee

Jong-Wook Lee, MD, PhD, Catholic University of Korea, Seoul, Republic of Korea


Zie: Keyslides


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