Ravulizumab: A New Complement Inhibitor for Patients With Paroxysmal Nocturnal Hemoglobinuria

Ravulizumab was noninferior to eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) who had never received treatment with complement inhibitors, according to findings from the multicenter, randomized, phase III ALXN1210-PNH-301 study. The study’s findings, which were published in Blood, also suggested that treatment with the newer, more potent complement inhibitor was associated with better quality of life than treatment with eculizumab.

“From a patient and health-care perspective, a fourfold longer dosing interval of ravulizumab vs. eculizumab may reduce treatment burden and health-care resource [use],” the authors, led by Jong Wook Lee, MD, from Seoul St. Mary’s Hospital and the Catholic University of Korea, wrote. “[Ravulizumab also] may expand access to patients who are unable to comply with the [biweekly] dosing of eculizumab.”

Results from the study supported the U.S. Food and Drug Administration’s approval of ravulizumab for the treatment of adult patients with PNH in December 2018.

The trial included 246 adult patients with PNH from 123 centers and 25 countries. Patients were eligible for inclusion if they had a documented diagnosis of PNH, confirmed by high-sensitivity flow cytometry of red and white blood cells with granulocyte or monocyte clone size of at least 5 percent and a lactate dehydrogenase (LDH) level ≥1.5 times the upper limit of normal (ULN). Those with current or previous exposure to a complement inhibitor, a history of bone marrow transplantation, platelet count <30,000/μL, or absolute neutrophil count <500 /μL at screening were excluded.

Prior to randomization, patients underwent a four-week screening period and were stratified based on their transfusion history and LDH level at screening. Participants were then randomized 1:1 to either ravulizumab (n=125) or eculizumab (n=119).

Ravulizumab was administered at a loading dose of 2,400 mg, 2,700 mg, or 3,000 mg (depending on weight) on day 1, followed by maintenance doses of 3,000 mg, 3,300 mg, or 3,600 mg on day 15 and every eight weeks thereafter. Patients assigned to eculizumab received induction doses of 600 mg on days 1, 8, 15, and 22, followed by maintenance dosing of 900 mg on day 29 and every two weeks thereafter.

All patients completed a 26-week treatment cycle with their assigned therapies.

The study evaluated two co-primary endpoints: transfusion avoidance (defined as the proportion of patients who remained transfusion-free and did not need a transfusion through day 183 of follow-up) and hemolysis (measured by LDH normalization to a of 246 U/L from day 29 through day 183).

By 26-week follow-up, ravulizumab was noninferior to eculizumab for both co-primary endpoints, although the authors added that “point estimates for both endpoints favored ravulizumab.”

Ninety-two of 125 patients (73.6%) receiving ravulizumab and 80 of 121 patients (66.1%) receiving eculizumab avoided transfusions, for a difference of (95% CI p for inferiority 0<0.0001). In addition, 53.6 percent of ravulizumab-treated patients and 49.4 percent of eculizumab-treated patients achieved LDH normalization (odds ratio = 1.19; 95% CI 0.80-1.77; p for inferiority <0.0001).

Noninferiority was also observed in all secondary endpoints, including percentage change in LDH levels (between-group difference = 0.83; 95% CI –5.21 to 3.56; p for inferiority <0.0001) and quality-of-life scores (measured via FACIT-Fatigue scale; between-group difference = 0.67; 95% CI –1.21 to 2.55; p for inferiority <0.0001).

The researchers also noted that patients who received ravulizumab reached LDH normalization an average of five days earlier than those who received eculizumab ();  a greater proportion of patients assigned to ravulizumab achieved normalization of LDH throughout the study.

The less-frequent, every-eight-week dosing with ravulizumab appeared to be associated with better quality of life, compared with eculizumab: A higher proportion of ravulizumab-treated patients experienced a ≥10-point improvement on quality-of-life questionnaires and had greater improvements in physical functioning scores (between-group difference = 4.8 points and 3.7 points, respectively; p values not reported).

No treatment discontinuations were observed for ravulizumab, while two patients discontinued treatment with eculizumab. The incidence of adverse events (AEs) was similar between the treatment arms, with headache being the most frequently reported AE (36.0% in ravulizumab and 33.1% in eculizumab). Eleven patients (8.8%) in the ravulizumab group and nine (7.4%) in the eculizumab group experienced a serious AE, which included pyrexia, neutropenia, pneumonia, and infection. One patient in the eculizumab arm died of lung cancer (unrelated to treatment) during the extension phase of the study, the authors reported.

The study findings are limited by the open-label design, which may have introduced bias, but the investigators noted that this was “the largest controlled study of patients with PNH who were na to complement inhibitor therapy” and ravulizumab showed “robust results … across a broad selection of clinically relevant endpoints, despite the challenges of using a highly efficacious comparator.”

The authors report financial relationships with Alexion, the sponsor of the trial.


Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2018 December 3. [Epub ahead of print]