Approval in Paroxysmal Nocturnal Hemoglobinuria With Pediatric Indication


The European Commission has granted an expanded approval to ravulizumab-cwvz to include children with a body weight of at least 10 kg, as well as adolescents, with paroxysmal nocturnal hemoglobinuria.

The European Commission has granted an expanded approval to ravulizumab-cwvz (Ultomiris) to include children with a body weight of at least 10 kg, as well as adolescents, with paroxysmal nocturnal hemoglobinuria (PNH).1

The approval is based on interim findings from a phase 3 trial (NCT03406507), in which the long-acting C5 complement inhibitor demonstrated efficacy and safety in the pediatric and adolescent patient population (n = 12) with PNH. Specifically, results showed that ravulizumab achieves complete C5 complement inhibition through 26 weeks in children and adolescents up to 18 years old.

In July 2021, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended the expanded indication for ravulizumab based on these data. In June 2021, the FDA granted an expanded approval for ravulizumab in the pediatric and adolescent patient population with PNH.

“PNH is a devastating disease, and [ravulizumab] provides an advancement for pediatric patients in the EU with an established safety and efficacy profile,” said Austin Kulasekararaj, MD, of King’s College Hospital, in London, United Kingdom. “By requiring fewer infusions each year than [eculizumab], [ravulizumab] may reduce the need for these young patients to miss school to receive treatment.”

PNH is a rare and severe blood disorder in which destruction of red blood cells causes thrombosis and leads to organ damage and potentially premature death. Ravulizumab initially received approval in the European Union in 2019 for the treatment of adult patients with PNH.

The interim findings from the multicenter, single-arm, open-label, phase 3 trial were presented during the 2021 European Hematology Association Congress.2 The study enrolled patients with complement inhibitor–naïve and eculizumab (Soliris)-experienced pediatric patients younger than 18 years old with PNH, across 9 sites in 6 countries.

The complement inhibitor–naïve patients were treated with a weight-based loading dose of ravulizumab on day 1, followed by a weight-based maintenance dose on day 15, then once every 8 weeks. For patients who switched from eculizumab, ravulizumab was given on day 1, 2 weeks following the last eculizumab dose.

Primary end points of the trial were ravulizumab maximum and trough serum concentration (Cmax, Ctrough), accumulation ratio, and change in free C5 concentration. Secondary outcome measures were percentage change in lactate dehydrogenase (LDH) from baseline, transfusion avoidance (TA), breakthrough hemolysis (BTH) and hemoglobin stabilization (Hgb-S).

Treatment-emergent adverse events (TEAE) and serious adverse events (SAE) were also evaluated.

In the interim analysis (n = 12), 4 patients were complement inhibitor–naïve, and 10 (83.3%) patients were at least 12 years old; the median age at the first ravulizumab infusion was 15.0 years (range, 9-17).

Data showed that the steady-state therapeutic serum concentrations were immediately achieved after the first dose of ravulizumab and were maintained throughout the primary evaluation period; there was no evidence of accumulation (mean [SD] Cmax and Ctrough accumulation ratios of 1.1 [0.1] and 1.1 [0.2], respectively).

Additionally, complete terminal complement inhibition was reached by the end of first ravulizumab infusion (defined as mean serum free C5 concentration < 0.5 μg/mL) and was sustained through day 183 in all patients.

The mean percentage change in LDH was –42.1% (59.0) in the patients who were complement inhibitor naïve; in the eculizumab-experienced patients, this remained stable at +4.65% (44.7). Ten patients (83.3%) achieved TA, 8 (66.7%) achieved Hgb-S, and 0 experienced BTH.

Regarding safety, 10 patients experienced TEAEs, the most frequent of which were abdominal pain and nasopharyngitis. However, no meningococcal infections occurred, nor any deaths or discontinuations due to these events. At least 1 SAE occurred in 3 patients, none of which were related to treatment.

“This approval of Ultomiris reflects our ongoing commitment to delivering new treatments that can make a meaningful difference in patients’ lives,” said Marc Dunoyer, chief executive officer, Alexion. “Ultomiris has become the standard of care for the treatment of adults with PNH and we will make it available to this younger patient population as soon as possible.”

Ravulizumab is administered every 4 or 8 weeks, depending on body weight, following a loading dose.

For more on the American Cancer Society, click here.


  1. Ultomiris approved in the EU for children and adolescents with paroxysmal nocturnal haemoglobinuria. News release. AstraZeneca. September 3, 2021. Accessed September 3, 2021.
  2. Kulagin A, Chonat S, Maschan A, et al. Pharmacokinetics, pharmacodynamics, efficacy and safety of ravulizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria: interim analysis of a phase 3, open-label study. Presented at: 2021 European Hematology Association Congress; June 9-17, 2021; virtual. Abstract EP590.
Related Videos
Juanita Mora, MD
Natasha Hoyte, MPH, CPNP-PC
Lauren Flagg
Jonathan Miller, MD
Related Content
© 2024 MJH Life Sciences

All rights reserved.