Ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria

ABSTRACT

Introduction: Eculizumab, which is indicated to treat patients with paroxysmal nocturnal hemoglobinuria (PNH), is a life-changing, life-saving therapy that decreases intravascular hemolysis and thrombosis and improves survival. Some eculizumab-treated patients, however, experience breakthrough hemolysis; and overall, the burden of the treatment schedule (intravenous infusions every 2 weeks) is substantial. Ravulizumab is a long-acting, second-generation complement component 5 (C5) inhibitor that is administered intravenously every 8 weeks. It is approved in the United States (December 2018), Japan (June 2019), Europe (July 2019), and Canada and Brazil (September 2019).

Areas covered: This article reviews data presented in journal articles identified on Medline/PubMed, abstracts presented at hematology meetings, and information posted on ClinicalTrials.gov and Alexion.com. Emphasis is placed on the non-inferiority of ravulizumab compared to eculizumab and the advantages of the 8-week, weight-based, dosing regimen.

Expert opinion: In phase 3 trials, ravulizumab has been shown to be as safe and efficacious as eculizumab, to be associated numerically with lower rates of breakthrough hemolysis (p for non-inferiority <0.0004), and to be preferred over eculizumab by most patients. Ravulizumab is likely to replace eculizumab as the first-line treatment for PNH both in patients who are naive to eculizumab treatment and in patients who are clinically stable on eculizumab.

KEYWORDS:

• Breakthrough hemolysis
• eculizumab
• paroxysmal nocturnal hemoglobinuria
• quality of life
• ravulizumab
• terminal complement inhibition

Article highlights

• Ravulizumab, a long-acting second generation C5 inhibitor, was recently approved for the treatment of adults with paroxysmal nocturnal hemoglobinuria in the United States, Japan, Europe, Canada, and Brazil.

• Ravulizumab was designed to alleviate the burden of the eculizumab treatment schedule and to reduce the frequency of breakthrough hemolysis; it is administered as a weight-based single induction dose, followed two weeks later by a weight-based maintenance dose every 8 weeks thereafter.

• Complete terminal complement inhibition (serum free C5 concentration <0.5 μg/mL) was observed in all ravulizumab-treated patients in both phase 3 studies and throughout the 26-week treatment period.

• In phase 3 trials, ravulizumab was safe and effective in patients who were naïve to complement inhibitor treatments and in patients who were clinically stable on eculizumab treatment. A recent analysis of data from the extension phase of the pivotal trial in eculizumab-naive patients showed that when patients were switched from treatment with eculizumab to treatment with ravulizumab for 26 weeks, the rate of breakthrough hemolysis dropped from 11% to 2% of patients.

• Ninety-three percent of patients reported a preference for ravulizumab over eculizumab; 98% of patients preferred the frequency of infusions with ravulizumab compared to that with eculizumab.

This box summarizes key points contained in the article.

Box 1. Drug summary box

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Acknowledgments

We would like to thank Hélène Dassule, PhD for her medical writing and editorial assistance in the preparation of this manuscript, which was conducted in accordance with Good Publication Practices and funded by Alexion Pharmaceuticals, Inc. Alexion, the marketing-authorization holder of ravulizumab and eculizumab, was also offered an opportunity to provide a scientific accuracy review of their data. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit.

Declaration of interest

Dr Jong Wook Lee and Dr Austin G Kulasekararaj have served on Alexion Pharmaceuticals, Inc advisory boards and have received speaker honoraria and research grants from Alexion Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

One of the reviewers of this manuscript has received research grants and symposium fees from Alexion, Novartis and Pfizer, and acts on boards for Alexion, Novartis and Pfizer. All additional peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was funded by Alexion Pharmaceuticals.