Emerging drugs for the treatment of paroxysmal nocturnal hemoglobinuria

ABSTRACT

Introduction

Eculizumab, the first anti-C5 monoclonal antibody approved for patients with paroxysmal nocturnal hemoglobinuria (PNH), has revolutionized the natural history of this disease, blocking intravascular hemolysis, reducing the risk of thromboembolic events, resulting in a significant improvement in survival and quality of life. However, the hematological response to eculizumab is extremely heterogeneous, with only one-third of PNH patients reaching normal hemoglobin levels.

Areas covered

This article reviews the current new drugs being investigated in phase II and III trials for adult PNH patients. Literature search was performed using Medline and Clinicaltrials.org databases.

Expert opinion

The new molecules have been classified according to the target of the complement system on which they act; we have novel terminal complement inhibitors, which target C5, and proximal complement inhibitors, which interfere with C3 or even further upstream (factor B and D). Ravulizumab is the first next-generation C5 inhibitor, approved by FDA and EMA, which reproduced the excellent results achieved with eculizumab, trying to improve the convenience of patients. However, unresolved issues remain, such as C3-mediated extravascular hemolysis, on which novel proximal complement inhibitors are showing their efficacy. Pegcetacoplan is the first C3-inihibitor approved by FDA. Long-term safety data for novel complement inhibitors are needed.

KEYWORDS:

• Paroxysmal nocturnal hemoglobinuria
• intravascular and extravascular hemolysis
• novels complement inhibitors

List of abbreviations (in alphabetical order)

AA:	=	aplastic anemia
EMA:	=	European Medicines Agency
FDA:	=	Food and Drugs Administration
LDH:	=	lactate dehydrogenase
MAC:	=	membrane attack complex
PNH:	=	paroxysmal nocturnal hemoglobinuria
RBCs:	=	red blood cells
SAA:	=	severe aplastic anemia
ULN:	=	upper limit of normal

Acknowledgments

We would like to thank David Williams for revising the use of English in our manuscript.

Declaration of interests

R Peffault de Latour has received research support from Alexion, Novartis, Pfizer and Amgen; lecture fees from Alexion, Novartis, Pfizer and Apellis/SOBI; served as member of advisory/investigator board for Alexion, Apellis/SOBI, Biocryst, Novartis, Roche, Samsung; and served as consultant for Alexion, Novartis and Apellis. F Sicre de Fontbrune has received speaker fees from Alexion, Novartis and Pfizer and research grants from Alexion, Apellis and Novartis. 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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.