Exploring treatment strategies for paroxysmal nocturnal hemoglobinuria: an overview of registered clinical trials

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease in which blood cells lack anchored proteins that regulate the complement system. The erythrocytes are then destroyed because of uncontrolled complement activity, leading to intravascular hemolysis (IVH) and a high risk of thrombosis outcome. A huge alteration in the treatment of the disease was the development of terminal complement inhibitors, with the achievement of IVH blockade, reduction or abolishment of red blood cell (RBC) transfusions, and thromboembolic events prevention. However, patients treated with these inhibitors can still present extravascular hemolysis (EVH) caused by C3 activation and residual IVH or clinically relevant levels of breakthrough hemolysis (BTH). Proximal complement inhibitors turned out to be the key to the solution of this problem by targeting components of the proximal complement pathway, avoiding intra and extravascular hemolysis. FDA approved eculizumab, ravulizumab (terminal inhibitors), pegcetacoplan, iptacopan, and danicopan (proximal inhibitors) as a treatment for PNH so far. Various clinical trials are underway to find the most effective method to treat patients with PNH. This review aimed to summarize 71 registered clinical trials in the ClinicalTrials.gov database with the various treatment drugs, possible mechanisms, and novel findings related to PNH treatment.

Keywords:

• Paroxysmal nocturnal hemoglobinuria
• clinical trials
• eculizumab
• ravulizumab
• pegcetacoplan
• iptacopan
• danicopan

Transparency

Declaration of funding

Declaration of financial/other relationships

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

A reviewer on this manuscript declared that they provide consultancy for Regeneron and Biocryst and lecture fees from Novartis, Pfizer, Alexion, Sobi and Amgen. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

Data curation, investigation, methodology, VPP; Formal analysis, VPP; Supervision, MV; Writing original draft preparation, VPP; Writing, review, and editing, VPP, MV and CP; All authors have read and agreed to the published version of the manuscript.

Acknowledgements

None.

Data availability statement

Available upon reasonable request.

Additional information

Funding

This paper was not funded.