July 2024: Paroxysmal nocturnal hemoglobinuria (PNH)

This month provided not just one, but two FDA approvals for antibody drugs treating patients with paroxysmal nocturnal hemoglobinuria (PNH)!

• PiaSky (crovalimab-akkz)

• Epysqli (eculizumab-aagh)

PNH is a rare, acquired, life-threatening blood disorder characterized by the destruction of red blood cells prematurely by the complement system. The prevalence is estimated to be between 0.5-1.5 per million people in the general population. Historically, treatment was mainly supportive, focusing on blood transfusions and iron supplements for anemia, anti-thrombosis prophylaxis, and bone marrow transplants for severe cases. PNH's pathogenesis involves complement-mediated hemolysis due to loss of proteins like CD55 and CD59, leading to complications such as thrombosis. Current treatments include complement pathway inhibitors like eculizumab and ravulizumab (both monoclonal antibodies), which block factor C5 to prevent hemolysis. Eculizumab significantly reduces transfusion needs and thrombotic risks but has limitations like breakthrough hemolysis and high costs. Ravulizumab, approved in 2018, offers a longer half-life and fewer side effects, potentially becoming the preferred first-line treatment.

On June 20, the FDA approved Genentech's PiaSky (crovalimab-akkz) for the treatment of PNH. Crovalimab was previously approved in China on February 8 earlier this year. As a monoclonal antibody that binds to complement protein C5 and inhibits its cleavage into C5a and C5b, the drug prevents the formation of the membrane attack complex.

The COMMODORE 1 and COMMODORE 2 trials of crovalimab for previously treated and treatment-naïve PNH, respectively, demonstrated efficacy and safety for both patient populations in comparison with the benchmark, eculizumab. Notably, a significant portion of patients successfully self-administered crovalimab at home, with the majority preferring it over eculizumab. Despite new PNH treatments like ravulizumab and pegcetacoplan emerging during the trials, crovalimab stands out due to its subcutaneous administration and potential for overcoming eculizumab resistance. Additionally, new oral therapies such as danicopan and iptacopan offer promising alternatives, though adherence concerns exist.

On July 22, the FDA approved Samsung Bioepis’ Epysqli (eculizumab-aagh), a biosimilar to Alexion Pharmaceuticals, Inc.'s Soliris (eculizumab). Epysqli is a monoclonal antibody and anti-C5 complement inhibitor approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).