A Real-world, Multi-center, Prospective, Observational Study for PNH in China

Overview

As a rare disease listed in the First Catalogue of Rare Diseases in China (National Health Commission of the People's Republic of China, 2019), PNH is poorly studied in China subse-quently leading to the inadequate elucidation of disease characteristics and clinical outcomes. Eculizumab was recently approved by NMPA. The availability of Eculizumab in China pro-vides people living with PNH with a new treatment option that can reduce disease symptoms and prevent the dysregulated complement system from causing further damage. A Phase Ⅳ study is necessary to understand the natural history of disease and the clinical outcomes with different medical interventions.

Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare and life-threatening acquired disorder of the pluripotent hematopoietic stem cell and therefore can affect erythrocytes, leukocytes, thrombocytes and probably some endothelial cells. These hematopoietic stem cells have acquired a somatic mutation in the phosphatidylinositol glycan class A (PIG-A) This gene is required for the synthesis of the glycosyl phosphatidyl-inositol (GPI) anchor, which is necessary to attach some proteins to the blood cell membrane. Therefore, a lack of two important complement regulatory proteins is observed on the cell surface: 'decay-accelerating factor' (DAF), also called 'CD55' and 'membrane inhibitor of reactive lysis' (MIRL), also called 'CD59' Thus, red blood cells are more vulnerable to the attack by the complement activation product MAC (complement membrane attack complex). This leads to a complement-mediated intravascular hemolysis. The predisposition of venous thrombosis, hemolytic anemia, complete thrombocytopenia, and thrombosis are the three main characteristics of the disease. Its incidence is not really known but estimated at 0.1\~0.6/100 000 per-sons/yr, and prevalence is estimated at 1\~4 cases/100,000 persons/yr. PNH was listed in the First Catalogue of Rare Diseases in China, and its incidence was previously reported to be 1/100,000 persons/year, peak onset age 20\~40 years. PNH can be classified into 3 different forms: classical PNH, PNH associated with aplastic anemia (PNH-AA), and subclinical PNH, based on clinical features, bone marrow characteristics, and the size of the mutant clone. The traditional treatment of PNH is still aimed at "protecting" the PNH clone, reducing complement attack and destruction, and alleviating hemolysis with symptomatic supportive therapy. In acute hemolytic episodes, could be administered adrenal glucocorticoids, complemented by cell membrane stabilizers, folic acid, and alkaline drugs. In case of PNH-AA syndrome, treatment with androgens and immunosuppressants may be used; anticoagulation and heparin therapy should be given for the occurrence of thrombosis; other symptomatic supportive treatments include transfusion of red blood cells and platelets if necessary as well as antibacterial drugs in case of infection. Bone marrow transplantation is the only curative therapy for PNH presupposes, but patient need to achieve complete remission with chemotherapy first and a suitable donor is needed. Besides supportive care, global guidance/consensus also recommend C5 complement inhibitor Eculizumab as a treatment method, and its use could significantly improve 5-year survival rate to 95.5%. Eculizumabis a humanized, first-in-class, anti-C5 antibody that binds with high affinity to C5 and blocks the terminal complement-C5a and C5b-9 formation, reducing the chronic uncontrolled complement activation and its consequences. Eculizumab has been approved for PNH by National Medical Products Administration in August, 2022.