PNH, a life-threatening condition and rare hematological disorder, is characterized by complement-mediated hemolysis, bone marrow failure (BMF), and severe thrombophilia (Risitano AM, 2012). PNH patients are affected by a clonal expansion of hematopoietic stem cells (HSCs) bearing a somatic mutation in the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) gene whose product is required for the first step in GPI anchor synthesis (Miyata T, 1994). PNH is a rare acquired hemolytic disorder that affects an estimated 7.3 to 15.9 people/million individuals worldwide (Petropoulou AD, 2010). In the United States, it is estimated that around 14,000 individuals are affected with PNH.
The clinical spectrum of PNH varies and includes anemia, thrombosis, smooth muscle dystonia, fatigue, hemoglobinuria, chronic kidney disease and pulmonary hypertension. Anemia in PNH is often multifactorial, and a result of the combination of intravascular and/or extravascular hemolysis and from various degrees of bone marrow failure. In patients with hemolytic PNH, intravascular hemolysis with moderate to severe anemia, increased reticulocytes, and markedly increased levels of lactate dehydrogenase (LDH) are common (Hill A, 2017).
Currently, the only curative therapy for PNH is hematopoietic stem cell transplantation (HSCT). However, its indication is limited predominantly to PNH with severe bone marrow failure such as patients with Severe Aplastic Anemia- PNH syndrome (De Latour RP, 2012). The risk of treatment-related mortality after SCT is relatively high, with graft-versus host disease (GvHD) accounting for most of the transplant-related deaths. The International Bone Marrow Transplant Registry (IBMTR) reported a 2-year survival probability of 56% in HLA-identical sibling transplants for PNH patients with the majority of the deaths in this study occurring within one year of transplantation (Brodsky RA, 2010). Due to the high risk of mortality with HSCT, standard of care (SoC) treatment consists of humanized monoclonal antibodies inhibiting protein C5 of the complement system; eculizumab and ravulizumab (engineered from eculizumab with prolonged dosing interval) are currently the two approved anti-C5 antibody therapies for the treatment of PNH.
Although the anti-C5 antibody therapy is generally effective in treating intravascular hemolysis (IVH), there remains a high unmet medical need for these patients due to extravascular hemolysis. Such non-/partial responder patients remain anemic and transfusion dependent, even though their transfusion requirements may decrease. Despite having serum LDH at or near normal levels, these patients continue to suffer from mild to moderate chronic anemia, related symptoms and potential long-term consequences, thus greatly impacting the patients’ quality of life (QoL).