Earlier this summer, AA&MDSIF called for research proposals addressing Paroxysmal Nocturnal Hemoglobinuria (PNH), made available through a generous donation by the Geczik family. Based on scientific review by an ad-hoc panel of PNH experts, AA&MDSIF selected three proposals to receive funding.
Robert A. Brodsky, MD., Johns Hopkins University, will receive an award for his project titled Preclinical Development of an Oral Factor D Complement Inhibitor to Treat PNH. PNH is a life-threatening hemolytic anemia that results from the loss of cell surface complement regulators. These patients have hemolytic anemia, risk for blood clots and early death. Eculizumab is an expensive FDA-approved drug to treat PNH but must be given intravenously. Up to 20% of PNH patients treated with eculizumab continue to need transfusions. The goal of this project is to address three major limitations of PNH treatment: continued hemolysis while on eculizumab; inconvenience of intravenous infusions; and high cost. Our previous data suggest that ACH4471, a factor D inhibitor, is more effective in blocking complement than eculizumab, because it is a small molecule, and can be developed as an oral drug. The objective of this proposal is to perform the preclinical development of what may become the first clinically approved oral agent to treat PNH and other complement related diseases.
Collaborative research led by Antonio M. Risitano, MD., Federico II University, Naples, Italy and Rodrigo Tocantins Calado, MD., Ph.D., University of São Paulo in Ribeirão Preto, SP, Brazil, was awarded funding. The project is titled A proof-of-concept phase Ib/II study with the C3-targeting complement inhibitor AMY-101 for the treatment of untreated PNH patients. The treatment of paroxysmal nocturnal hemoglobinuria (PNH) has changed with the introduction of the first complement inhibitor eculizumab, which led to a remarkable clinical benefit for the majority of patients. However, a substantial proportion of patients remain transfusion-dependent; for these patients there is an obvious unmet clinical need. Preclinical data produced by our group suggest that alternative strategies of complement inhibition may be effective for these (and possibly all) PNH patients. The proposed research is an initial clinical study in PNH to investigate the effect of the novel complement inhibitor AMY-101; our study aims to prove the efficacy of this drug, paving the way for larger clinical studies.
Kohei Hosokawa, MD., PhD. Postdoctoral Fellow, National Heart, Lung and Blood institute, National Institutes of Health will be awarded funding for his project titled Whole transcriptome sequence in paroxysmal nocturnal hemoglobinuria/aplastic anemia. PNH is caused by a somatic mutation in the PIG-A gene, which is responsible for a cellular protein deficiency that is detectable in approximately 60% of aplastic anemia patients and in 20% of low-risk MDS patients as well as PNH patients. In this project, RNA sequencing will be used to examine the functional effects of the PIG-A mutation in CD34+ cells and T- cells shared by PNH, MDS and aplastic anemia patients. The goal is to identify the novel pathways that are responsible for selective advantage of PNH clone, and the immune response in T cells that attack the hematopoietic stem cells. A better understanding of the novel pathways in PNH pathophysiology will allow for the development of potential therapeutic strategies to block these pathways.
Congratulations to the grantees, and we extend our sincere appreciation to the Geczik family, to all those who submitted proposals, and a special thanks to the ad-hoc review committee.