Phase 3 clinical trials are investigating use of nomacopan in the treatment of pediatric patients with severe hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA)
Thrombotic microangiopathy (TMA) is a rare but serious complication of hematopoietic stem cell transplant (HSCT) that appears to involve complement activation, inflammation, tissue hypoxia and blood clots, leading to progressive organ damage and death. Mortality in patients who develop severe transplant-related TMAs is 80%.1
Currently, there are no approved treatment options in the U.S. or Europe.
Rationale for Bispecific (C5+LTB4) Nomacopan in HSCT-TMA
Complement C5 activation is a key driver of HSCT-TMA
- Elevated baseline complement activity
- Chronic complement present during active TMA
- With endothelial injury and progressive organ damage, especially in kidneys
Leukotriene B4 (LTB4) in HSCT-TMA
- LTB4 activity in endothelial surfaces2 and neutrophil extracellular traps (NETs)2,3,4,5 resulting in a prothrombotic state and elevated inflammation, which further activates complement
- LTB4 is elevated in patients with graft-versus-host disease (GVHD) and may impact GVHD progression6
Nomacopan Development Pathway
The U.S. Food and Drug Administration (FDA) has granted Orphan and Fast Track designations for nomacopan in severe pediatric HSCT-TMA. The Phase 3 Part A clinical trial of nomacopan in severe pediatric HSCT-TMA is currently enrolling patients.
Nomacopan in Pediatric HSCT-TMA Phase 3 Clinical Trial
- Rosenthal J. Hematopoietic cell transplantation-associated thrombotic microangiopathy: a review of pathophysiology, diagnosis, and treatment. J Blood Med. 2016;7:181-186. Published 2016 Sep 2.
- Folco EJ, et al. Neutrophil Extracellular Traps Induce Endothelial Cell Activation and Tissue Factor Production Through Interleukin-1α and Cathepsin G. Arterioscler Thromb Vasc Biol. 2018;38(8):1901-1912.
- Carestia A, et al. NETosis before and after Hyperglycemic Control in Type 2 Diabetes Mellitus Patients. PLoS One. 2016 Dec 22;11(12):e0168647.
- Mawhin MA, et al. The receptor EP3 to PGE2: A rational target to prevent atherothrombosis without inducing bleeding. Prostaglandins Other Lipid Mediat. 2015 Sep;121(Pt A):4-16.
- Klopf J, et al. Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease. Int J Mol Sci. 2021 Jan 8;22(2):559.
- Takatsuka H, et al. Predicting the severity of intestinal graft-versus-host disease from leukotriene B4 levels after bone marrow transplantation. Bone Marrow Transplant. 2000;26(12):1313-1316.