Ligand has a track record of success in discovering small molecule agonists of cytokine receptors. In a research collaboration with GSK, we discovered small molecule thrombopoietin (TPO) receptor agonists, resulting in the clinical development by GSK of eltrombopag (Promacta®); the first FDA-approved oral TPO receptor agonist therapy now owned and marketed by Novartis. Ligand's research team has more recently utilized its expertise to discover small molecule agonists of the human erythropoietin (EPO) receptor, partnered with Viking Therapeutics, and the human granulocyte colony stimulating factor (GCSF) receptor as novel treatments of anemia and neutropenia, respectively.
GCSF acts on its receptor to stimulate the differentiation of bone marrow hematopoietic cells to form neutrophils. Several biologic versions of injectable recombinant human GCSF (e.g. Neupogen®, Neulasta® and Neutrogin®) are approved to treat chemotherapy-induced neutropenia, neutropenia associated with hematopoietic stem cell transplantation, and severe chronic neutropenia. We have discovered a series of novel small molecules that selectively activate human GCSF receptor function. This first-in-class program may provide the most significant innovation in the treatment of neutropenia since the approval of the first GCSF biologic in the early 1990's. Lead molecules have been identified which stimulate GCSF-dependent cell growth, increase the STAT phosphorylation, and induce the differentiation of human bone marrow cells into granulocytes. Further optimization of the chemical series should provide orally-available molecules to treat neutropenia with improved safety and convenience compared to current injectable GCSF.