EPO and GCSF

Ligand's Cytokine Receptor Drug Discovery Programs

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 development by GSK of eltrombopag (Promacta®); the first FDA-approved oral TPO receptor agonist therapy for the treatment of adult patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP). We subsequently discovered and developed our own TPO receptor agonist, LGD-4665, later granting GSK exclusive rights for development and commercialization.

Ligand's research team has recently utilized its expertise to discover small molecule agonists of the human erythropoietin (EPO) receptor and the human granulocyte colony stimulating factor (GCSF) receptor as novel treatments of anemia and neutropenia, respectively.

 

EPO Receptor Agonist Program

Erythropoietin (EPO) acts on its receptor to stimulate the differentiation of bone marrow hematopoietic cells to form red blood cells. Various recombinant human EPO derivatives are marketed as erythropoiesis-stimulating agents (ESAs) for the treatment of anemia due to renal failure or cancer chemotherapy (e.g., Aranesp^TM, Epogen^TM, Eprex^TM, and Procrit^TM).

We have discovered a series of orally-available, small molecule agonists of the EPO receptor that should provide additional benefit in the treatment of anemia with improved safety, tolerability, and patient acceptance due to the convenience of oral administration and the lack of excessive erythropoietic stimulation. In December of 2010, we presented preclinical data on our EPO receptor agonist LG5640 at the 52nd American Society of Hematology (ASH) Annual Meeting, highlighting its unique mechanism of action and selective profile.

In addition to LG5640, highly potent and selective EPOR agonists have been identified that display oral bioavailability in the mouse, rat and monkey, and have a desirable in vitro and in vivo safety profile for preclinical development. We are seeking a partner to advance pre-clinical and clinical development, and commercialization.

GCSF Receptor Agonist Program

Granulocyte colony stimulating factor (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.