Ligand Pharmaceuticals reports preclinical study data on erythropoietin receptor agonists

Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) announced data from a preclinical study on the erythropoietin (EPO) receptor agonist LG5640 at the upcoming 52nd American Society of Hematology (ASH) Annual Meeting being held in Orlando, Florida at the Orange County Convention Center, December 4 - 7, 2010. The poster presentation highlighted the unique mechanism of action and selective profile of LG5640, a novel oral EPO receptor agonist being developed as a more convenient and safer treatment alternative to current erythropoiesis-stimulating agent therapies (ESAs).

Ligand tested the effect of LG5640 on EPO-dependent cell lines and in cultures of CD34-positive human bone marrow cells, a well-established model for the effects of EPO on erythroid progenitor cells and their maturation into red blood cells (erythropoiesis). Ligand's findings suggest the potential for these small molecule EPOR agonists to 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 that may contribute to the adverse effects of the current injectable ESAs.

The study evaluated the activity of LG5640 versus rHuEPO in cell-based models of EPO-dependent proliferation and viability, on the various EPO-EPOR signaling pathways, and on the ability to induce erythroid differentiation in CD34-positive bone marrow cells, as measured by the expression of the erythroid marker CD235a and by formation of blast-forming erythroid colonies (BFUe). LG5640 displays an efficacy greater than the efficacy of the normal serum EPO concentration (~0.01 U/ml), but partial to the maximal effect induced by recombinant human EPO (rHuEPO) in models of EPO-stimulated erythropoiesis.

Pre-clinical Highlights

• LG5640 increased erythroid cell viability with partial efficacy to rHuEPO.
• LG5640 blocked erythroid cell apoptosis following EPO withdrawal with equivalent efficacy to rHuEPO.
• LG5640 increased differentiation of human CD34-positive bone marrow cells into erythrocytes. In addition, in combination experiments, LG5640 was seen to increase rHuEPO-stimulated erythropoiesis.
• LG5640 was found to display a unique mechanism of action, selectively activating the EPOR-GATA-1 signaling pathway, and induced the expression of GATA-1 regulated genes expressed during erythroid maturation.

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.

About Small Molecule Programs Targeting Hematopoiesis

The proprietary research tools developed by Ligand have resulted in the discovery of small molecule agonists of Thrombopoeitin (TPO), Erythropoietin (EPO) and Growth Colony Stimulating Growth Factor (G-CSF) receptors. Eltrombopag, a TPO receptor small molecule agonist approved in the U.S., Europe and Japan for the treatment of chronic idiopathic thrombocytopenic purpura (ITP), was discovered as a result of a research collaboration between Ligand and GlaxoSmithKline (GSK), and developed by GSK. In addition to the EPOR agonist program, Ligand is also conducting lead optimization studies with novel small molecule G-CSF receptor agonists for the treatment of neutropenia. Both EPOR and G-CSFR agonist programs are fully owned by Ligand.