A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440 (Voxelotor), a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, Voxelotor is currently in clinical trials to explore its potential as a disease-modifying agent in sickle cell patients, and has been granted the Break Through Designation by the FDA.
Dr. Sham joined GBT in July 2014 as senior vice president, chemistry and was appointed senior vice president, Research in May 2016. He has significant experience and accomplishments in pharmaceutical research and discovery. Prior to GBT, he served as head of research and development at iOneWorldHealth/Path.org (PATH), a non-profit pharmaceutical development organization. Prior to that, he served as senior vice president of research and head of chemical sciences at Elan Pharmaceuticals, Inc., where he led the chemistry team in the discovery of two clinical candidates for the treatment of Alzheimer's disease. Before that, he worked at Abbott Laboratories Inc., where he and his team discovered and advanced 10 clinical candidates spanning cardiovascular disease, HIV, oncology and diabetes. His 24-year tenure at Abbott Laboratories culminated in his appointment as a distinguished research fellow in global pharmaceutical discovery division.
Dr. Sham is the co-inventor of Norvir® and the primary inventor of Kaletra®, Abbott Laboratories' first- and second-generation HIV protease inhibitors approved for the treatment of HIV. Dr. Sham has published more than 180 scientific articles in peer-reviewed journals and is a named inventor on 84 issued U.S. patents and numerous international patents. Dr. Sham was named National Inventor of the year in 1997; Hero of Chemistry by the American Chemical Society in 2003; and Distinguished Alumni of the University of Hawaii in 2011.
Dr. Sham holds a Ph.D. in synthetic organic chemistry from the University of Hawaii and completed his post-doctoral training in the department of chemistry at Indiana University.