Preclinical data show promise in sickle cell disease

Global Blood Therapeutics presents data at the recent American Society of Hematology meeting demonstrating its lead drug candidate, GTx011, prevents the sickling of red blood cells in preclinical models of sickle cell disease (SCD)

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SOUTH SAN FRANCISO, Calif.—Global Blood Therapeutics, a biopharmaceutical company focused on developing novel, orally-available therapeutics for chronic blood diseases, announced new preclinical data demonstrating that GTx011, its lead drug candidate for the treatment of sickle cell disease (SCD), prevents the sickling of red blood cells in preclinical models of SCD. The data were presented today during an oral presentation (abstract number 316) at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans. Additional data on the effects of GTx011 were presented at ASH on Sunday, December 8 in a poster presentation titled GTx011, a Novel Agent That Improves Rheological Properties of Sickle Cell Blood By Increasing Oxygen Affinity For Hemoglobin (abstract number 2207).
"This is our first report that GTx011, our lead product candidate, significantly delays in vitro polymerization of the mutated form of hemoglobin that causes SCD, and also markedly reduces sickling of red blood cells from preclinical models of disease and from SCD patients. With these properties, GTx011 addresses the underlying cause of this devastating blood disease, which may lead to benefits in both the acute symptoms and chronic consequences of SCD," said Mark A. Goldsmith, M.D., Ph.D., chief executive officer of Global Blood Therapeutics. "These data, including preclinical pharmacokinetics, help to validate our best-in-class hemoglobin modifier strategy, and enable us to continue advancing toward clinical development."
“We’re extremely excited,” Goldsmith told DDNews. “Our focus has been on molecular and cellular mechanisms. When red blood cells carrying the sickle gene enter low oxygen tissue environments, the abnormal hemoglobin aggregates, polymerizing and changing cell shape. GTx011 has been engineered to favor binding of oxygen, even in low oxygen environments. We now have high-resolution images of the co-crystal structure of our compound bout to hemoglobin so we know that GTx011 does bind.”
As of this date, Global is not releasing images of the crystal structure because patents are pending. “We have filed for patents on the specific compound, the class of compounds and other considerations,” Goldsmith relates. “To date, we have not identified any undesirable characteristics that would affect long-term use among individuals who are homozygous for SCD. GTx011 demonstrates good oral bioavailability and pharmacokinetics across various species and can be dosed once daily at moderate levels.”
Goldsmith notes that GTx011 also reduces blood viscosity. “Abnormal cell shape and, more important, lack of deformity, are important aspects of the physiology of the disease. As we know, blood must pass through very small vessels. The inability to do so contributes to acute sickle crisis and chronic manifestations resulting in end organ death.”
Sickle Cell Disease (SCD) is a global health challenge with very limited treatment options and no therapies that address the underlying cause of the disease. SCD is caused by a single genetic mutation that alters the oxygen-transport protein hemoglobin and results in the "sickling"—or change to a crescent shape—of red blood cells. There are approximately 100,000 SCD patients in the United States and more than 7 million worldwide. It is particularly prevalent among individuals of African descent. SCD patients suffer severe pain, vaso-occlusion, anemia, organ damage, high risk of stroke and renal insufficiency. There is typically an early onset of symptoms and reduced life expectancy. While blood transfusions and bone marrow transplants can be used in select settings, these procedures are costly, require matching donors and extensive medical infrastructure for delivery, and themselves can lead to life-threatening complications— factors limiting their accessibility to patients in developing countries. Hydroxyurea is the only approved pharmaceutical treatment in the United States.
Global Blood Therapeutics is a biopharmaceutical company developing novel, orally available therapeutics for chronic blood diseases. The company is addressing severe, non-malignant blood-based diseases for which there are currently no effective cures and only limited therapeutic options. Global Blood Therapeutics is focused on the critical need for therapeutics that address the underlying causes of blood diseases, not just the symptoms. The company's extensive drug discovery capabilities— combining world-class medicinal chemistry with deep expertise in blood biology—are driving its product pipeline of mechanism-based therapeutics, including programs in sickle cell disease and hereditary angioedema. Global Blood Therapeutics is a private company launched in 2012 by Third Rock Ventures with an experienced leadership team and scientific founders.

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