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Gbt440 and SCD

Athiwat Hutchaleelaha, Mira Patel, Carla Washington, Vincent Siu, Elizabeth Allen, Donna Oksenberg, Daniel D Gretler, Timothy Mant, Josh Lehrer-Graiwer
AIMS: Voxelotor (previously GBT440) is a hemoglobin (Hb) modulator that increases Hb-oxygen affinity, thereby reducing Hb polymerization and sickling of red blood cells (RBCs), being developed as a once-daily oral drug to treat sickle cell disease (SCD). This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of voxelotor in healthy volunteers and SCD patients. METHODS: A total of 40 healthy volunteers (100, 400, 1000, 2000, or 2800 mg) and 8 SCD patients (1000 mg) were randomly assigned to a single dose of voxelotor once daily (n = 6 per group) or placebo (n = 2 per group)...
February 11, 2019: British Journal of Clinical Pharmacology
Jo Howard, Claire Jane Hemmaway, Paul Telfer, D Mark Layton, John Porter, Moji Awogbade, Timothy Mant, Daniel D Gretler, Kobina Dufu, Athiwat Hutchaleelaha, Mira Patel, Vincent Siu, Sandra Dixon, Noel Landsman, Margaret Tonda, Joshua Lehrer-Graiwer
New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class, oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin for oxygen, thus inhibiting HbS polymerization and the downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD which was followed by a single-arm, open-label extension study...
January 17, 2019: Blood
Lidiane Torres, Nicola Conran
Sickle cell disease (SCD) is an inherited disease with lifelong morbidity, whose complications include frequent acute painful vaso-occlusive episodes (VOEs) that often require hospitalization. The only pharmacotherapy currently in regular use for SCD management is hydroxyurea (hydroxycarbamide). Areas covered: We review recent advances in pharmacotherapy for SCD and summarize promising synthetic agents that are in late-stage development (phase 3) for SCD. Expert opinion: Emerging SCD therapies have been developed to target specific pathophysiological mechanisms of the disease, as either preventative or abortive approaches to VOEs...
February 2019: Expert Opinion on Pharmacotherapy
Paul Telfer, Irene Agodoa, Kathleen M Fox, Laurie Burke, Timothy Mant, Marzena Jurek, Margaret Tonda, Josh Lehrer-Graiwer
For many patients with sickle cell disease (SCD), jaundice is a significant clinical disease manifestation that impacts on patient well-being. We report a case of a patient with SCD and chronic jaundice treated with voxelotor (GBT440), a novel small molecule hemoglobin oxygen affinity modulator and potential disease-modifying therapy for SCD. The case patient is a 27-year-old Black male with a long history of SCD with clinical jaundice and scleral icterus. After starting voxelotor, the patient reported that his jaundice cleared within one week, and that he felt much better with more energy, and was relieved after his eyes cleared...
May 14, 2018: Hematology Reports
Kobina Dufu, Mira Patel, Donna Oksenberg, Pedro Cabrales
BACKGROUND: In sickle cell disease (SCD), polymerization of hemoglobin S (HbS) leads to the formation of rigid, non-deformable sickled RBCs. Loss of RBC deformability, sickling and irreversible membrane damage causes abnormal blood rheology, and increases viscosity which contributes to vasoocclusion and other SCD pathophysiology. GBT440 (generic name voxelotor) is a novel anti-polymerization and anti-sickling agent currently undergoing clinical evaluation for the treatment of SCD. OBJECTIVE: The purpose of this study was to determine the effects of GBT440 on deformability of sickle RBCs (SS RBCs) and the hyperviscosity of sickle cell blood (SS blood)...
2018: Clinical Hemorheology and Microcirculation
Kobina Dufu, Josh Lehrer-Graiwer, Eleanor Ramos, Donna Oksenberg
In sickle cell trait (SCT), hemoglobin A (HbA) and S (HbS) are co-expressed in each red blood cell (RBC). While homozygous expression of HbS (HbSS) leads to polymerization and sickling of RBCs resulting in sickle cell disease (SCD) characterized by hemolytic anemia, painful vaso-occlusive episodes and shortened life-span, SCT is considered a benign condition usually with minor or no complications related to sickling. However, physical activities that cause increased tissue oxygen demand, dehydration and/or metabolic acidosis leads to increased HbS polymerization and life-threatening complications including death...
September 28, 2016: Hematology Reports
Donna Oksenberg, Kobina Dufu, Mira P Patel, Chihyuan Chuang, Zhe Li, Qing Xu, Abel Silva-Garcia, Chengjing Zhou, Athiwat Hutchaleelaha, Larysa Patskovska, Yury Patskovsky, Steven C Almo, Uma Sinha, Brian W Metcalf, David R Archer
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, 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...
October 2016: British Journal of Haematology
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