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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 (Hb) for oxygen, thus inhibiting HbS polymerization and 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, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof of concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.

Background: Sickle cell disease (SCD) is a genetic disorder caused by a mutated hemoglobin S (HbS) that polymerizes in the deoxygenated state and triggers the downstream effects of red blood cell deformation (sickling), hemolysis, vaso-occlusion, and inflammation. Injury from SCD starts in infancy and accumulates over a lifetime causing end-organ damage and ischemic tissue injury, leading to fatigue, pain (vaso-occlusive crisis), and other clinical complications that are underrecognized, undertreated, and associated with early death. Voxelotor is an oral, once-daily therapy that modulates hemoglobin (Hb) affinity for oxygen, thereby inhibiting Hb polymerization. GBT440-007 is a phase 2a study designed to assess the safety, pharmacokinetics (PK), and efficacy of voxelotor in pediatric patients with SCD (HbSS or HbSβ0 thalassemia). Methods: This ongoing study is evaluating multiple doses of voxelotor at 2 dose levels, 900 mg/day and 1500 mg/day, for 24 weeks in adolescents aged 12 to 17 years. The primary objective is to assess the effect of voxelotor on anemia. Secondary objectives include the effects on clinical measures of hemolysis, PK (PK parameters determined using population PK analysis), cerebral blood flow as assessed by transcranial doppler ultrasound (TCD), and safety. Results: Results for adolescents treated with 900 mg/day have been previously reported. As of June 18, 2018, partial data are available for 13 patients (9 females and 4 males). The median age was 14 years (range, 12-17 years) and median weight was 47 kg (range, 31-72 kg). All participants were on hydroxyurea (HU), and 46% had 2 or more painful crises (range, 2-15) in the year prior to enrollment. The median baseline TCD flow velocity was 112 cm/s (range, 92-177 cm/s), and all were less than 135 cm/s at baseline except for 1 with a baseline of 177 cm/s. Data for measures of hemolysis and TCD are available for 5 adolescents who received voxelotor for 12 weeks. The median increase in Hb was 1.0 g/dL at 12 weeks (Table). Median reductions in reticulocytes and indirect bilirubin were 29% and 18%, respectively (Table), consistent with previously reported results of voxelotor in adults with SCD. Preliminary data suggest linear PK up to 1500 mg, the highest dose evaluated. The adolescent with a baseline conditional TCD (177 cm/s of the bifurcation of the internal carotid artery) on background HU at the maximum tolerated dose (29 mg/kg) had a reduction in TCD flow velocity of 20 cm/s with a concordant increase in Hb of 1.7 g/dL at week 24 with voxelotor compared to baseline and a decrease in reticulocytes from 16.45% to 10.4% (Figure). TCD flow velocities in all other arterial segments showed an overall decline at week 24. All treatment-related adverse events were grade 1 or 2, and there were no treatment-related serious adverse events. Data for all adolescents treated with voxelotor 1500 mg/day for up to 24 weeks will be presented at the conference. Conclusions: Preliminary results indicate that voxelotor at 1500 mg/day was well tolerated. Data from 5 adolescents at 12 weeks show a marked improvement in Hb and reductions in clinical measures of hemolysis. Importantly, hematologic improvements are seen in adolescents already managed at the maximally tolerated dose of HU. Compared to previously reported data at 900 mg/day, this indicates a dose-dependent improvement in hemolytic anemia. One adolescent with conditional TCD, despite background HU, achieved normalized TCD flow velocity after voxelotor therapy. Overall, these results are consistent with in vivo inhibition of HbS polymerization by voxelotor and support the ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adolescents with SCD. Disclosures Brown: Global Blood Therapeutics: Consultancy, Research Funding. Inati:Global Blood Therapeutics: Research Funding; Astra Zeneca: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Woods:Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; Guidepoint: Honoraria; Putman: Honoraria; Children's Mercy Hospital: Employment, Membership on an entity's Board of Directors or advisory committees. Hsu:Global Blood Therapeutics: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ironwood: Research Funding; Emmi: Consultancy; Hilton Publishing: Consultancy; Gerson Lehman Group: Consultancy; Guidepoint: Consultancy. Piccone:Novartis: Consultancy. Fong:Global Blood Therapeutics: Employment. Dixon:Global Blood Therapeutics: Employment. Tonda:Global Blood Therapeutics: Employment. Washington:Global Blood Therapeutics: Employment. Lehrer-Graiwer:Global Blood Therapeutics: Employment.

Background: Sickle cell disease (SCD) is caused by polymerization of hemoglobin S (HbS), resulting in hemolysis and vaso-occlusion. Currently, no therapy achieving direct pancellular inhibition of HbS polymerization is available for adults or children with SCD. GBT440 is an oral, once-daily novel small molecule inhibitor which increases hemoglobin oxygen affinity, thereby preventing HbS polymerization and red blood cell sickling. Study GBT440-007 was designed to evaluate the safety, treatment response and pharmacokinetics (PK) of GBT440 in a pediatric population (6 to 17 years of age). This single dose, safety and PK study represents the first evaluation of GBT440 in children with SCD (6 to 11 years of age) and is designed to estimate the appropriate clinical dose of GBT440 in children in this age range. Methods: This is an ongoing, open-label, Phase 2a study in pediatrics (6 to 17 years of age) with SCD (HbSS or HbSβ0 thalassemia). This study is being conducted in 2 parts: Part A, single-dose (GBT440 600 mg) and Part B, multiple-dose (GBT440 900 mg and 1500 mg) for 24 weeks. The primary objective of Part A is PK and the primary objectives of Part B are treatment response and safety. This abstract focuses on results from Part A in children (6 to 11 years of age). PK samples to measure whole blood and plasma GBT440 concentrations were collected up to 15 days postdose following a single oral dose of GBT440 600 mg. Population PK (PPK) models of whole blood and plasma data will be developed using non-linear mixed effects modeling (NONMEM) to identify GBT440 dosing regimens for pediatric populations with SCD. In addition, developmental physiology (liver size, renal function, liver blood flow) and biochemistry (hematocrit, albumin, cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) ontogeny) will be integrated within a physiologically-based PK (PBPK) model to determine the exposures of GBT440 and help support dose selection in children (9 months to Results: Six patients (3 females and 3 males) have received a single oral dose of GBT440 600 mg. The median age of patients was 8.5 years (range 6 to 10 years) and the median body weight was 21.1 kg (range 16 to 38 kg). All six patients were on concurrent hydroxyurea treatment. Preliminary data suggest GBT440 was well tolerated and no treatment-related adverse events were reported. PK data along with planned doses and estimated exposures based on PPK, allometric scaling and PBPK modeling in pediatric patients with SCD will be presented. Conclusions: This is the first study that will be used to develop a GBT440 PPK model in pediatric patients with SCD Disclosures Washington: Global Blood Therapeutics: Employment, Equity Ownership. Green: Global Blood Therapeutics: Consultancy. Inati: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Hoppe: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Balaratnam: Global Blood Therapeutics: Employment, Equity Ownership. Dixon: Global Blood Therapeutics: Employment, Equity Ownership. Fong: Global Blood Therapeutics: Employment, Equity Ownership. Hutchaleelaha: Global Blood Therapeutics: Employment, Equity Ownership. Tonda: Global Blood Therapeutics: Employment, Equity Ownership. Lehrer: Global Blood Therapeutics, Inc.: Employment, Equity Ownership.