Efficacy and Safety of 1500 mg Voxelotor in a Phase 2a Study (GBT440-007) in Adolescents with Sickle Cell Disease
Authors: Brown Clark , Hoppe Carolyn , Inati Adlette , Abboud Miguel R. , Wang Winfred , Liem Robert , Woods Gerald , Hsu Lewis L. , Gordeuk Victor R. , Piccone Connie , Drachtman Richard A. , Fong Erica , Dixon Sandra , Tonda Margaret , Washington Carla , Lehrer-Graiwer Joshua 
Published: October 2019

Abstract
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.