The Pharmacokinetics (PK) of GBT440 Following Single Doses in Pediatric Patients with Sickle Cell Disease (SCD)
Authors: Washington Carla B , Green Michelle , Inati Adlette C. , Brown Clark , Hoppe Carolyn C , Wang Winfred , Balaratnam Ganesh , Dixon Sandra , Fong Erica , Hutchaleelaha Athiwat , Tonda Margaret E , Lehrer Josh 
Published: April 2021

Abstract
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 &lt;12 years).
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 &lt;12 years of age. This study was designed to enable the selection of appropriate doses in children using a combination of PPK, allometric scaling and PBPK modeling to accelerate the evaluation of GBT440, a potentially disease modifying therapy for SCD, in infants and children age 9 months and older.

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.