BACKGROUND • Sickle cell disease (SCD) is an autosomal recessive inherited disorder caused by a mutation in the β-chain of hemoglobin (Hb) that leads to the production of sickle hemoglobin S (HbS). When deoxygenated, HbS polymerizes into rigid chains that deform red blood cells (RBCs); this results in sickled RBCs, hemolysis, vaso-occlusion, and organ damage

• SCD is a congenital hemoglobinopathy whose disease complications begin in early childhood

• Voxelotor (previously called GBT440) is a first-in-class, oral, once-daily therapy that is designed to modulate the affinity of Hb for oxygen. Oxygenated HbS does not polymerize, so it is believed that voxelotor blocks polymerization and the resultant sickling of RBCs, thereby potentially modifying the course of SCD (Figures 1 and 2)

• GBT440-007 is an ongoing phase 2a study in pediatric patients (aged 6–17 years, including children [aged 6–11 years] and adolescents [aged 12–17 years]). The data presented are a summary of the analysis of a cohort of children (aged 6–11 years) receiving a single dose of voxelotor from Part A (Figure 3)

Figure 1. Voxelotor: designed to bind Hb with high selectivity.

Voxelotor

• Reversible covalent binding to the N-terminus of the Hb α-chain stabilizes oxy-Hb conformation

• Profile confirms properties with high selectivity for Hb – 1:1 stoichiometry of voxelotor to Hb tetramer binding – Preferential partitioning into RBCs – Potent, dose-dependent increase in Hb–oxygen (O2) affinity

Figure 2. Voxelotor mechanism of action: upstream interruption of HbS polymerization with potential to modify disease.

HbSPolymerization

Voxelotor

RBC Damage

HemolyticAnemia

Fatigue Organ Damage Pain Crisis

Mortality

Vaso-occlusion

Figure 3. GBT440-007 study design.

Part A – Single Oral Dose • Adolescents (12–17 years) 600 mg• Children (6–11 years) 600 mg

Part B – Multiple Oral Doses • Adolescents (12–17 years) 900 mg daily for 24 weeks• Adolescents (12–17 years) 1500 mg daily for 24 weeks

OBJECTIVESPart A Objectives • Primary:

– To characterize the pharmacokinetics (PK) of voxelotor in whole blood and plasma following a single dose of the drug in children and adolescents with SCD

• Secondary – To evaluate the safety and tolerability of voxelotor following a single dose of the drug in children and adolescents with SCD

The Pharmacokinetics (PK) of Voxelotor (GBT440) Following Single Doses in Pediatric Patients With Sickle Cell Disease (SCD)Carla B. Washington,1 Michelle Green,2 Adlette C. Inati,3 Clark Brown,4 Carolyn C. Hoppe,5 Winfred Wang,6 Ganesh Balaratnam,1 Sandra Dixon,1 Erica Fong,1 Athiwat Hutchaleelaha,1 Margaret E. Tonda,1 Josh Lehrer1

1Global Blood Therapeutics, South San Francisco, CA; 2Certara Strategic Consulting, Menlo Park, CA; 3Rafik Hariri University Hospital, Beirut, Lebanon; 4Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA; 5Children’s Hospital Oakland, Oakland, CA; 6St. Jude Children’s Research Hospital, Memphis, TN

980

PK Objectives • To compare the PK properties of voxelotor in children to those observed in adolescents and adults

• To support dose selection in ongoing studies evaluating the safety and efficacy of voxelotor in children and adolescents

• To select doses for children aged <12 years based on PK data and population PK (PPK) modeling to achieve similar exposures to the 2 doses (900 mg and 1500 mg) that are currently being investigated in the phase 3 HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) study

METHODSKEY INCLUSION CRITERIA • Children aged 6 to 11 years with sickle cell anemia (SS) or sickle beta zero thalassemia (Sβ0 thal)

• Participants taking hydroxyurea needed to be on a stable regimen for ≥3 months

• Written informed parental/guardian consent ± subject assent

KEY EXCLUSION CRITERIA • Any of the following requiring medical attention within 14 days of signing the informed consent ± assent: – Vaso-occlusive crisis – Acute chest syndrome – Splenic sequestration crisis – Dactylitis

• Chronic transfusion therapy or transfusion within 30 days prior to consent • Having history of stroke or abnormal transcranial Doppler (ie, 2 transcranial Doppler measurements ≥200 cm/sec)

PK METHODS • Samples for PK analysis of voxelotor were collected at predose and at 2, 8, 24 hours (day 2), 48 hours (day 3), 96 hours (day 5), 168 hours (day 8), and 336 hours (day 15)

• Concentrations of voxelotor were determined in whole blood and plasma using validated liquid chromatography with tandem mass spectrometry assays

• A noncompartmental PK analysis using Phoenix® WinNonlin™ version 6.4.0 (Certara, Princeton, NJ) was performed using all available samples collected

• The single-dose PK data in children (aged 6–11 years) was compared to those in adolescents (aged 12–17 years)

• PPK models for whole blood and plasma were developed using NONlinear Mixed Effects Modeling (NONMEM) version 7.3 for children (aged 6–11 years) using the adult and adolescent PPK models with the addition of weight-based allometric scaling on clearance and central volume

• Prior in vitro and in vivo voxelotor data, including metabolism, protein binding, and physiochemical properties, were incorporated into a physiologically based PK (PBPK) model within Simcyp® Simulator version 14.1 (Certara) to estimate voxelotor exposures in children (aged <12 years)

RESULTS • All children (aged 6–11 years) have completed Part A of GBT440-007. The baseline characteristics for participants are summarized in Table 1

Table 1. Baseline Characteristics

Baseline Characteristics Part A n=6

Female, n 3

Male, n 3

Age, years, median (range) 8.5 (6–10)

Genotype, n

SS 5

Sβ0 thal 1

Concurrent hydroxyurea use, n (%) 6 (100)

Baseline Hb, g/dL, median (range) 8.5 (7.0–10.4)

Number of VOC during the past 12 months, n

0 2

1 3

4 1Hb, hemoglobin; Sβ0 thal, sickle beta zero thalassemia; SS, sickle cell anemia; VOC, vaso-occlusive crises.

SAFETY RESULTS • Voxelotor was well tolerated following a single dose (600 mg) in children (aged 6–11 years)

• No serious or severe, defined as grade ≥3, adverse events related to study drug were observed

PK RESULTS • Following a single oral dose of voxelotor in children (6–11 years), maximum concentrations in whole blood and plasma were reached at 8 hours and 2 hours, respectively (Table 2)

• Voxelotor concentrations decreased in a monophasic manner, with a half-life in whole blood of 29.3 hours and plasma of 42.3 hours (Figure 4 and Table 2)

• Voxelotor PK exposures in children following a single dose of 600 mg were higher than those observed in adolescents (Figure 5 and Table 3)

• The PK parameters for adolescents were previously shown to be similar to adults,1 which was also confirmed in the estimated PPK parameters (Table 4)

• The same PPK model structures used to describe the adult (≥18 years) and adolescent voxelotor concentration profiles in whole blood and in plasma were used to describe the concentration profiles and estimate PPK parameters in children (Table 4)

• PPK model validation using visual predictive checks (VPCs) confirmed good agreement between the observed PK data for children and simulated profiles based on the pooled adult, adolescent, and children voxelotor PK model (Figures 6 and 7)

• Voxelotor exposures are higher in children (aged <12 years) compared with adults and adolescents and support lower weight-based dosing in this population. The weight-based doses are expected to provide voxelotor exposures similar to those observed in adults and adolescents (Figure 8 and Table 5)

• PBPK modeling also confirmed the need for lower doses in children aged <12 years and predicted similar weight-based voxelotor doses in this population (Table 5)

Table 2. Whole Blood and Plasma PK Parameters Following a Single Dose of Voxelotor 600 mg in Children Aged 6–11 Years (noncompartmental PK analysis)

PK Parameters Voxelotor in Whole Blood Voxelotor in Plasma

Cmax (µg/mL)a 47.3 (41.7%) 4.11 (49.3%)

Tmax (hr)b 8.0 2.0

AUC0-t (hr•µg/mL)a 2785.4 (51.8) 177.4 (34.8%)

T1/2 (hr)c 29.3 ± 7.7 42.3 ± 13.5

AUC0-t, area under curve to the time of the last quantifiable concentration; Cmax, maximum observed blood concentration; Tmax, time-average maximum; T1/2, time needed for concentration to reduce by half (half-life).aValues reported as geometric means (percentage of coefficient of variation).bMedian.cValues reported as arithmetic means ± standard deviation.

Figure 4. Whole blood and plasma voxelotor concentrations following a single dose of voxelotor 600 mg in children aged 6–11 years.

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Figure 5. Voxelotor plasma and whole blood exposures in children are higher than those observed in adolescents.

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Table 3. Voxelotor Single-Dose Whole Blood PK Exposures Were Higher in Children Compared With Adolescents

Voxelotor Whole Blood PK Parameters:

Children Aged 6–11 Years

Voxelotor Whole Blood PK Parameters:

Adolescentsn=6 n=7

Cmax (µg/mL)a 47.3 (41.7%) 24.2 (47.7%)Tmax (hr)b 8.0 24.0AUC0-t (hr•µg /mL)a 2785.4 (51.8%) 1663.1 (43.8%)T1/2 (hr)c 29.3 ± 7.7 32.3 ± 6.1

AUC0-t, area under curve to the time of the last quantifiable concentration; Cmax, maximum observed blood concentration; Tmax, time-average maximum; T1/2, time needed for concentration to reduce by half (half-life). aValues reported as geometric means (percentage of coefficient of variation).bMedian. c Values reported as arithmetic means ± standard deviation.Similar differences in exposures were also observed in plasma.

Figure 6. Goodness-of-fit plots and VPC for the PPK model.

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VPC, visual predictive check.The goodness-of-fit plots indicate that the pooled PPK model describes the data adequately with little model bias. The prediction-corrected VPC shows the model fit and observed data after a single voxelotor dose in children and adolescents.

VOXELOTOR PPK MODEL DESCRIPTION • The PPK of voxelotor in children, adolescents, and adult patients with SCD was best described by a 2-compartment model with first-order absorption and first-order elimination. Key model parameters are summarized in Table 4

• For the voxelotor PPK model in whole blood, the typical value of the apparent intercompartmental clearance (Q/F) was 0.0015 L/hr and the typical value of the apparent peripheral volume of distribution (Vp/F) was 0.34 L

• For the voxelotor PPK model in plasma, the typical value of the apparent Q/F was 0.38 L/hr and the typical value of the apparent Vp/F was 79 L

• The PPK model included estimates of between-subject variability on apparent clearance (CL/F) and apparent central volume (Vc/F). A proportional residual error model was used

• The prediction-corrected VPC and goodness-of-fit diagnostic plots for the whole blood model (Figure 6) and plasma model (not shown) indicate that the model describes the data adequately

Figure 7. Individual plots for the pediatric PPK model.

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Individual plots showing the observed data from GBT440-007 (black symbols) overlaid with individual (IPRED, red line) and population (PRED, blue dashed line) predictions from the adolescent PPK model.

Table 4. Model PPK Parameter Estimates for Voxelotor in Adult and Adolescent Participants With SCD

PK Parameters

Voxelotor in Whole Blood: Adults

Voxelotor in Whole Blood: Adolescents

Voxelotor in Whole Blood: Children Aged 6–11 Years

n 42 17 6

CL (L/hr) 0.43 0.40 0.24

V (L) 21.4 18.9 9.55

Ka (1/hr) 0.34 0.30 0.33

T1/2 (hr) 34.5 32.7 27.8

Voxelotor in Plasma: Adults

Voxelotor in Plasma: Adolescents

Voxelotor in Plasma: Children Aged 6–11 Years

CL (L/hr) 7.63 5.48 3.67

V (L) 373 267 140

Ka (1/hr) 2.83 1.57 3.3

T1/2 33.9 33.8 26.4

CL, apparent clearance; Ka, absorption rate constant; T1/2, half-life; V, apparent volume of distribution.

Figure 8. Simulations of whole blood voxelotor exposures following 900 and 1500 mg-equivalent doses in children.

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Modeling and simulation were used for the selection of doses based on weight bands for pediatric patients down to 9 months of age. Preliminary dose estimates of 200, 400, and 600 mg voxelotor are supported in patients weighing 5 to <10 kg, 10 to <20 kg, and 20 to <40 kg, respectively, to provide exposures similar to adolescent patients at 900 mg. Dose estimates of 400, 600, and 900 mg, respectively, are supported to provide exposures similar to adolescent patients at 1500 mg. The horizontal dashed lines indicate the interquartile range of simulated adolescent exposures.

Table 5. Voxelotor Projected Doses Selected for Children Aged <12 Years Based on PPK Modeling and PBPK Modeling

Population 900 mg-Equivalent Adult Dose

1500 mg-Equivalent Adult Dose

5 to <10 kg 200 mg 400 mg

10 to <20 kg 400 mg 600 mg

20 to <40 kg 600 mg 900 mg

≥40 kg 900 mg 1500 mg

CONCLUSIONS • Voxelotor was well tolerated following a single dose (600 mg) in children (aged 6–11 years)

• Voxelotor PK exposures were higher in children compared with adolescents and adults, so lower doses are recommended in children

• Body weight was a significant covariate on voxelotor clearance (CL) and volume (Vc) supporting weight-based doses in children aged <12 years

• PPK and PBPK modeling are being used to simulate voxelotor PK parameters to support voxelotor dose selection for evaluation in younger children aged 9 months to <12 years

• These analyses combining PPK and PBPK modeling provide an innovative approach to minimize experimental dosing in children and accelerate dose selection

REFERENCE1. Washington C et al. Poster presented at: 22nd Congress of the European Hematology Society;

June 22–25, 2017; Madrid, Spain.

ACKNOWLEDGMENTSThe authors thank all of the participants, families, caregivers, research nurses, study coordinators, and support staff who contributed to this study. Medical writing and editorial assistance was provided by ApotheCom (San Francisco, CA) and was supported by Global Blood Therapeutics, Inc.

DISCLOSURESCarla B. Washington, Ganesh Balaratnam, Sandra Dixon, Erica Fong, Athiwat Hutchaleelaha, Margaret E. Tonda, and Josh Lehrer are employees of and have equity ownership in Global Blood Therapeutics. Michelle Green is a consultant for Global Blood Therapeutics. Adlette C. Inati is an advisor for Novo Nordisk. Carolyn C. Hoppe is a consultant or advisor for Bioverativ, Novartis, Cydan (Imara), and Global Blood Therapeutics. Winfred Wang receives funding from Global Blood Therapeutics for participation in the GBT440-007 and GBT440-031 studies. Clark Brown has nothing to disclose.

This study was sponsored by Global Blood Therapeutics. http://bit.ly/2zX7Mog

© 2017 Global Blood TherapeuticsPresented at the 59th ASH Annual Meeting & Exposition; December 9–12, 2017; Atlanta, Georgia.