Regular Article

CLINICAL TRIALS AND OBSERVATIONS

A phase 1/2 ascending dose study and open-label extension

study of voxelotor in patients with sickle cell disease
Jo Howard,1,2 Claire Jane Hemmaway,3 Paul Telfer,4 D. Mark Layton,5 John Porter,6 Moji Awogbade,7 Timothy Mant,1,8,9 Daniel D. Gretler,10
Kobina Dufu,11 Athiwat Hutchaleelaha,11 Mira Patel,11 Vincent Siu,11 Sandra Dixon,11 Noel Landsman,11 Margaret Tonda,11
and Joshua Lehrer-Graiwer11
1
Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom; 2Department of Haematological Medicine, King’s College London, London, United

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Kingdom; 3Queen’s Hospital, Romford, United Kingdom; 4Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and
Dentistry, Queen Mary University of London, London, United Kingdom; 5Department of Haematology, Hammersmith Hospital Campus, Imperial College London,
London, United Kingdom; 6Department of Haematology, University College London, London, United Kingdom; 7King’s College Hospital NHS Foundation Trust,
London, United Kingdom; 8IQVIA, Reading, United Kingdom; 9Department of Clinical Pharmacology, Faculty of Life Sciences and Medicine, King’s College
London, London, United Kingdom; 10Independent Drug Development Consultant, San Francisco, CA; and 11Global Blood Therapeutics, Inc, South San Francisco, CA

KEY POINTS New treatments directly targeting polymerization of sickle hemoglobin (HbS), the prox-
imate event in the pathophysiology of sickle cell disease (SCD), are needed to address the
l In a randomized,
placebo-controlled, severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is
phase 1/2 study in a first-in-class oral therapy specifically developed to treat SCD by modulating the affinity of
patients with SCD, hemoglobin (Hb) for oxygen, thus inhibiting HbS polymerization and downstream adverse
voxelotor (500-
1000 mg per day) was
effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized,
well tolerated. 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
l All patients receiving
extension study. This report describes results of voxelotor (500-1000 mg per day) in
voxelotor for ‡28
days demonstrated patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmaco-
hematologic kinetic, and pharmacodynamic properties of voxelotor and established proof of concept by
improvements, improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with
suggesting disease-
modifying activity SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients
in SCD. 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 he-
matologic 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. (Blood. 2019;133(17):1865-1875)

Introduction There are currently no licensed therapies that were designed to

directly target the molecular mechanism of HbS polymerization.
Sickle cell disease (SCD) is an autosomal-recessive disorder
Because oxygenated HbS cannot polymerize, it is expected that
caused by a mutation of the b-globin gene, HBB:c.20A.T
(p.Glu7Val), leading to the production of sickle hemoglobin (HbS).1 modifying HbS to increase the proportion of oxygenated to de-
Upon deoxygenation, HbS polymerizes, deforming red blood oxygenated HbS in RBCs would modify disease severity.8,9 At the
cells (RBCs) into a sickle shape and causing permanent cell time of this study, the only approved therapy for SCD was hy-
membrane damage.1-3 These damaged RBCs block capillaries and droxyurea, which is indicated to reduce the frequency of painful
undergo hemolysis, causing anemia, tissue ischemia, painful vaso- crises and the need for blood transfusions in patients with recurrent
occlusive crisis (VOC), vascular injury, and end-organ damage. moderate to severe sickle cell crises.10 Voxelotor (previously called
This leads to fatigue, reduced quality of life, and early death.1,3 GBT440) is a first-in-class oral therapy developed to treat SCD by
SCD affects ;100 000 people in the United States and millions modulating the affinity of hemoglobin (Hb) for oxygen. Voxelotor
worldwide, most of whom are in sub-Saharan Africa.4-6 New forms a reversible covalent bond with the N-terminal valine of the a
therapeutic options for SCD have evolved very slowly and the chain of Hb, resulting in an allosteric modification of Hb,9 which
treatment of SCD remains a serious, unmet medical need.7 increases oxygen affinity.11 By increasing the oxygen affinity of Hb,

© 2019 by The American Society of Hematology blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 1865
voxelotor decreases the concentration of deoxygenated HbS, the screening. Other exclusion criteria included alanine aminotrans-
HbS conformation that forms polymers. The therapeutic rationale of ferase or alkaline phosphatase .3 times the upper limit of normal
reducing the concentration of polymerizing HbS is supported in or aspartate aminotransferase .4 times the upper limit of normal,
part by the observation that individuals who are compound het- or moderate or severe renal dysfunction (defined as calculated
erozygotes for HbS and a deletional form of hereditary persistence modification of diet in renal disease [MDRD] estimated glomerular
of fetal Hb who maintain 20% to 30% of nonpolymerizing fetal Hb in filtration rate [eGFR] ,60 mL/min/1.73 m2, appropriately cor-
a pancellular distribution do not have clinical manifestations of rected for race and sex). All patients provided written informed
SCD12-16; this suggests that targeting 20% to 30% Hb occupancy consent prior to the commencement of any study-related procedures.
with voxelotor may be beneficial.
Study design
Preclinical studies with purified HbS demonstrate that voxelotor- Voxelotor was administered as multiple doses (500, 700, or
modified HbS is as effective as fetal Hb in delaying HbS poly- 1000 mg) for 28 days and multiple doses (700 or 900 mg) for
merization. In vitro studies using blood from SCD patients as 90 days (Figure 1). Patients from the 90-day, 900-mg cohort were
well as in vivo animal studies indicate that voxelotor has high offered continuation with voxelotor; patients who were interested
specificity for binding to Hb, has a half-life supporting once-daily enrolled into a separate, open-label extension study to provide 6
dosing, increases Hb-oxygen affinity, reduces sickling, improves months’ cumulative treatment with voxelotor 900 mg (NCT03041909).

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sickle RBC deformability, reduces blood viscosity, prolongs RBC The highest dose of 900 mg selected for the 90-day cohort was
half-life, and exhibits a linear pharmacokinetic (PK)/pharmaco- based on the availability of 300-mg capsules, which allowed for
dynamic (PD) relationship.11,17 a more convenient study drug administration of 3 3 300-mg
capsules vs 9 3 100-mg capsules.
The GBT440-001 (NCT02285088) phase 1/2 study was designed
to evaluate the safety and tolerability of single and multiple Voxelotor was administered orally as 100-mg or 300-mg cap-
doses of voxelotor administered to healthy volunteers and SCD sules with matching placebo capsules. The capsule strength of
patients. Secondary objectives included characterization of 300 mg was introduced for the 90-day, 900-mg cohort. Prior
the PK of voxelotor in plasma and whole blood; the PD effect to the availability of the 300-mg capsules, all patients received
of increasing Hb-oxygen affinity; the PK-PD relationship; proof of the 100-mg capsules. Eight patients were enrolled in each
concept on improving sickling, anemia, and hemolysis; and an dose cohort and were randomized 6:2 to receive voxelotor or
evaluation of voxelotor effect on cardiovascular parameters at matching placebo. Two dose cohorts (500 mg and 700 mg for
rest and during exercise. Herein, we present results of voxelotor 28 days) were expanded to include up to a total of 16 patients
treatment, administered as multiple doses in patients with SCD. to better characterize the safety of and effect of voxelotor on
anemia and hemolysis. The starting dose of voxelotor for the first
SCD cohort was 700 mg administered for 28 days, based on
achieving a target of 20% Hb modification. The 700-mg (n 5 16),
Methods 500-mg (n 5 14), and 1000-mg cohorts recruited sequentially
Patients and methods upon completion of the previous cohort.
This was a phase 1/2, randomized, double-blind, placebo-controlled
study of voxelotor in healthy volunteers and patients with SCD. A safety monitoring committee (SMC) consisting of the principal
Data from healthy volunteers and SCD patients treated with investigator, sponsor medical monitor, and an independent safety
single doses and from healthy volunteers treated with multiple physician was responsible for safety and tolerability decisions for
doses are reported separately. After characterizing the PK/PD dose escalation to the next cohort. If $2 patients in a given cohort
and safety in at least 1 multiple-dose cohort of healthy volunteers receiving voxelotor experienced a dose-limiting toxicity (DLT) and
and in 1 single-dose cohort of SCD patients, screening for no patients receiving placebo had the same or similar DLT, dose
the multiple-dose investigation for 28 days in SCD patients was escalation was to be stopped. DLT was defined as any moderate,
initiated. The study was conducted in accordance with Good grade $2 adverse event (AE) or any worsening by $1 grade of
Clinical Practice guidelines, and in conformity with the ethical a preexisting condition in patients with SCD that was related to
principles of the Declaration of Helsinki, and was compliant with study drug. Additionally, the SMC reviewed safety data from the
all relevant country-specific laws and regulations in the United 90-day cohort when the first patient reached days 28, 60, and
Kingdom and United States. The study protocol and all other 90 to approve continued dosing in the cohort through 90 days.
appropriate study-related information were reviewed and ap-
proved by an independent ethics committee. Enrollment in the 90-day cohorts was initiated following the SMCs’
review of safety data from all completed (500 mg and 700 mg) and
Patient selection ongoing (1000 mg) multiple-dose, 28-day cohorts (Figure 1). The
Patients with SCD were referred by 7 clinics in the United starting dose for the first 90-day cohort was 700 mg. Enrollment in
Kingdom to the Quintiles Drug Research Unit at Guy’s Hospital in the 900-mg cohort was initiated after all 8 patients (6 voxelotor and
London. Key inclusion criteria included patients with SCD (sickle 2 placebo) were enrolled in the 700-mg cohort.
cell anemia [HbSS] or HbS/b0 thalassemia), aged 18 to 60 years,
and .50 kg at screening. Women of childbearing potential and Assessments
all men were required to use contraception. For patients receiving Efficacy was assessed by standard clinical hematology laboratory
hydroxyurea, the dose must have been stable for $3 months prior measures (Hb, reticulocytes, unconjugated bilirubin, dense
to screening, with no anticipated need for dose adjustment during RBCs, and lactate dehydrogenase [LDH]) and percentage of
the study. Key exclusion criteria included Hb levels ,6.0 g/dL or sickled red cells. For patients enrolled in the 28-day cohorts,
.10.4 g/dL, or transfusion or hospitalization within 30 days of hematology laboratory measures were collected at screening and

1866 blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 HOWARD et al

Figure 1. Study flowchart for the SCD cohort of the GBT440-001
study. Multiple Doses for 28 days
Patients with SCD
3 cohorts

700 mg/day (n=12)

Placebo (n=4)

After completion of 700 mg/day cohort,

recruitment for 500 mg/day cohort began

500 mg/day (n=10)

Placebo (n=4)

After completion of 500 mg/day cohort,

recruitment for 1000 mg/day cohort began

1000 mg/day (n=6)

Placebo (n=2)

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The multiple doses for 90 days cohorts were initiated
after the safety monitoring committee’s review of safety
data from the completed 500 mg/day and 700 mg/day
cohorts and the ongoing 1000 mg/day cohort

Multiple Doses for 90 days

Patients with SCD
2 cohorts

700 mg/day (n=6)

Placebo (n=2)
Enrollment into the 900 mg/day cohort
began after enrollment into the
700 mg/day cohort was complete
900 mg/day (n=6)
Placebo (n=2)
Patients from the 900 mg/day 90-day cohort were
offered continuation into the open-label extension study;
patients who were interested were enrolled

Open-Label Extension
900 mg/day for 6 months
(n=4)

baseline and on days 4, 8, 15, 22, and 28. For the patients enrolled exercise stress and to ensure that the voxelotor-related increase in
in the 90-day cohorts, hematology laboratory measures were Hb-oxygen affinity did not impair oxygen delivery. CPET assess-
collected at screening and baseline; on days 4, 15, 22, 28, 44, 60, ments were collected at baseline and on days 28 and 91.
75, and 90; and then monthly for the patients enrolled in the
extension study. Assessments were also collected 30 days fol- Safety was assessed in all patients who received at least 1 dose of
lowing the last dose of study treatment in all patients. The per- study drug. Safety assessments included symptoms inquiry, physical
centage of sickled red cells was analyzed from blood smears by examinations, vital signs (blood pressure, heart rate, temperature),
2 independent blinded readers. Six independent microscopy standard clinical laboratory tests (chemistry panel, complete hema-
fields were randomly selected and imaged at 340 magnification tology panel, urinalysis, pregnancy tests), 12-lead electrocardiogram,
per smear. Greater than 500 RBCs from 3 or more different fields and AE reporting from the time of study drug administration to
were counted per blood smear. Elongated crescent-shaped RBCs 30 days after the last dose of study drug. Erythropoietin was
with tapering of opposite ends that culminated in a point were collected as a biomarker related to tissue oxygen delivery. In the
counted as sickled.18 Elliptical RBCs with smooth rounded edges 90-day cohort, functional exercise capacity was evaluated using
were counted as normal.18 Results were reported as percentage of bicycle CPET at baseline and after 90 days of dosing. CPET was
sickled red cells, calculated as the number of sickled red cells conducted as per guidelines developed by the American Thoracic
divided by the total number of RBCs, multiplied by 100. Society/American College of Chest Physicians.

Cardiopulmonary exercise testing (CPET) was performed in PK and PD

the 90-day dosing cohorts with bicycle ergometer and ventilatory Serial whole blood samples were collected to determine voxelotor
gas analysis to assess the adequacy of tissue oxygen delivery during concentrations in whole blood, plasma, and RBCs and Hb-oxygen

VOXELOTOR IN PATIENTS WITH SICKLE CELL DISEASE blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 1867
Table 1. Patient demographics and baseline characteristics

Multiple dose for 28 d Multiple dose for 90 d

Voxelotor/
placebo, mg/d Placebo 500 700 1000 Placebo 700 900

N 10 10 12 6 4 6 6

Median age (range), y 38 (21-53) 29 (20-48) 29 (20-56) 40 (25-47) 28 (18-48) 41 (29-53) 37 (25-42)

Male sex, n (%) 6 (60) 8 (80) 4 (33) 2 (33) 3 (75) 4 (67) 3 (50)

Median BMI (range), 23.5 (19.6-30.5) 21.4 (17.2-27.5) 23.0 (17.8-34.4) 22.4 (20.2-26.1) 18.8 (17.2-28.4) 26.9 (21.9-35.3) 22.8 (20.0-27.3)
kg/m2

Median baseline Hb 8.1 (7.2-10.0) 7.9 (7.0-9.7) 9.1 (7.5-9.8) 8.2 (7.5-8.4) 7.9 (7.2-9.3) 8.3 (7.1-9.7) 9.0 (7.6-9.7)
(range), g/dL

Hospitalizations due 1 (0-7) 0 (0-1) 1 (0-7) 1 (0-4) 1 (0-2) 0 (0-2) 0 (0-1)

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to painful crisis
in the previous
12 mo, median
(range)

Patients with 5 7 5 3 2 4 5
0 events in
previous 12 mo, n

Blood transfusions 0 (0-1) 0 (0) 0 (0-4) 0 (0-5) 0 (0) 0 (0) 0 (0-1)

in previous 12 mo,
median (range)

Current use of HU, 3 (30) 1 (10) 3 (25) 2 (33) 1 (25) 0 (0) 2 (33)
n (%)

BMI, body mass index; HU, hydroxyurea.

affinity. A validated liquid chromatography–tandem mass spec- samples were collected in sodium citrate vacutainers and kept at
trometry method was used to analyze samples. Analytical ranges 4°C until analyzed (within 12-43 hours after collection) according
were 10 to 10 000 ng/mL for blood and 5 to 5000 ng/mL for plasma to the method previously described11 to obtain p20 and p50
samples. Voxelotor concentration in RBCs was calculated from: values (partial pressure of O2 at which Hb is 20% or 50% satu-
rated with O2). D p20 and D p50 values were determined by
RBC Conc 5 (Blood Conc 2 [(1 2 Hematocrit) subtracting the day 21 p20 or p50 value from the sample p20 or
3 PlasmaConc])/Hematocrit p50 value. Due to the biphasic nature of the OECs upon Hb
modification with voxelotor, the p20 value is more sensitive than
Oxygen equilibrium curves (OECs) and changes in Hb-oxygen the p50 value and, therefore, was used to calculate percentage
affinity were measured using a TCS Hemox Analyzer. Clinical Hb modification with voxelotor.19

Table 2. Change in hemolysis measures from baseline to day 28

Change from baseline to day 28 Multiple dose for 28 d

Voxelotor/placebo, mg/d Placebo 500 700 1000

N 10 10 12 6

Hb, median (25th, 75th percentile), g/dL 20.1 (20.4, 0.4) 0.4 (0.1, 0.7) 0.7 (0.5, 1.0) 0 (20.4, 0.3)

Unconjugated bilirubin, median (25th, 75th 23.6 (225.9, 6.7) 230.6 (248.9, 215.4) 242.6 (244.4, 223.8) 256.3 (257.8, 247.1)
percentile), % change

Percentage of reticulocytes, median (25th, 9.0 (21.7, 13.7) 231.2 (248.9, 220.8) 237.0 (252.6, 24.5) 249.9 (264.3, 234.4)
75th percentile), % change

LDH, median (25th, 75th percentile), 26.6 (216.8, 22.9) 219.9 (239.0, 6.2) 212.0 (230.2, 25.7) 212.4 (220.2, 212.1)
% change

Sickled red cells, median (25th, 75th 12.9 (213.6, 12.9) 256.4 (270.2, 226.2) 245.9 (293.0, 26.0) 245.7 (257.9, 5.9)
percentile), % change

1868 blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 HOWARD et al

Table 3. Change in hemolysis measures from baseline to 90 days or more

Change from P* for pooled

baseline to end voxelotor vs
of treatment Dosing duration ‡90 d placebo

Voxelotor/placebo, mg/d 700† 900‡ 700/900 Placebo

N 6 7§ 13 4

Hb, median (25th, 75th 1.1 (0.6, 1.3) 0.8 (0.5, 1.3) 1.0 (0.6, 1.3) 20.1 (20.2, 0.1) ,.05
percentile), g/dL

Unconjugated bilirubin, 237.2 (243.4, 223.7) 242.9 (258.4, 230.5) 239.7 (249.9, 228.8) 14.8 (1.8, 18.5) ,.05
median (25th,
75th percentile),
% change

Percentage of 221.0 (232.9, 218.1) 218.9 (235.4, 26.2) 218.9 (232.9, 215.0) 8.9 (2.5, 25.5) ,.05

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reticulocytes, median
(25th, 75th percentile),
% change

LDH, median (25th, 75th 0.8 (214.7, 1.1) 247.7 (263.4, 212.5) 212.9 (247.7, 0.9) 0.5 (20.7, 7.2) NS
percentile), % change

Dense RBC, median 235.5|| (263.1, 18.1) 221.0¶ (260.5, 11.3) 231.4# (262.5, 11.3) 3.8** (221.3, 4.3) NS
(25th, 75th percentile),
% change

Sickled red cell, median 272.6 (279.0, 260.6) 279.2¶ (291.3, 257.7) 274.0†† (288.6, 257.0) 6.9 (3.9, 10.3) ,.05
(25th, 75th percentile),
% change

NS, not significant.

*Wilcoxon rank-sum test.
†Ninety days of dosing.
‡Ninety days to 6 months of dosing (2 patients had 90 days of dosing, 1 patient had 118 days of dosing, and 4 patients had 6 months of dosing).
§Includes 1 patient who received placebo in GBT440-001 and voxelotor 900 mg for 6 months in GBT440-024.
||n 5 4.
¶n 5 6.
#n 5 10.
**n 5 3.
††n 5 12.

Statistical analyses Overall, baseline demographics and clinical characteristics of

Demographic data were summarized by treatment. Efficacy, safety, SCD were generally well balanced across treatment groups; in
and PK/PD results were summarized using descriptive statistics this stable adult population, most patients were not taking hy-
by treatment. No formal power calculations were performed for droxyurea, and most patients had either 0 or 1 VOC that required
the sample size. PK parameters including maximum concentration hospitalization in the prior year (Table 1). All patients had the
(Cmax) and area under the concentration-time curve over 24-hour HbSS genotype. For the 28-day cohorts, 38 patients were ran-
dose intervals at steady-state (AUC0-24) were derived using non- domized. The cohorts were 500 mg of voxelotor (n 5 10), 700 mg
compartmental methods with Phoenix WinNonlin version 6.4 of voxelotor (n 5 12), 1000 mg of voxelotor (n 5 6), or placebo
(Certara, Princeton, NJ). (n 5 10). For the 90-day cohorts, 16 patients were randomized
to receive 700 mg per day voxelotor (n 5 6), 900 mg per day
voxelotor (n 5 6), or placebo (n 5 4). In addition, 4 patients from
Clinical trial data sharing
the 900-mg cohort of the randomized study received voxelotor
Summary participant data underlying the results reported herein,
900 mg in the extension study for a cumulative treatment duration
after deidentification, will be shared.
of 6 months, including 1 patient who received placebo in the
randomized study and received 900 mg per day voxelotor for
6 months in the extension study. There was complete compliance
Results with study drug administration in 91% of patients based on the
Patients daily diary and pill counts for the entire dosing period; there
Data obtained from healthy volunteers and SCD patients treated were few missed doses due to noncompliance reasons, with 5
with single doses and healthy volunteers treated with multiple patients missing 1 to 4 doses over the course of the study.
doses for 15 days will be reported in a separate publication. Here, Compliance while outside of the research facility was facilitated
we report results on SCD patients who received multiple doses. by the instruction to complete the diary on a daily basis with

VOXELOTOR IN PATIENTS WITH SICKLE CELL DISEASE blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 1869
 Figure 2. Time-dependent change in hemoglobin from
Hemoglobin (g/dL) baseline to day ‡90.
1.4
Placebo (n=4)
Voxelotor Overall (700 mg and 900 mg, n=13)
1.2

1.0

0.8
Change from baseline*

0.6

0.4

0.2

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0
Baseline Day 15 Day 28 Day 44 Day 60 ≥Day 90
-0.2

-0.4 *Relative change from baseline, median and 25th and 75th percentile

frequent telephone reminders and the high self-motivation of with an increase of ;7% for placebo (Table 3; Figure 4). No
the patients. patients had a previous history of splenectomy. For the 90-day
dosing cohorts, a dose response effect was not observed; the PK
Efficacy parameters for these 2 dose levels were very similar. Therefore,
By 2 weeks of treatment, all doses of voxelotor resulted in an in- efficacy results are summarized together for 700 mg and 900 mg,
crease in median Hb levels and/or reduction in clinical laboratory which show an improvement over placebo.
markers of hemolysis (Tables 2 and 3; Figure 2). Long-term dosing
with 900 mg showed these improvements were durable through Interestingly, with 28-day dosing, a time dependency was ob-
6 months of treatment, with a median increase in Hb of ;1 g/dL served in the effect on Hb but not on other measures of he-
(Table 3). Furthermore, nearly half of these patients (46%) achieved molysis: an initial rapid rise in Hb at all doses was evident by day
an increase in Hb of $1 g/dL from baseline (Figure 3). Improve- 15, with a transient attenuation of effect on Hb between days 22
ments in Hb were observed in patients regardless of hydroxyurea and 28. This transient attenuation of effect likely accounts for the
use (Figure 3). Statistically significant improvements in unconju- absence of Hb increase in the 1000-mg cohort at the 28-day time
gated bilirubin and reticulocyte counts were observed with dosing point (Table 2). With longer-duration dosing for up to 6 months
at 90 days to 6 months, favoring voxelotor over placebo; LDH at 700 mg and 900 mg, a sustained and durable increase in Hb is
showed greater variability (Table 3). Additionally, improvements evident (Figure 2).
were observed for dense RBCs favoring voxelotor over placebo;
however, the difference was not statistically significant. All treat- Safety and tolerability
ment doses demonstrated reductions in the percentage of sickled Overall, voxelotor was well tolerated at doses up to and in-
red cells, including a statistically significant difference for patients cluding 1000 mg per day for 28 days and 900 mg per day for
treated long-term; a reduction of 73% and 79% from baseline was 6 months. A maximum tolerated dose was not identified.
demonstrated at 700 mg and 900 mg, respectively, compared Treatment-emergent AEs (TEAEs) reported in $10% of patients

2.7* Voxelotor 900 mg (≥ 90 days)

Voxelotor 700 mg (90 days)
Placebo
Hb change (g/dL)

2.0

1.5†
1.3
1.2
1.0‡ 0.9 1 g/dL
0.8
0.6 0.6
Figure 3. Hb change from baseline to last observation 0.4‡
(‡90 days): responder analysis for ‡1 g/dL. *Day 15 0.2 0.2‡
presented due to a protocol-specified dose reduction 0§ 0
on day 17 (because of a 2.7 g/dL increase in Hb). †Day 150 -0.1
presented because this is the last time point collected -0.3
for Hb while the patient was receiving study drug. ‡Con- Baseline Hb 9.7 8.0 9.3 9.7 8.1 9.2 7.1 7.6 8.7 8.9 8.4 9.5 8.5 8.5 7.3 9.3 7.2
current hydroxyurea. §Documented nonadherence with (g/dL)
study drug regimen.

1870 blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 HOWARD et al

 A

C 25
Voxelotor 700 mg x 90 days
Placebo (n = 2)
Baseline
0

% change from baseline

-25

†
-50

B
-75

-100

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0 28 60 90
Days 90 Days

Figure 4. Sickled red cells. Change from (A) baseline (Wright-Giemsa stain) to (B) day 90 (Wright-Giemsa stain) in SCD patients. (C) Percentage of sickled red cells. Relative
change from baseline, median, and 25th and 75th percentile; baseline irreversibly sickled cell (ISC) counts ranged from 3.1% to 17.2%. †Represents 5 of 6 subjects at day 90 (D90).

are presented in Table 4. The majority of TEAEs were grade 1 or hold) and were considered to be related to the underlying SCD.
2. Treatment-related TEAEs included headache, diarrhea, and In the 4 patients who received voxelotor for 6 months, 1 patient
rash. TEAEs of headache occurred in patients receiving vox- experienced a grade 3 VOC 30 days after the last dose of study
elotor or placebo (Table 4). There were no treatment-related, drug; this patient had a history of 2 VOCs in the prior year. Four
grade $3 TEAEs. In voxelotor-treated patients, all VOC events patients had dose reductions due to TEAEs: grade 1 abdominal
occurred off-treatment (ie, after the last dose or during a dose discomfort and nausea (n 5 1; 700 mg), grade 1 increased

Table 4. TEAEs occurring in 10% or more of patients

Voxelotor/placebo, mg/d

500 700 700 900 1000 All Pooled placebo

Days 28 28 90 90 d to 6 mo 28 28-90

N 10 12 6 7* 6 41* 14

Headache, n (%) 4 (40) 5 (42) 1 (17) 2 (29) 4 (67) 16 (39) 8 (57)

Back pain, n (%) 2 (20) 3 (25) 0 2 (29) 2 (33) 9 (22) 2 (14)

Pain, n (%) 1 (10) 4 (33) 0 2 (29) 1 (17) 8 (20) 4 (29)

Pain in extremity, n (%) 1 (10) 1 (8) 1 (17) 2 (29) 0 5 (12) 0

Diarrhea,† n (%) 0 2 (17) 0 2 (14) 2 (33) 6 (15) 0

Cough, n (%) 0 2 (17) 2 (33) 0 1 (17) 5 (12) 0

Rash,‡ n (%) 0 0 1 (17) 1 (14) 3 (50) 5 (12) 1 (7)

Sickle cell anemia with crisis,§ n (%) 2 (20) 2 (17) 2 (33) 2 (29) 1 (17) 9 (22) 1 (7)

*Includes 1 patient who received placebo in GBT440-001 and transitioned to voxelotor 900 mg in the extension study.
†Grade 1; all resolved with continued dosing.
‡Two patients had treatment-related rashes (preferred terms of rash and rash papular): 1 in the voxelotor 1000-mg group and 1 in the voxelotor 900-mg group. Other TEAEs of rash were not
consistent with drug rashes.
§Also referred to as VOC. Events occurred off-treatment (during posttreatment follow-up; n 5 9) or after a dose hold/dose reduction (voxelotor 900-mg group; n 5 1).

VOXELOTOR IN PATIENTS WITH SICKLE CELL DISEASE blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 1871
Table 5. Peak exercise oxygen uptake, ventilatory threshold, and erythropoietin with voxelotor treatment

P* for pooled
Voxelotor-treated voxelotor
Voxelotor/placebo Placebo 700 mg/d 900 mg/d pooled vs placebo

N 4 6 6 12

Peak exercise oxygen

uptake VO2 max,
mL/min/kg
Median baseline (range) 23.3 (15.7-23.8) 16.7 (8.2-19.6) 21.2 (17.1-23.4) 18.9 (8.2-23.4)
Median change at day 91 22.4 (27.5 to 0.3) 1.0 (26.6 to 2.1) 21.9 (25.0 to 20.4) 20.4 (26.6 to 2.1) NS
(range)

Ventilatory threshold
oxygen uptake,
mL/min/kg

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Median baseline (range) 11.9 (11.7-12.7) 9.4 (6.4-12.4) 12.8 (11.5-16.3) 12.0 (6.4-16.3)
Median change at day 91 21.4 (25.5 to 2.3) 1.6 (20.1 to 4.7) 21.4 (21.8 to 1.4) 0.6 (21.8 to 4.7) NS
(range)

Erythropoietin
Median baseline mU/mL 112.2 (46.5, 183.0) 91.2 (77.6, 125.0) 113.5 (42.4, 150.0) 104.4 (68.6, 137.5)
(IQR 25%:75%)
% Median change to day 90 243.5 (279.3, 19.7) 0.4 (232.9, 27.6) 27.2 (211.5, 24.7) 25.2 (222.2, 14.8) NS
(IQR 25%:75%)

Vital signs: heart rate at rest

Median baseline, beats per 83 (75-93) 81 (65-101) 87 (71-99) 81 (65-101)
minute (range)
Median change to day 91 17 (17) 11 (6-38) 3 (0-5) 6 (0-38) NC
(range)

Vital signs: heart rate at

peak exercise
Median baseline, beats per 162 (160-162) 150 (116-173) 171 (146-184) 164 (116-184)
minute (range)
Median change to day 91 212 (228 to 4) 22 (220 to 16) 1 (27 to 8) 22 (220 to 16) NC
(range)

CPET (peak exercise and ventilatory threshold) not available in all patients. CPET data available for n 5 3 (placebo), n 5 5 (900 mg), n 5 11 (voxelotor-treated pooled).
IQR, interquartile range; NC, not calculated; NS, not significant.
*Two-sample Student t test.

hepatic enzyme (n 5 2; 700 mg), and grade 2 papular pruritic rash 28 days and $90 days are shown in Table 6. Following multiple daily
(n 5 1; 900 mg); the rash did not recur with dose escalation back to dosing, the Cmax and AUC increased proportionally with dose. The
900 mg. One patient at 900 mg who had a 2.7 g/dL increase in Hb Cmax and AUC0-24 at steady state at 1000 mg, the highest dose
at day 15 had a dose reduction on day 17 to 700 mg and further tested, were 483 mg/mL and 10 100 h 3 mg/mL, respectively.
reduction to 600 mg on day 22 (Figure 3); this reduction was The accumulation was ;3.5-fold compared with day 1 exposure,
protocol-defined based on an Hb increase of .2.0 g/dL over which is as expected from the single-dose PK.
baseline. One patient (1000 mg) discontinued study treatment
due to a grade 2 rash. Twelve serious AEs (SAEs) were reported for The PD effect of voxelotor was measured by changes in Hb-oxygen
12 patients who received multiple doses of study drug. The affinity. Voxelotor treatment resulted in a concentration-dependent
majority of SAEs were grade 3 VOC. None of the SAEs were decrease in p20 and p50, indicating an increase in Hb-oxygen affinity
considered related to treatment. There were no deaths reported. (Figure 5; Table 6). Patients receiving 900 mg and 1000 mg achieved
a mean percentage Hb modification near the 20% to 30% predicted
CPET showed that the change in oxygen consumption (VO2 max) therapeutic window.11 The PD effect was highly correlated to PK
from baseline to maximal exercise and ventilatory threshold (RBC voxelotor concentration, R2 5 0.70; Figure 6).
were similar between patients receiving voxelotor or placebo for
90 days (Table 5). In addition, there was no evidence of voxelotor-
related decrease in workload, increase in erythropoietin levels, or
increase in heart rate at rest or during peak exercise (Table 5). Discussion
These results show that multiple doses of voxelotor in SCD
PK and PD patients from 500 to 1000 mg daily resulted in dose-dependent
PK and PD parameters of voxelotor derived from plasma and RBC drug exposure and PD effects, with a dose-dependent increase
concentration time profiles following multiple doses (500-1000 mg) for in Hb-oxygen affinity.

1872 blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 HOWARD et al

Table 6. Mean (plus or minus SD) PK and PD parameters in SCD patients

Dosing duration 28 d* Dosing duration ‡90 d†

Voxelotor/placebo, mg/d Placebo 500 700 1000 700 900

RBC PK parameters
Cmax, mg/mL — 271 6 102 329 6 129 483 6 239 242 6 99.7 336 6 61.8
AUC0-24, h 3 mg/mL — 5050 6 1320 7560 6 2210 10 100 6 4790 5200 6 2300 7250 6 1430

Plasma PK parameters
Cmax, mg/mL — 3.6 6 0.8 5.2 6 1.9 8.1 6 2.8 4.9 6 2.0 6.3 6 1.9
AUC0-24, h 3 mg/mL — 60 6 12.9 95.7 6 28.2 151 6 49.7 83.1 6 38.8 128 6 27.1

PD parameters (obtained from whole

blood)
p50, mm Hg 34.3 6 3.3 30.9 6 2.1 29.6 6 2.6 28.0 6 3.2 ND ND
18.4 6 1.6 15.1 6 1.8 13.9 6 3.1 10.0 6 3.2

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p20, mm Hg ND ND
% Hb Mod, % 21.4 6 4.4 10.6 6 7.2 14.7 6 9.6 27.0 6 11.6 12.7 6 4.4‡ 19.8 6 4.5‡

—, not applicable; AUC0-24 indicates area under the concentration-time curve from time 0 to 24 hours; Cmax, maximum blood or plasma concentration; % Hb Mod, percentage hemoglobin
modification; ND, not determined; p20 and p50, partial pressure of O2 at which Hb is 20% or 50% saturated with O2; SD, standard deviation.
*Parameters on day 28 (at 6 hours postdose for PD).
†Parameters on day 90 (at 6 hours postdose for PD).
‡Percentage Hb occupancy derived from voxelotor RBC concentrations at 6 hours postdose on day 90.

Patients treated with voxelotor for $90 days showed a 1.0 g/dL reduction in hemolysis. These findings are consistent with an
median increase in Hb and a substantial and durable reduction in inhibition of intracellular erythrocyte HbS polymerization as
hemolysis and peripheral blood sickled red cells, with ;40% re- a potential mechanism responsible for the reduction in hemo-
duction in unconjugated bilirubin, 20% reduction in reticulocytes, lysis in SCD.
30% reduction in dense RBCs, and .70% reduction in sickled red
cells. The median Hb concentration increased rapidly after initiating The improvement in hemolytic anemia with voxelotor treatment
dosing with voxelotor treatment, starting as early as day 4. These is promising because chronic hemolytic anemia has increasingly
improvements were sustained with long-term dosing for $90 days become recognized as a critical driver of SCD pathophysiology
and almost half of the patients achieved an improvement in Hb via both chronic anemia and a systemic hemolysis-related vas-
concentration of $1 g/dL. Fluctuations in Hb levels over the first culopathy. Chronic hemolytic anemia is an independent and
8 weeks may reflect the time needed to achieve a new steady state. powerful predictor of chronic organ damage, including stroke,
Although the number of patients receiving concurrent hydroxyurea silent infarcts, renal failure, and pulmonary hypertension, as well
in this study was small, improvements were observed regardless of as early mortality in SCD.20 Notably, low Hb is a powerful pre-
concurrent hydroxyurea use, and the benefit of voxelotor on he- dictor of stroke; for every 1 g/dL reduction in Hb in the Co-
matologic parameters appears to be additive to hydroxyurea. operative Study, the risk of ischemic stroke increased by nearly
twofold.21 By improving hemolytic anemia, voxelotor has the
Overall, these data in a limited number of patients indicate that potential to improve long-term clinical outcomes and potentially
voxelotor treatment leads to a rapid, substantial, and durable survival.

A B
25 45
ns
* ns *
ns *
20 40
ns ns
p50 (mm Hg)
p20 (mm Hg)

15 35

10 30

5 Day -1 25 Day -1
Day -28 Day -28
0 20
Placebo 500 mg 700 mg 1000 mg Placebo 500 mg 700 mg 1000 mg
Dose Dose

Figure 5. A summary of the p20 and p50 values observed in SCD patients after 28 days of dosing. (A) p20 values; (B) p50 values. *Sidak multiple comparisons tests were
used to measure statistical significance. ns, not significant.

VOXELOTOR IN PATIENTS WITH SICKLE CELL DISEASE blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 1873
 current study, there were no clinical signs of tissue hypoxia in
Y = 0.97*x - 0.45
patients treated with voxelotor (eg, electrocardiogram changes,
40 R2 = 0.70
resting tachycardia) and no increase in erythropoietin levels
N = 163
compared with placebo. Furthermore, CPET was performed with
30 quantitation of exercise capacity and oxygen consumption
during maximal exercise stress. These results showed no evi-
(derived from OECs)
% Hb modification

20
dence of compromised tissue oxygen delivery in patients treated
with voxelotor up to 1000 mg for 28 days and up to 900 mg for
90 days. In addition, reticulocytes were significantly reduced
10 with voxelotor dosing, which is consistent with improved RBC
survival, improved anemia, and improved oxygen delivery to
0 tissues. Reassuringly, regarding oxygen delivery, voxelotor treat-
10 20 30 40 ment increased Hb-oxygen affinity modestly, with p50s achieved
-10 % Hb occupancy in the normal range. This study therefore demonstrates that Hb-
(derived from voxelotor RBC concentrations) oxygen affinity modulation to a therapeutic range may be safely
achieved.

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Figure 6. Linear correlation. Linear correlation observed between the percentage As expected, the PK and PD were highly correlated and the PD
of Hb modification (derived from OECs) and the percentage of Hb occupancy effects demonstrated that voxelotor doses $900 mg are likely to
(derived from voxelotor RBC concentrations) in time-matched samples from SCD achieve percentage Hb modification within the expected ther-
patients.
apeutic range of 20% to 30%. Voxelotor PK in whole blood and
plasma showed a remarkable partitioning into the RBC com-
This current study also provides preliminary evidence that partment (;99% of the voxelotor in blood is within the RBCs),
voxelotor is generally safe and well tolerated. In these patients which provides evidence of specificity of binding to Hb and limits
with SCD treated with voxelotor for 28 days to $90 days, all the potential for off-target binding and resulting safety concerns.
treatment-related AEs were grade 1 or 2 and did not require
treatment discontinuation (except for 1 patient with a rash). This In conclusion, this study suggests a favorable benefit-risk profile
study was not sufficiently powered or long enough in duration to of voxelotor for the treatment of SCD. Voxelotor was well tol-
assess the effect of voxelotor on the incidence of VOC. However, erated at doses up to 1000 mg for 28 days and 900 mg up to
there were no sickle cell crises during treatment; all VOC events 6 months. The linear, dose-proportional PK and long half-life
in voxelotor-treated patients occurred in the 28-day follow-up of voxelotor support once-daily dosing. Voxelotor demonstrated
period after study drug was stopped or after a dose hold. There rapid, sustained, and clinically meaningful improvement in
were no treatment-related grade 3 events, no treatment-related anemia, sickling, and clinical laboratory markers of hemolysis,
SAEs, and no events indicative of systemic drug hypersensitivity supporting the potential for voxelotor to serve as a disease-
reactions. There were no dose- or exposure-related safety sig- modifying therapy for SCD, which is being further investigated
nals or concerns that would limit further exploration of 900 mg or in patients with SCD in the ongoing phase 3 HOPE study
higher doses. Overall, voxelotor was well tolerated for $90 days (NCT03036813).
of treatment, with a low incidence of treatment-related TEAEs
(headache, diarrhea, rash), and most TEAEs were consistent with
SCD. However, safety data in more patients beyond 90 days are Acknowledgments
needed to assess the long-term safety profile of voxelotor. The authors thank all of the patients, families, caregivers, research nurses,
study coordinators, and support staff; Theresa Thuener and Carla Washington
(Global Blood Therapeutics, Inc, South San Francisco, CA) and Gabriella
Individuals with a thalassemia have less hemolysis and higher Passacquale (IQVIA Drug Research Unit at Guy’s Hospital, London, United
Hb, which is associated with an increased risk for VOC due Kingdom); and clinical subinvestigators who contributed to this study.
to increased blood viscosity of sickled RBCs.22 Furthermore, The latter stages of the study were carried out in the National Institute
in clinical studies of senicapoc, an experimental Gardos channel for Health Research (NIHR) Biomedical Research Centre at Guy’s and
St. Thomas’ NHS Foundation Trust and King’s College London.
inhibitor targeting an improvement in RBC hydration in SCD
patients, an Hb increase led to an increase in VOC, possibly This work was supported by Global Blood Therapeutics, Inc (South San
through increased blood viscosity.23 Voxelotor’s mechanism Francisco, CA). Medical writing support was provided by Valerie
of action differs from senicapoc. Voxelotor acts upstream by Hilliard (ApotheCom, San Francisco, CA), funded by Global Blood
inhibiting HbS polymerization, which is expected to improve Therapeutics, Inc.
RBC function and, therefore, not lead to an increase in viscosity.
In contrast, senicapoc acts downstream of HbS polymerization
by inhibiting the Gardos channel to prevent dehydration of al- Authorship
Contribution: J.H., C.J.H., P.T., D.M.L., J.P., and M.A. helped design the
ready damaged sickled RBCs. Data from patients treated with
study for patients with SCD, referred patients with SCD, and reviewed
senicapoc show that no significant reduction in intracellular Hb and provided input into the manuscript writing; T.M. was the principal
concentration occurred, and thus it is unlikely to affect HbS investigator, responsible for study conduct under International Confer-
polymerization.24 ence on Harmonisation Good Clinical Practice guidelines, and reviewed
and provided input into this publication; D.D.G. was the independent
safety physician for the safety committee, and reviewed and provided
To fully evaluate the potential benefit/risk profile of voxelotor, it input into the manuscript writing; K.D. performed experiments to
was important to assess whether the mechanism of action of measure sickled red cells, discussed and interpreted data, and con-
increased oxygen affinity would create safety concerns. In this tributed to manuscript writing; A.H. helped design and plan study,

1874 blood® 25 APRIL 2019 | VOLUME 133, NUMBER 17 HOWARD et al

oversaw PK sample analysis, performed PK/PD data analysis, suggested honoraria from Novartis and Celgene. M.A. is a consultant for, and receives
dose-escalation levels between cohorts, and contributed to manuscript honoraria from, Novartis. T.M. is an employee of, and owns shares of, IQVIA.
writing; M.P. designed and implemented the in vitro model for Hb D.D.G. is an independent consultant. K.D., A.H., M.P., V.S., S.D., M.T., and
modification, trained the staff for OEC determinations, troubleshooted J.L.-G. are employees of, and have equity ownership in, Global Blood
and analyzed PD data, prepared figures, discussed and interpreted data, Therapeutics, Inc. N.L. is a consultant clinical site liaison for Global Blood
and contributed to manuscript writing; V.S. performed experiments Therapeutics, Inc. C.J.H. declares no competing financial interests.
to develop and implement the in vitro Hb modification model, trained
the staff at the clinical site for OEC determinations, and troubleshooted Correspondence: Jo Howard, Guy’s Hospital, Great Maze Pond, London
and analyzed PD data; S.D. was the sponsor’s biostatistician, reviewed SE1 9RT, United Kingdom; e-mail: jo.howard@gstt.nhs.uk.
and interpreted data, and contributed to manuscript writing; N.L. pro-
vided input to the study design, reviewed study data, and contributed to
manuscript writing; M.T. provided input to the study design, reviewed
and interpreted data, and contributed to manuscript writing; and J.L.-G.
Footnotes
was the sponsor’s principal investigator, was a member of the safety Submitted 13 August 2018; accepted 21 December 2018. Prepublished
committee, designed the study, and reviewed and provided input into online as Blood First Edition paper, 17 January 2019; DOI 10.1182/
manuscript writing. blood-2018-08-868893.

Conflict-of-interest disclosure: J.H. is a consultant/advisor for Novartis; There is a Blood Commentary on this article in this issue.
Global Blood Therapeutics, Inc; Bluebird Bio; and Terumo BCT. P.T. is

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a consultant/advisor for Apopharma; Bluebird Bio; Global Blood Ther- The publication costs of this article were defrayed in part by page
apeutics, Inc; Novartis; and Terumo. D.M.L. is a consultant/advisor for charge payment. Therefore, and solely to indicate this fact, this article is
Agios, Cerus, and Novartis. J.P. received research funding from Novartis; hereby marked “advertisement” in accordance with 18 USC section
was a consultant/advisor for Novartis, Shire, and Celgene; and received 1734.

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