Download INTRODUCTION OBJECTIVES AND STUDY DESIGN RESULTS

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Long-Term Dosing in Sickle Cell Disease Subjects with GBT440, a Novel HbS Polymerization Inhibitor
Jo Howard, MD1; Claire Jane Hemmaway, MD2; Paul Telfer, FRCPath, MD3; Mark Layton, MB, FRCP4; Moji Awogbade, MD5; John Porter, MB, FRCP, FRCPath6; Timothy Mant, MB, FFPM, FRCP7; Sandra Dixon, MS8; Kobina Dufu,
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PhD ; Athiwat Hutchaleelaha, PhD ; Margaret Tonda, PharmD ; Kenneth Bridges, MD ; Eleanor Ramos, MD ; Joshua Lehrer-Graiwer, MD, MPhil, FACC
Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK; 2Queens Hospital, Romford, UK; 3The Royal London Hospital, London, UK; 4Imperial College NHS Foundation Trust, London, UK; 5Department of Haematology, King's College Hospital, London, UK;
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Department of Haematology, University College London Hospital, London, UK; 7Quintiles Drug Research Unit at Guy’s Hospital, London, UK; 8Global Blood Therapeutics, South San Francisco, CA. USA
1
INTRODUCTION
Figure 3. GBT440-001 study design
●● Sickle cell disease (SCD) is a genetic disorder resulting in the production of mutated hemoglobin S
Figure 4. Significant proportion of patients achieve large Hb response (> 1 g/dL)
2.7a
sickled RBCs, hemolytic anemia, and vaso-occlusion
Hb change to end of treatment
or last available (g/dL)
Part A – Single Dose
• HV: 5 cohorts (100, 400, 1000, 2000, 2800 mg)
• SCD patients: 1 cohort (1000 mg)
(HbS) that, upon deoxygenation, polymerizes and distorts red blood cells (RBCs) resulting in
Part B – Multiple Doses (15 and 28 d)
• HV : 3 cohorts (300, 600, 900 mg/d × 15 d)
• SCD patients: 3 cohorts (500, 700, 1000 mg/d × 28 d)
• Variant genotype cohort ongoing (600 mg/d × 28 d)
●● Management strategies have evolved very slowly and treatment of SCD remains a serious
unmet medical need, with significant end-organ damage and ischemic tissue injury leading to
Part C – Multiple Doses (90 d)
• SCD subjects: 2 cohorts (700 mg/d, 900 mg/d × 90 d)
• Cohort 16 (700 mg) and Cohort 17 (900 mg)
clinical complications (pain, fatigue, and vaso-occlusive crisis) that are under-recognized and
under-treated
Extension up to 6 months
• Cohort 17, 900 mg: Ongoing enrollment
Cohort = 8 subjects (6 active, 2 placebo)*
●● GBT440 is an oral, once-daily therapy that modulates hemoglobin (Hb) affinity for oxygen, thereby
inhibiting Hb polymerization in SCD (see Figures 1 and 2)
900 mg GBT440
700 mg GBT440
Placebo
2
1.4
1.3
1.2
1.2
1
1 g/dL
0.9
0.8
0.7
0.6
0.0
–0.1
–0.3
9.7
8.0
8.7
9.7
8.1
9.9
9.2
7.1
7.6
8.4
8.9
9.5
8.5
8.5
7.3
9.3
Day 15 data presented due to a protocol-specified dose reduction on Day 17 because of a large increase in Hb
b
Patient documented non-adherence with study drug regimen
–– 38 patients have been enrolled into 28-day cohorts
•• 28 patients received GBT440 (500, 700, or 1000 mg)
•• 10 patients received placebo
–– 2 patients with the HbSC genotype have been enrolled; enrollment ongoing (data not yet available)
–– 16 patients have been enrolled into 90-day cohorts
•• 12 patients received GBT440 (700 or 900 mg)
•• 4 patients received placebo
• Reversible covalent binding to N-terminus of Hb α chain ➡
stabilizes oxy-Hb conformation
• Profile confirms properties with high selectivity for Hb
– 1:1 stoichiometry of GBT440 to Hb tetramer binding
– Preferential partitioning into RBCs
– Potent, dose-dependent increase in Hb-O2 affinity
GBT440
Table 2. Significant Hb increase maintained with dosing for 3-6 months
Median change to
end of treatment
(25th and 75th percentile)
Proportion of patients
with >1 g/dL increase
●● 5 patients have continued into the extension study (all at GBT440 900 mg)
Figure 2. G
BT440 clinical hypothesis - increase in HbO2 affinity inhibits HbS
polymerization
HbSS RBC
Table 1. Baseline characteristics and patient disposition
Hemolysis
Oxy‑SS RBC
O2
Sickled RBC
α α
β β
Oxy‑HbS O2
monomer
Cohort 17
900 mg × 3-6 mo
(n = 7)a
Placebo (pooled)
(n = 4)
2 (33)
3 (33)
1 (25)
Men, n (%)
Occluded
Blood Flow
Median (range) age, y
Current hydroxyurea, n (%)
α α
α α
α α
β β β β β ββ ββ ββ β
α α
α α
α α
Median (range) baseline Hb, g/dL
Deoxy‑HbS polymer
Modify course of SCD disease
4 (67)
4 (67)
3 (75)
41 (29, 53)
36 (25, 42)
27 (18, 48)
0
2 (29)
1 (25)
8.3 (7.1, 9.7)
9.2 (7.6, 9.9)
7.9 (7.2, 9.3)
Hospitalizations due to painful crisis in prior year, n (%)
GBT440 inhibits Hb polymerization ➔ decreases RBC damage
Improves blood flow
Cohort 16
700 mg × 90 d
(n = 6)
Women, n (%)
Stops hemolysis and
improves anemia
0
4 (68)
5 (71)
2 (50)
1
1 (17)
1 (14)
1 (25)
>2
1 (17)
1 (14)
1 (25)
700 mg × 90 d
900 mg × 90 d
Placebo (pooled)
Dosed
6
7a
4
Discontinued early due to AE
0
0
0
Completed 90 d of dosing
6
7
4
Dosed > 90 d
0
5
0
Subject Disposition
OBJECTIVES AND STUDY DESIGN
●● GBT440-001 is an ongoing, Phase 1/2 randomized, double blind, placebo-controlled study to
a
–– Sickle cell disease (SCD) patients
•• HbSS, HbS/β0thalassemia, Hb 6-10 g/dL
••
HbSC, HbS/β+thalassemia, Hb 6-11.5 g/dL
•• No vaso-occlusive crisis or RBC transfusion within 30 days; stable hydroxyurea allowed
●● Key objective in SCD patients was to assess the effect of GBT440 compared to placebo on clinical
measures of hemolysis and anemia
©2016 Global Blood Therapeutics
1.1 g/dL
(0.6, 1.3)
1.0 g/dL
(0.8, 1.3)
50%
All total
Placebo
patients treated (pooled across all
(N = 13)
Cohorts)
(N = 14)
1.0 g/dL
(0.7, 1.3)
43%
-0.1
(-0.3, 0.2)
46%
P Value for
GBT440 vs
placebo
<0.001
0
0.006
Total patients
treated
(n = 13)
-39.7
(-49.9, -32.2)
-12.9
(-51.4, 0.9)
-18.5
(-32.9, -12.6)
-28.6c
(-50.0, 15.0)
-76.6d
(-83.6, -63.0)
Placebo
(pooled across all cohorts)
(N = 14)
2.0
(-19.9, 11.8)
-2.9
(-9.1, -1.1)
9.0
(0.8, 13.3)
1.9b
(-5.3, 4.0)
9.7
(-2.7, 18.6)
P Value for
GBT440 vs.
placebo
<0.001
ns
0.002
ns
<0.001
Data available for n = 4; bData available for n = 5; cData available for n = 9; dData available for n = 11
ns: not significant
Placebo
(N = 4)
16.7 (8.2–19.6)
21.2 (17.1−23.4)
18.9 (8.2−23.4)
23.3 (15.7−23.8)
1.0 (-6.6−2.1)
-1.9 (-5.0−0.4)
-0.4 (-6.6−2.1)
-2.4 (-7.5−0.3)
Baseline
median (range)
9.4 (6.4−12.4)
12.8 (11.5-16.3)
12.0 (6.4−16.3)
11.9 (11.7−12.7)
Change at day 90
baseline mU/mL
1.6 (-0.1−4.7)
-1.4 (-1.8−1.4)
0.6 (-1.8−4.7)
-1.4 (-5.5−2.3)
P Value for
GBT440 vs.
placebo
Change at day 90
median (range)
ns
ns
Erythropoietin
Baseline mU/mL
median (IQR 25%, 75%)
91.2 (77.6, 125) 113.5 (42.4, 150.0) 98.9 (73.1, 131.3) 112.2 (46.5, 183.0)
Change at day 90
median (IQR 25%, 75%)
-0.3 (-27.6, 32.9)
7.2 (4.7, 11.5)
5.2 (-8.3, 16.9)
43.4 (-19.6, 79.3)
ns
CPET data not available for all subjects
a
CPET data available for n = 5; bCPET data available for n = 11
ns: not significant
IQR: interquartile range
CONCLUSION
●● Long-term dosing up to 6 months continues to show favorable safety profile
●● GBT440 treatment leads to a rapid, profound, and durable reduction in hemolysis and sickled cells
in all SCD patients dosed to date
–– Supports in vivo inhibition of polymerization
–– Significant proportion of patients achieve a large Hb response (> 1 g/dL)
●● Results support Phase 3 HOPE study design
SAFETY AND TOLERABILITY
–– Supports primary endpoint of hemoglobin response (> 1 g/dL)
–– Key secondary objective is to demonstrate translation to clinical benefit towards SCD symptom
●● GBT440 was well tolerated up to 6 months of dosing
exacerbations (refer to Poster # 4760)
●● No serious or severe adverse events (AEs) were related to study drug
●● No sickle cell crises events while on study drug
●● All treatment-related AEs were Grade 1 or 2 in severity (see Table 4)
Acknowledgments
●● No evidence of tissue hypoxia was noted (see Table 5)
●● The authors wish to thank all the healthy volunteers and the sickle cell patients, families, caregivers,
research nurses, study coordinators, and support staff who contributed to this study
–– No increase in erythropoietin
–– No decrease in O2 consumption with exercise
●● The authors wish to thank the following contributors
●● No treatment-related AEs have occurred with dosing beyond 90 days
Table 4. The most common treatment-related AEs were Grade 1 and
included headache and gastrointestinal disorders
One placebo subject transitioned to GBT440 in the Expansion study and is included in both Cohort 17 and pooled placebo
AE, n (%)
EFFICACY
Headache
Grade 1
Grade 2
Gastrointestinal Disorders (SOC)*
all Grade 1
Abdominal discomfort
Diarrhea
Dyspepsia
Nausea
Vomiting
●● All SCD patients (N = 41) receiving GBT440 for up to 6 months have shown hematologic response
(Hb, reticulocytes, and/or bilirubin; see Figure 3 and Table 2)
●● Profound and durable reduction in hemolysis and peripheral blood sickle cells (see Table 3)
–– 46% of patients demonstrated a clinically significant increase in Hb (>1 g/dL increase) vs 0% of
placebo patients (P value = 0.006)
–– Greater than a 70% median decrease in irreversibly sickled cells
●● The treatment response data are consistent with in vivo inhibition of HbS polymerization
Cohort 17
900 mg
(n = 7)
-42.9
(-61.8, -32.8)
-51.4
(-58.1, -12.5)
-15.0
(-35.4, 1.8)
-28.6b
(-41.9, 15.0)
-79.7b
(-87.5, -70.0)
a
evaluate safety, pharmacokinetics and pharmacodynamics (see Figure 3 and Table 1):
–– Healthy volunteers
Cohort 17
(900 mg × 3-6
mo)
(N = 7)
Change from baseline to end Cohort 16
of treatment (median, 25th
700 mg
and 75th percentile)
(n = 6)
-37.2
Unconjugated bilirubin (%)
(-43.4, -23.7)
0.8
Lactate dehydrogenase (%)
(-14.7, 1.1)
-21.0
% Reticulocytes (%)
(-32.9, -18.1)
-35.5a
Dense RBCs (%)
(-56.5, -1.4)
-72.0
Irreversibly sickled cells (%)
(-78.7, -60.8)
●● Data presented include efficacy results for SCD patients who received multiple doses of GBT440 for
3 to 6 months (Part C) and safety results for all SCD patients who received multiple doses of GBT440
for 28 days to 6 months (Parts B and C)
Baseline characteristics from
GBT440-001
Cohort 16
(700 mg × 90 d)
(N = 6)
Table 3. Reduction in hemolysis, reticulocytosis, and sickled cells
–– Median treatment: 118 days (range, 92-178 days)
Total patients
treated
(n = 12)b
7.2
a
●● As of November 7, 2016, a total of 56 SCD patients have been enrolled into GBT440-001 (see Table 1)
Cohort 17
900 mg
(N = 6)a
Ventilatory threshold
oxygen uptake (mL/min/kg)
0.2
0.0b
RESULTS
Cohort 16
700 mg
(N = 6)
Baseline
median (range)
0.2
Baseline Hb
(g/dL)
Parameter (unit)/
study day
Peak exercise
oxygen utake (mL/min/kg)
*Except SCD patients in Part B: 500-mg cohort (10:4); 700-mg cohort (12:4)
Figure 1. GBT440 is designed to bind Hb with high selectivity
Table 5. No evidence of tissue hypoxia by oxygen consumption with
exercise or erythropoietin measurement with long-term dosing
500 mg
× 28 d
(N = 10)
700 mg
× 28 d
(N = 12)
700 mg
x 90 d
(N = 6)
900 mg 1000 mg
All
Placebo
× 90 d
× 28 d treated × 28-90 d (pooled)
(N = 7) (N = 6) patients
(N = 14)
(N = 41)
2 (29)
1 (17)
12 (29)
5 (36)
1 (14)
0
9 (22)
3 (21)
1 (14)
1 (17)
3 (7)
2 (14)
4 (40)
3 (30)
1 (10)
4 (33)
4 (33)
0
1 (17)
1 (17)
0
0
3 (25)
0
2 (29)
1 (17)
6 (15)
3 (21)
0
0
0
0
0
1 (8)
1 (8)
0
2 (17)
0
0
0
0
0
0
1 (14)
2 (29)
0
0
0
0
0
1 (17)
0
0
2 (5)
3 (7)
1 (2)
2 (5)
0
0
0
0
2 (14)
1 (7)
A subject experiencing multiple AEs is only counted once per system organ class
Treatment-related adverse events by individual AE or SOC system organ class occurring in > 10% of all SCD patients receiving GBT440
–– Global Blood Therapeutics: Allison Intondi, Theresa Thuener, Brian Metcalf
–– King’s College Hospital (currently NIH/NHLBI): Professor Swee Lay Thein
●● This study was supported by Global Blood Therapeutics
Disclosure
Jo Howard, Claire Jane Hemmaway, Paul Telfer, Mark Layton, Moji Awogbade, and John Porter have
no conflicts of interest to disclose. Timothy Mant is currently employed by Quintiles. Sandra Dixon,
Kobina Dufu, Athiwat Hutchaleelaha, Margaret Tonda, Kenneth Bridges, Eleanor Ramos, and
Joshua Lehrer-Graiwer are currently employed by and have equity ownership of
Global Blood Therapeutics.
a
To access the poster digitally, plese use the following QR code
PRESENTED AT the 58th annual meeting of the American Society of Hematology (ASH); December 3‑6, 2016; San Diego, CA