Interim Results from Two Phase 2 Clinical
Trials in Adults with Beta-Thalassemia
Ellis Neufeld, MD PhD
Data adapted from presentations at 19th European Hematology Congress
in Milan, Italy June 14, 2014
Studies supported by Acceleron Pharma and Celgene
Disclosure for Dr. Neufeld
• Safety Committee for Acceleron for one of the
studies I am presenting. Data limited to public
information
Background: ACE-536 and Sotatercept
• Protein therapeutics (biologics)
• Both molecules act during late-stage erythropoiesis to increase release of
mature red blood cells into circulation
• Novel mechanism of action, distinct from EPO
• May work by turning down the “brakes” on normal red cell formation.
• Effective in mouse model of thalassemia.
• ACE-536 and sotatercept are currently in Phase 2 studies in Europe in
patients with transfusion-dependent and non-transfusion dep. beta-thal
• Drugs administered by a subcutaneous injection once every 3 weeks
Sotatercept
ACE-536
ECD of
ActRIIA
Fc Domain
of human
IgG1
Antibody
Page 3
Suragani, Nature Medicine
Carrancio S, et al. Br J Haematol. 2014;165:870-82
Modified ECD
of ActRIIB
Fc Domain
of human
IgG1
Antibody
Mean Change in Hemoglobin - NTD Patients
Sotatercept -Thalassemia Phase 2 Clinical Trial
• Dose-dependent increase in hemoglobin
Hb change from baseline (g/dL)
• Effects are maintained while on treatment
3
0.75 mg/kg
0.5 mg/kg
2
0.3 mg/kg
1
0
−1
0.1 mg/kg
−2
−3
1
49
97
145
193
241
Days
Page 4
Interim data as of February 7, 2014
289
337
385
433
Maximum Change in Hemoglobin (9 Weeks) – NTD Patients
Sotatercept -Thalassemia Phase 2 Clinical Trial
Maximum change in Hb during the first 9 weeks
100%
100
83%
Patients (%)
80
67%
60
50%
40
20
0
33%
0.1
mg/kg
(n = 6)
0.3
mg/kg
(n = 6)
0.5
mg/kg
(n = 6)
0%
≥ 1 g/dL increase
Page 5
0.75
mg/kg
(n = 4)
0.1
mg/kg
(n = 6)
0.3
mg/kg
(n = 6)
0%
0%
0.5
mg/kg
(n = 6)
≥ 2 g/dL increase
Hb values are not included if measured within 2 weeks after a transfusion.
0.75
mg/kg
(n = 4)
Reduction in Red Cell Burden for Transfused Patients
Sotatercept -Thalassemia Phase 2 Clinical Trial
Dose dependent reduction in transfusion burden in TD patients,
including β-thalassemia major and β0/β0 genotype
100
Patients (%)
80
67%
60
50%
40
33%
0.1
mg/kg
(n = 2)
20
0%
0
0.3
mg/kg
(n = 3)
33%
0.5
mg/kg
(n = 2)
0.75
mg/kg
(n = 3)a
0.1
mg/kg
(n = 2)
0.3
mg/kg
(n = 3)
0.5
mg/kg
(n = 2)
0%
0%
0%
≥ 20% reduction
≥ 50% reduction
Change in transfusion burdenb
aTransfusion
Page 6
bChange
burden evaluated up to the last known efficacy record, adjusted to 168 days.
in transfusion burden (units/168 days) from baseline.
0.75
mg/kg
(n = 3)a
Mean Change in Hemoglobin - NTD Patients
ACE-536 -Thalassemia Phase 2 Clinical Trial
• Dose-dependent increase in hemoglobin
Mean Change in Hemoglobin (g/dL)
• Effects are maintained while on treatment
3
2
Planned ACE-536 Dose
Follow-up Period
1
0
-1
Study Day 1
Page 7
0.2 mg/kg
0.4 mg/kg
0.6 mg/kg
0.8 mg/kg
22
43
64
85
Preliminary data as of 28 April 2014
113
141
Max. Change in Hemoglobin ≥ 1 or 2 g/dL - NTD Patients
Patients (%)
ACE-536 -Thalassemia Phase 2 Clinical Trial
100
90
80
70
60
50
40
30
20
10
0
100
Spacer
0.2 mg/kg
0.4 mg/kg
0.6 mg/kg
67
0.8 mg/kg
67
33
33
20
n=6
n=6
n=5
n=3
n=6
n=6
0
0
≥ 1.0 g/dL
Page 8
Preliminary data as of 28 April 2014
n=5
≥ 2.0 g/dL
n=3
Transfusion Response - TD Patients (n=4)
ACE-536 -Thalassemia Phase 2 Clinical Trial
• Reduction in transfusion burden >50% observed in 100% (4/4) transfusiondependent patients
Patient ID
0306
0401
0403
0406
0.6
0.8
0.8
0.8
Percent change in transfusion
burden
-78.5%
-66.7%
-66.7%
-69.8%
Maximum percent change in
serum ferritin
-39.7%
-27.5%
-59.5%
-42.7%
Dose Level (mg/kg)
* Patient discontinued after 8.4 weeks on study
Page 9
Preliminary data as of 28 April 2014
Conclusions
ACE-536 and Sotatercept -Thalassemia Phase 2 Clinical Trials
• Both drugs were safe and well-tolerated in adults with βthalassemia. A few patients have had bone pain at higher doses.
• Dose-dependent increases in hemoglobin demonstrated in nontransfusion dependent patients
• Reduction in transfusion burden observed in transfusiondependent patients
• Further dose escalation is ongoing; longer-term extension
studies are planned
• Phase 3 studies are planned
Page 10