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AHA 2018 Poster SRJ-Ver 4acceleronpharma.com/.../2018/11/SRJ-AHA-2018-Poster.pdf · 2019-11-08 ·...
1
RAP-011, a Murine Ortholog of ACTRIIA-FC (Sotatercept), Improves Pulmonary Hemodynamics and Restores Right Ventricular Structure and Function in a Preclinical Model of Severe Angio-obliterative Pulmonary Arterial Hypertension Sachindra R. Joshi, PhD 1 , Jun Liu MS 1 , R. Scott Pearsall, Ph.D 1 , Gang Li, PhD 1 , Ravindra Kumar, Ph.D 1 1. Acceleron Pharma, Cambridge MA Introduction Results Methods Conclusion 1. RAP-011 improves pulmonary hemodynamics in advanced stages of PAH RAP-011 (Sotatercept) treatment, distinct from sildenafil, improves pulmonary hemodynamics, RV structure and cardiac function, and may provide a novel disease- modifying benefit to patients with PAH. Novel therapies that reverse remodeled pulmonary arteries, improve pulmonary hemodynamics and restore right ventricular (RV) structure and function are warranted Results Acknowledgements Paul B. Yu, M.D., Ph.D. Research Support: Acceleron Right Ventricular Systolic Pressure SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13Wks Pre-treatment Normal RAP-011 5- 9 Wks RAP-011 3-7 Wks RAP-011 9- 13 Wks Sildenafil 5- 9 Wks Advanced Stage Early Stage RV LV Pre-treatment Pre-treatment Pre-treatment 5 Wk SU-Hx-Nx-PAH 9 Wk SU-Hx-Nx-PAH RAP-011 5-9 Wks Sildenafil 5-9 Wks Results 2. RAP-011 improves flattening of septal wall and right ventricular geometry 3. RAP-011 improves pulmonary vascular resistance and right ventricular structure and function 4. RAP-011 resolves vascular remodeling N ormal P A H R AP-0 1 1 S ild enaf il 0 50 100 150 * # @ RVSP [mmHg] No r m a l PAH RAP-011 0 20 40 60 80 100 * # RVSP [mmHg] No r m a l PA H RAP-011 S i l d enafi l 0.0 0.5 1.0 1.5 2.0 2.5 * # @ # TPRI [mmHg/mL/min/kg] Normal P AH RA P - 0 11 0.0 0.5 1.0 1.5 2.0 2.5 * # TPRI [mmHg/mL/min/kg] No r m a l PAH RA P - 0 11 S ild e n afil 0.0 0.2 0.4 0.6 0.8 * # @ RV/LV+S Normal P AH RAP-011 0.0 0.2 0.4 0.6 0.8 # * RV/LV+S Normal P AH RA P - 0 11 Sildenafil 0.0 0.5 1.0 1.5 2.0 2.5 * # @ RVWT [mm] No r m a l PAH RAP-011 0.0 0.5 1.0 1.5 2.0 2.5 # * RVWT [mm] No r m a l PAH RAP-011 S ilden afil 0 20 40 60 * #@ RV FAC % Normal P AH RAP-011 0 20 40 60 * RV FAC % SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13 Wks SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13 Wks SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13 Wks SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13 Wks Pulmonary Vascular Resistance Index Right Ventricular Wall Thickness Fulton’s Index Right Ventricular Fractional Area Change Normal SUGEN 5416-HYPOXIA-NORMOXIA (SU/Hx/Nx) PAH Normal SU/HX/NX-PAH RAP-011 Sildenafil 100 m 100 m 100 m 100 m 200 m 200 m 200 m 200 m 200 m 100 m * p<0.05 vs Normal # p<0.05 vs PAH @ p<0.05 vs Sildenafil in pulmonary arterial hypertension (PAH). Aberrant BMP/TGFβ signaling plays a prominent role in pulmonary vascular remodeling. RAP-011 (a murine analog of Sotatercept), a recombinant homodimeric fusion protein consisting of extracellular domain of human ActRIIA linked to murine immunoglobulin (Ig) G1 Fc domain, was recently shown to rebalance BMP/TGFβ signaling and attenuate early stage PAH in preclinical models. Sotatercept, a selective ligand trap for activin/GDFs, is currently being evaluated in the PULSAR Phase 2 trial in PAH. RAP-011 (Sotatercept) is distinct from sildenafil in its ability to improve pulmonary hemodynamics as well as restore RV structure and function. Hypothesis Pulmonary hemodynamics, Pulmonary arteriopathy, RV structure and function were assessed at the end of the study period (week 9 or 13, N= 3-8 per group).
Transcript of AHA 2018 Poster SRJ-Ver 4acceleronpharma.com/.../2018/11/SRJ-AHA-2018-Poster.pdf · 2019-11-08 ·...
RAP-011, a Murine Ortholog of ACTRIIA-FC (Sotatercept), Improves Pulmonary Hemodynamics and Restores Right Ventricular Structure and Function in a Preclinical
Model of Severe Angio-obliterative Pulmonary Arterial HypertensionSachindra R. Joshi, PhD1, Jun Liu MS1, R. Scott Pearsall, Ph.D1, Gang Li, PhD1, Ravindra Kumar, Ph.D1
1. Acceleron Pharma, Cambridge MA
Introduction
Results
Methods
Conclusion
1. RAP-011 improves pulmonary hemodynamics in advanced stages of PAH
RAP-011 (Sotatercept) treatment, distinct from sildenafil,improves pulmonary hemodynamics, RV structure andcardiac function, and may provide a novel disease-modifying benefit to patients with PAH.
Novel therapies that reverse remodeled pulmonary arteries, improve pulmonary hemodynamics and restore right ventricular (RV) structure and function are warranted
Results
Acknowledgements
Paul B. Yu, M.D., Ph.D.
Research Support: Acceleron
Right Ventricular Systolic Pressure
SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13Wks
Pre-treatmentNormal
RAP-011 5- 9 WksRAP-011 3-7 Wks RAP-011 9- 13 WksSildenafil 5- 9 Wks
Advanced StageEarly Stage
RV LV
Pre-treatment Pre-treatment Pre-treatment
5 Wk SU-Hx-Nx-PAH
9 Wk SU-Hx-Nx-PAH
RAP-011 5-9 Wks
Sildenafil 5-9 WksResults
2. RAP-011 improves flattening of septal wall and right ventricular geometry
3. RAP-011 improves pulmonary vascular resistance and right ventricular structure and function
4. RAP-011 resolves vascular remodeling
Normal
PAH
RAP-0
11
Silden
afil
0
50
100
150
*# @
RV
SP
[m
mH
g]
Normal
PAH
RAP-011
0
20
40
60
80
100*
#
RV
SP
[m
mH
g]
Normal
PAH
RAP-0
11
Silden
afil
0.0
0.5
1.0
1.5
2.0
2.5 *
# @
#
TP
RI [
mm
Hg
/mL
/min
/kg
]
Normal
PAH
RAP-011
0.0
0.5
1.0
1.5
2.0
2.5 *
#
TP
RI [
mm
Hg
/mL
/min
/kg
]
Normal
PAH
RAP-0
11
Silden
afil
0.0
0.2
0.4
0.6
0.8
*# @
RV
/LV
+S
Normal
PAH
RAP-011
0.0
0.2
0.4
0.6
0.8
#
*
RV
/LV
+S
Normal
PAH
RAP-011
Silden
afil
0.0
0.5
1.0
1.5
2.0
2.5
*# @
RV
WT
[m
m]
Normal
PAH
RAP-011
0.0
0.5
1.0
1.5
2.0
2.5
#
*
RV
WT
[m
m]
Normal
PAH
RAP-011
Silden
afil
0
20
40
60
*
# @
RV
FA
C %
Normal
PAH
RAP-011
0
20
40
60
*
RV
FA
C %
SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13 Wks SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13 Wks
SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13 Wks SU/Hx/Nx 5-9 Wks SU/Hx/Nx 9-13 Wks
Pulmonary Vascular Resistance Index Right Ventricular Wall Thickness
Fulton’s Index Right Ventricular Fractional Area Change
Normal
SUGEN 5416-HYPOXIA-NORMOXIA (SU/Hx/Nx) PAH
Normal SU/HX/NX-PAH
RAP-011 Sildenafil
100 m
100 m
100 m
100 m
200 m
200 m
200 m
200 m
200 m 100 m
* p<0.05 vs Normal # p<0.05 vs PAH @ p<0.05 vs Sildenafil
in pulmonary arterial hypertension (PAH). Aberrant BMP/TGFβ signaling plays a prominent role in pulmonary vascular remodeling. RAP-011 (a murine analog of Sotatercept), a recombinanthomodimeric fusion protein consisting of extracellular domain of human ActRIIA linked to murine immunoglobulin (Ig) G1 Fc domain, was recently shown to rebalance BMP/TGFβ signaling and attenuate early stage PAH in preclinical models. Sotatercept, a selective ligand trap for activin/GDFs, is currently being evaluated in the PULSAR Phase 2 trial in PAH.
RAP-011 (Sotatercept) is distinct from sildenafil in its ability to improve pulmonary hemodynamics as well as restore RV structure and function.
Hypothesis
Pulmonary hemodynamics, Pulmonary arteriopathy,RV structure and function were assessed at the end ofthe study period (week 9 or 13, N= 3-8 per group).
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