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).