ACTRIIA-Fc rebalances BMP and activin/TGF- signaling to attenuate - - PowerPoint PPT Presentation

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ACTRIIA-Fc rebalances BMP and activin/TGF- signaling to attenuate - - PowerPoint PPT Presentation

Oct 25, 2023 265 likes •431 views

ACTRIIA-Fc rebalances BMP and activin/TGF- signaling to attenuate experimental pulmonary hypertension Lai-Ming Yung, Ph.D 1 ; R. Scott Pearsall, Ph.D 2 ; Geoffrey Bocobo, B.S. 1 ; Dianne S. Sako 2 ; Teresa Dinter, B.S. 1 ; Ravindra Kumar, Ph.D 2

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SLIDE 1

ACTRIIA-Fc rebalances BMP and activin/TGF-β signaling to attenuate experimental pulmonary hypertension

Lai-Ming Yung, Ph.D1; R. Scott Pearsall, Ph.D2; Geoffrey Bocobo, B.S.1; Dianne S. Sako2; Teresa Dinter, B.S.1; Ravindra Kumar, Ph.D2; Paul B. Yu, M.D., Ph.D.1

1Division of Cardiovascular Medicine, Brigham & Women’s Hospital

and Harvard Medical School, Boston, MA;

2Acceleron Pharma, Cambridge, MA

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SLIDE 2

BMPRII BMPR2 HPAH ALK1 ACVRL1 HHT2-HPAH ENG ENG HHT1 SMAD4 SMAD4 JP-HT SMAD9 SMAD9 HPAH BMP9 GDF2 HHT5

SMAD2/3 Nucleus P P P P I II SMAD 1/5/9 SMAD 1/5/9 P P P P P I II SMAD2/3 P TGF SMAD 4 SMAD 1/5/9 P SMAD4 CAGA SMAD2/3 P SMAD4 * BMP TGF BMP

TGFBRII ACTRIIA ALK4 ALK5 ALK7 ALK1 ALK2 ALK3 BMPRII Endoglin

activin

BRE

Mutations of Heritable PAH syndromes implicate loss of BMP function in pulmonary vascular disease

myogenic and fibrogenic differentiation vascular homeostasis

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SLIDE 3

PAH is characterized by deficient BMP signaling and exaggerated TGFβ/activin signaling

  • Genetics implicates deficient BMP9-

BMPRII-ALK1-ENG-SMAD1/5/9 axis

  • Non-genetic forms of PAH exhibit

deficient BMP, and exaggerated TGFβ/activin signaling

  • Pattern recapitulated in multiple

animal models of PH

  • Approved therapies appear to

improve this balance

SMAD2/3 Nucleus P P P P I II SMAD 1/5/9 SMAD 1/5/9 P P P P P I II SMAD2/3 P TGF SMAD 4 P SMAD4 CAGA SMAD2/3 P SMAD4 * BMP TGF BMP

TGFBRII ACTRIIA ALK4 ALK5 ALK7 ALK1 ALK2 ALK3 BMPRII Endoglin

activin

BRE SMAD 1/5/9

Yung LM, AJRCCM 2016 Yan Y, Int J Cardiol 2016 Long L, Nat Med 2015 Yndestad A, J Appl Physiol 2009 Atkinson L, Circ 2002 Ogo T, Circ 2013 Yang J, Circ Res 2010

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SLIDE 4

What is the impact of selective activin/GDF blockade in pulmonary arterial hypertension?

BMP9 BMP10 activin A activin B TGFβ1 TGFβ3 TGFβ2 GDF8 GDF11 BMP2 BMP4 BMP6 BMP7 activin AC BMP12

SMAD 1/5/9 SMAD 2/3

ACTRIIA-Fc (ACE-011/Sotatercept) TGFBRII-Fc Yung LM et al. AJRCCM 2016

myogenic and fibrogenic differentiation vascular homeostasis

Hypothesis: Blockade of activin ligands attenuates pulmonary vascular remodeling by rebalancing SMAD1/5/8 vs. SMAD2/3 signaling

*Primary ligands inhibited

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SLIDE 5

62.3 57.9 36.4 41.6 0.9 66.9** ACTRIIA-Fc (10 mg/klg)

100%

Sildenafil (60 mg/day) 25.8** 7.3* Vehicle 1.4 Partially muscularized Non-muscularized Completely muscularized Weight Ratio mm Hg P < 0.001 P < 0.001 P < 0.05 P < 0.05

RV / LV+S MPAP

10 20 30 40 50

Vehicle ACTRIIA-Fc Sildenafil

0.1 0.2 0.3 0.4 0.5 0.6 0.7

Vehicle ACTRIIA-Fc Sildenafil

Impact of ACTRIIA-Fc (15 mg/kg S.C. twice weekly x 4 weeks) prophylaxis in rats treated with MCT (60 mg/kg)

*p ≤ 0.05 vs. control **p ≤ 0.01 vs. control

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SLIDE 6

72.5 67.4 27.4 31.6 1.0 69.3** ACTRIIA-Fc (10 mg/kg)

100%

Sildenafil (60 mg/day) 29.3** 1.4* Vehicle 0.1 Partially muscularized Non-muscularized Completely muscularized Weight Ratio mm Hg P < 0.001 P < 0.001 P < 0.001 P < 0.001

RV / LV+S MPAP

Impact of ACTRIIA-Fc (10 mg/kg weekly x 4 weeks) prophylaxis in rats treated with SUGEN5416 (200 mg/kg) and hypoxia

10 20 30 40 50

Vehicle ACTRIIA-Fc Sildenafil

0.1 0.2 0.3 0.4 0.5 0.6 0.7

Vehicle ACTRIIA-Fc Sildenafil

*p ≤ 0.05 vs. control **p ≤ 0.01 vs. control

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SLIDE 7

Impact of ACTRIIA-Fc prophylaxis on PV remodeling in SU-Hx rats

Sugen hypoxia, lung histology (αSMA/elastin Staining) SUGEN-Hypoxia SUGEN-Hypoxia + Sildenafil SUGEN-Hypoxia + ACTRIIA-Fc

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SLIDE 8

SU-Hx Model Treatment n Control Vehicle 8 ACTRIIA-Fc 1 mg/kg twice weekly 7 3 mg/kg twice weekly 7 10 mg/kg twice weekly 8

SU-Hx (3 weeks) Echo RV function Right heart catheterization Fulton’s Index PV and RV Histology

Normobaric hypoxia (FIO2 = 0.10) SU5416 (20 mg/kg S.C., weekly) Sprague Dawley Rat

Normoxia (3 weeks)

Impact of ACTRIIA-Fc on progression of established PH in SU-Hx rats

ACTRIIA-Fc SU5416

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SLIDE 9
  • ne-way ANOVA dose trend p = 0.03

SU-Hx 1 3 10 20 40 60 RVSP (mmHg)

p=0.02

(8) (7) (7) (8)

ActRII-Fc (mg/kg twice weekly)

  • ne-way ANOVA dose trend p = 0.05

ACTRIIA-Fc attenuates PH progression in SU-Hx rats

69.3** 29.3**

SU-Hx 1 3 10 50 100

Percent of Total Vessels

RAP-011 (mg/kg twice weekly)

18.5 31.9 42.3 11.8 31.2 18.8 22.4 27.5 68.0 47.9 28.8 45.2 *one-way ANOVA trend p = 0.05

SU-Hx 1 3 10 0.0 0.1 0.2 0.3 0.4 0.5

RV/(LV+S)

p=0.05

(8) (7) (7) (8)

ActRII-Fc (mg/kg twice weekly)

Non -muscularized Partially muscularized Completely Muscularized

ACTRIIA-Fc (mg/kg twice weekly)

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SLIDE 10
  • ne-way ANOVA trend p = 0.01
  • ne-way ANOVA trend p = 0.05

SU-Hx 1 3 10 20 40 60 80 100 % Fully Muscularized Vessels ActRIIa-Fc (mg/kg twice weekly)

p=0.05

(8) (7) (7) (8) SU-Hx 1 3 10 20 40 60 Medial wall thickness index (%) ActRII-Fc (mg/kg twice weekly) (8) (7) (7) (8)

p=0.02

SU-Hx 1 mg/kg

SMA vWF

3 mg/kg 10 mg/kg 50 µm

ACTRIIA-Fc attenuates intimal-medial remodeling in SU-Hx rats

DAPI

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SLIDE 11

ACTRIIA-Fc de-represses activin inhibition of BMP9 signaling

1 1

BMP9 activin A ACTRIIA-Fc

  • +
  • +

+

  • +

+ +

  • +
  • BMP9

activin B ACTRIIA-Fc

  • +
  • +

+

  • +

+ +

  • +
  • BRE-Luciferase

Activity (RLU) BRE-Luciferase Activity (RLU) BMP Response Element (BRE-Luciferase) activity in A204 reporter cell line

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SLIDE 12

% Reduction in mPAP Agent

Bosentan1

21 30

Sildenafil4

24 18

Beraprost NP2 255

28 ACTIIA-Fc4 56 47

% Reduction in RVH RV/(LV+S)

Monocrotaline - Prevention

% Reduction in mPAP Agent

Macitentan3

365 31

Sildenafil4

22 10

Beraprost NP2 275

32 ACTRIIA-Fc4 51 54

% Reduction in RVH RV/(LV+S)

SUGEN-Hypoxia - Prevention

% Reduction in RVSP Agent

10 19

Riociguat1

10 20

Tadalafil + Macitentan2

28 28 ACTRIIA-Fc3 33 30

% Reduction in RVH RV/(LV+S)

SUGEN-Hypoxia – Therapeutic Sildenafil1

  • 1. Lang et al. PLoS One. 2012;7(8):e43433

Sildenafil 50 mg/kg/d; Riociguat 10 mg/kg/d 2 Boucherat et al. Sci Rep. 2017 Jul 3;7(1):4546 Tadalafil 10 mg/kg/d; Macitentan 30 mg/kg/d

  • 3. Current study; 10 mg/kg twice weekly
  • 1. Clozel etal Exp. Biol and Med (2006) 231: 967-973; Bosentan 300 mg/kg/d
  • 2. Akagi et al J Cardiovasc Pharmacol 2016; 67; 290-298; Beraprost NP 150 μg/kg
  • 3. Shinohara et al Am J Physiol Lung Cell Mol Physiol 2015; Macitentan 30 mg/kg/d
  • 4. RAP-011 and Sildenafil (60 mg/kg/d) were tested in same study at CorDynamics
  • 5. Right ventricular systolic pressure

Comparison of ACTRIIA-Fc to approved therapies in PH models

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SLIDE 13

Summary

  • 1. ACTRIIA-Fc is a potentially mechanism-targeted, non-vasodilator PAH

therapy that potently inhibits neo-intimal and medial remodeling.

  • 2. ACTRIIA-Fc inhibits signaling of activins/GDFs and may augment BMPs;

multiple mechanisms of action and cellular targets being considered.

  • 3. Sotatercept has favorable pharmacokinetics, dosed SC every three weeks.
  • 3. Human clinical experience includes nearly 400 patients across 13 trials.
  • 4. Well tolerated at 0.3, 0.7, and 1.5 mg/kg in human subjects, corresponding

to human equivalent doses of 1.8, 4.2 and 10 mg/kg in rats, overlapping with efficacious doses in rat models.

  • 6. Phase 2 studies for PAH are planned.
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SLIDE 14

Acknowledgements

Yu laboratory – BWH Cardiology Lai-Ming Yung, PhD Peiran Yang, PhD Ivana Nikolic, MD Geoff Bocobo, BS Teresa Dinter, BS Megan McNeil, BS Luca Troncone, PhD Acceleron Pharma Ravindra Kumar, Ph.D

  • R. Scott Pearsall, Ph.D

Dianne S. Sako, B.S. Funding NHLBI R01-HL131910 NHLBI R42-HL132742 B-BIC DRIVE GRANT Fondation Leducq

Lai-Ming Yung, PhD Teresa Dinter, BS Geoff Bocobo, BS Brian Peiran Yang, PhD

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SLIDE 15

SMAD2/3 Nucleus P P P P I II SMAD 1/5/9 SMAD 1/5/9 P P P P P I II SMAD2/3 P TGF SMAD 4 SMAD 1/5/9 P SMAD4 CAGA SMAD2/3 P SMAD4 * BMP TGF BMP

TGFBRII ACTRIIA ALK4 ALK5 ALK7 ALK1 ALK2 ALK3 BMPRII Endoglin activin

BRE

ACTRIIA-Fc fusion protein (RAP-011/Sotatercept) is an activin/GDF ligand trap

ACTRIIA-Fc (RAP-011/Sotatercept) traps activin A, activin B, GDF8, GDF11

BMP BMP BMP BMP

ACTRIIA-Fc

+