Whats in the PAH Nitric Oxide Pathway Pathway Pathway - - PowerPoint PPT Presentation

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What’s in the PAH Therapeutic Pipelines?

Dunbar Ivy, MD

Approved Therapies for PAH

Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.

cGMP cAMP

Vasoconstriction and proliferation Endothelin receptor A

Endothelin- receptor antagonists

Endothelin receptor B

Phosphodiesterase type 5 inhibitor

Vasodilation and antiproliferation Phosphodiesterase type 5 Vasodilation and antiproliferation

Prostacyclin derivatives

Nitric Oxide Endothelin-1 Pre-proendothelin L-arginine Prostaglandin I2 L-citrulline

Nitric Oxide Pathway Endothelin Pathway Prostacyclin Pathway

Endothelial cells Proendothelin Endothelial cells Arachidonic acid Smooth muscle cells

Prostacyclin (prostaglandin I2)

Smooth muscle cells Exogenous nitric oxide sGC stimulator

Approved Therapies for PAH

Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.

cGMP cAMP

Vasoconstriction and proliferation Endothelin receptor A

Endothelin- receptor antagonists

Endothelin receptor B

Phosphodiesterase type 5 inhibitor

Vasodilation and antiproliferation Phosphodiesterase type 5 Vasodilation and antiproliferation

Prostacyclin derivatives

Nitric Oxide Endothelin-1 Pre-proendothelin L-arginine Prostaglandin I2 L-citrulline

Nitric Oxide Pathway Endothelin Pathway Prostacyclin Pathway

Endothelial cells Proendothelin Endothelial cells Arachidonic acid Smooth muscle cells

Prostacyclin (prostaglandin I2)

Smooth muscle cells Exogenous nitric oxide sGC stimulator

Ralinepag Selective IP Agonist

Outline

• Cancer / Metabolic agents: Dichloroacetate
• Anti-estrogen: Anastrazole / Tamoxifen
• Enhance BMPR2 Signaling: FK 506
• Iron therapy
• Tocilizumab: IL-6 Receptor Antagonist
• Elastase Inhibitors
• Epigenetics
• DNA Damage

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Cancer traits by pulmonary vascular cells during PAH progression

Boucherat, et al. Pulm Circ 2017 Jun; 7(2): 285–299

Comparison of Glycolysis Between Normal Tissue and Proliferated Tissue

95% 5%

Richard Feinman

Dichloroacetate Blocks PDK

Ryan, Archer. Circulation. 2015;131:1691-1702

Clinical Trial DCA

Michelakis et al., Sci. Transl. Med. 9, eaao4583 (2017) N=20

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Estrogen Paradox

• Female IPAH preponderance (1.5-4:1 Female:Male)
• Female IPAH patients survive longer
• Female BMPR2 carriers more likely to develop PAH
• 20% of carriers develop PAH
• 43% female vs 14% male
• Pregnancy induced PAH
• Estrogen levels higher in males and females with

PAH

Estrogen Paradox

• BMPR2 gene expression reduced in females likely

through estrogen receptor alpha binding to BMPR2 promoter (Austin, Biol Sex Differences, 2012)

• Females metabolizing estrogen to 16-oestrogens

but not 2- or 4- oestrogens more likely to develop PAH (Austin, ERJ 2009)

Signaling by Estrogens

Adapted from: Lahm Crit Care Med 2008

Adapted from Lahm et al Crit Care Med 2008

Rapid Nongenomic Effects

• 1. Vasodilation
• Increase eNOS
• Increase PGI2
• 2. Promote angiogenesis
• 3. Modify injury response

Genomic Effects Alter gene expression  Increase proliferative  Increase migration

Aromatase Inhibition: Anastrozole in PAH (AIPH)

• Anastrozole Phase II Trial (PI: Kawut; NHLBI)
• Reduce extragonadal estrogen production
• Anastrazole blocks conversion of androgens to estrogens
• Randomized, double-blind, placebo-controlled
• 3 months
• PAH patients on background therapy
• Males & Postmenopausal females
• Anastrozole 1 mg (n=12) daily vs. Placebo (n=6)
• Primary Outcomes:
• Change Estradiol (E2)
• TAPSE

Kawut, et al AJRCCM 2017; 195(3):360-368

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AIPH Result: Safe & Tolerated

E2 Levels 6MWTD Change ** Kawut (PI), Ventetuolo and colleagues recently funded by NHLBI for AIPH2 ** Kawut, et al AJRCCM 2017; 195(3):360-368

Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension (T3PAH)

24 week, double-blind, randomized placebo-controlled proof of concept trial of tamoxifen in 24 pulmonary arterial hypertension (PAH) patients.

• 12 tamoxifen
• 12 placebo

NIH P01 HL 108800 (Loyd)

Tamoxifen: Block Estrogen Signaling

Augment BMPR2 signaling

• BMPR2 most common genetic mutation in PAH
• BMPR2 signaling diminished in most forms of PAH
• High throughput screening of 3600 drugs - FK 506

(Tacrolimus) identified as potent BMPR2 activator

• Experimental evidence of reversal of endothelial

dysfunction

• Early clinical evidence of improvement

Spiekerkoetter, J Clin Invest 2013 Spiekerkoetter, AJRCCM 2015

FK506 in Human PAH

Spiekerkoetter, European Respiratory Journal 2017 50: 1602449 <2 ng/ml 2-3 ng/ml 3-5 ng/ml

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FK506 in Human PAH

Spiekerkoetter, European Respiratory Journal 2017 50: 1602449

Secondary Changes: FK 506

Spiekerkoetter, European Respiratory Journal 2017 50: 1602449

Exercise in iron Deficient IPAH Patients Before / After Iron

Ruiter, G, et al. Pulm Circ 2015 Sep;5(3):466-72 N=15

Tocilizumab: IL-6 Receptor Antagonist

• Inflammation and autoimmunity
• Tocilizumab used in rheumatoid arthritis
• Tocilizumab reversed PAH in MCTD and Lupus
• TRANSFORM-UK
• Group 1 PAH
• IV Q month for 6 months
• CoPrimary: Safety and PVR
• Secondary: 6MWTD, NTproBNP, QOL, FC

Hernandez-Sanchez, Pulmonary Circulation 2017; 8(1) 1–8

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Elafin: Elastase Inhibitor

Rabinovitch, Pulmonary Circulation 2017; 8(1) 1–8

Elafin increase Caveolin-1 induced BMPR2 signaling

Nickel, Am J Respir Crit Care Med Vol 191, Iss 11, pp 1273–1286

Epigenetics and PH

Pullamsetti, Pulm Circ 2016 Dec; 6(4): 448–464

Epigenetics and PH

Pullamsetti, Pulm Circ 2016 Dec; 6(4): 448–464 Valproic Acid HDAC Inhibitor

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Epigenetics and PH

Pullamsetti, Pulm Circ 2016 Dec; 6(4): 448–464 DMD: premature stop codon into the dystrophin mRNA Ataluren increases 6MWTD in DMD PAH: Increased BMPR2 signaling?

DNA Damage and PH

Ranchoux, et al. Int. J. Mol. Sci. 2016, 17, 990; doi:10.3390/ijms17060990

Pathogenesis of PAH

Boucherat, et al. Pulm Circ 2017 Jun; 7(2): 285–299