Inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction

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$Inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction 4th Annual Pulmonary Hypertension Drug Discovery and Development Symposium July -, 7$

1 Inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction 4th Annual Pulmonary Hypertension Drug Discovery and Development Symposium July -, 7 Berlin, Germany Marc A. Simon, MD, MS Associate Professor of Medicine Director, Heart Failure Research & PH Translational Research Comprehensive Pulmonary Hypertension Program, Heart Failure & Transplantation Cardiology

2 Disclosure Research grant from Aires Pharmaceuticals, a wholly owned subsidiary of Savara Inc. (formerly Mast Therapeutics)

3 Nitric Oxide N O

4 Shear Stress ACH M ENDOTHELIUM L-arginine NOS NO L-citrulline NO SMOOTH MUSCLE guanylyl cyclase (inactive) guanylyl cyclase (active) cgmp GTP Relaxation

5 Limitations for enos dependent NO signaling Endocrine activity limited by short half-life of NO in blood (Half life of < milliseconds because NO scavenged by hemoglobin) Lack of intrinsic mechanism for hypoxic response (enos requires a molecule of oxygen to form NO) NO synthase is uncoupled and fails to generate NO with inflammatory and oxidant stress in disease

6 salt: NaNO, KNO, HNO NO -

7 Two parallel systems for NO generation in mammals Lundberg, Weitzberg, Gladwin Nature Rev Drug Discov 8

8 therapeutics?

9 Nature Chemical Biology 5, 8 Nat Drug Rev Disc 9 Nat Drug Rev Disc 4

10 therapeutics for PH (Group and disease)?

11 Clinical Development of for PH One and -month rat and canine toxicology studies show only methemoglobinemia at very high doses Dose escalation phase IA studies complete in normal volunteers Safe dosing to 95 mg on background sildenafil in normal volunteers and five Group I PAH patients Phase I-II dose finding safety trial in 4 countries closed for data analysis Phase II catheterization study supported by NHLBI PO and MAST Therapeutics

12 Ongoing Phase II Acute Hemodynamic Study 43 enrolled (ClinicalTrials.gov NCT4333) Group (enrollment closed) 7 Group (of planned) 6 Group 3 (of planned) Group Group Group 3 MPAP (mm Hg) PCWP (mm Hg) 5 > 5 5 TPG (mm Hg) > PVR (Woods units) 3

13 Acute Hemodynamic Effects of Inhaled in Pulmonary Hypertension due to Left Heart Disease (HFpEF)!!!!!!! Simon Gladwin. JCI: Insight. 6;(8):e896.

14 PH-HFpEF mpap (mm Hg) mpap Cardiac Index (L/Min/m) Right Atrial Pressure (mm Hg) 5 5 RA PCWP (mm Hg) PAWP Simon Gladwin. JCI: Insight. 6;(8):e896. PVR (Woods units) 6 4 PA Compliance (ml/mm Hg) 5 5 Cpa

15 PH Group (PAH) 7 4. mpap (mm Hg) Cardiac Index (L/Min/m) Right Atrial Pressure (mm Hg) PCWP (mm Hg) Simon Gladwin. JCI: Insight. 6;(8):e896. PVR (Woods units) 5 5 PA Compliance (ml/mm Hg) 4 3

16 PH Group 3 (Lung Dz) 7 4. mpap (mm Hg) Cardiac Index (L/Min/m) Right Atrial Pressure (mm Hg) 5 PCWP (mm Hg) Simon Gladwin. JCI: Insight. 6;(8):e896. PVR (Woods units) 5 PA Compliance (ml/mm Hg) 4 3

17 Acute Hemodynamic Effects of Inhaled in Pulmonary Hypertension due to Left Heart Disease (HFpEF) Resistance-Compliance (RC) Curve Simon Gladwin. JCI: Insight. 6;(8):e896.

18 Inhaled Sodium nitrite improves exercise hemodynamics and ventricular performance in HFpEF Inhaled sodium nitrite (9mg) vs placebo (n=3 per group) Decrease PCWP, RA, mpap at rest and with exercise Increase resting PA Compliance 5 by guest on August 8, 6 by guest on August 8, 6 Downloaded from Effect on Exercise PCWP RAP PCWP mpap PAC Placebo Downloaded from 4 mmhg or ml/mmhg PCWP (nmhg) p=.5 p=. ANCOVA p=. Placebo p=.7 p=.46 PCWP (mmhg) 3 Placebo Rest Exercise Rest Exercise Borlaug et al. Circ Res. 6;9(7):88-6.

Pressures PA Compliance Adapted from Borlauget al. JACC.

19 Physiology of improved exercise capacity with nitrite in PH-HFpEF Skeletal Muscle Metabolism RV Filling Pressures PA Compliance Adapted from Borlauget al. JACC. 5;66(5):67-8. Lai YC Gladwin MT. Circulation. 6;33(8):77-73.

20 Development of Nebulized Inhaled Squeezable plastic ampule kit consisting of 8 mg/ml phosphate buffered Sodium has been developed Nebulized 3-4 times a day with the Philips I-neb Portable, rechargeable Monitors compliance

Currently Enrolling Studies INDIE-HFpEF Inorganic Delivery to Improve Exercise Capacity in HFpEF Heart Failure Network (US) Mulitcenter Study, goal n=, blinded placebo

21 Currently Enrolling Studies INDIE-HFpEF Inorganic Delivery to Improve Exercise Capacity in HFpEF Heart Failure Network (US) Mulitcenter Study, goal n=, blinded placebo controlled, 4 week crossover ClinicalTrials.gov #NCT749 HFpEF (clinical or RHC or BNP or echo evidence) Primary Endpoint: Peak VO after 4 weeks treatment with inhaled nitrite

22 Currently Enrolling Studies INABLE-HF: Inorganic to Amplify the Benefits and tolerability of Exercise training Barry A. Borlaug, MD Mayo Clinic Single Center Study ClinicalTrials.gov #NCT736 HFpEF (clinical or RHC or BNP or echo evidence) and HF is primary limit to activity Primary Endpoint: Peak VO after 4 weeks treatment with inhaled nitrite

23 Conclusions is potent hypoxic vasodilator at physiological concentrations. In studies to date, nitrite appears safe and tolerable. In PH-HFpEF, inhaled nitrite acutely lowers filling pressures, pulmonary pressures, mediated by a primary physiological effect of increasing pulmonary vascular compliance. Phase studies are underway to assess the effects of chronic therapy on exercise capacity and/or hemodynamics.

Vanderpool Medhi Nouraie Masataka Sugahara John Gorcsan Aires

24 Acknowledgment University of Pittsburgh Mark Gladwin Charly Lai Pamela White Nikki Helbling Nydia Chien Tim Bachman Rebecca Vanderpool Medhi Nouraie Masataka Sugahara John Gorcsan Aires Pharmaceuticals, Inc. (Savara Inc.) Ed Parsley Funding: NIH RO HL5886 Mast Therapeutics

Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction

$Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction$ Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction Marc A. Simon, 1,2,3,4 Rebecca R. Vanderpool, 2,3 Mehdi Nouraie,