PHA Thanks the Medical Education Fund Sponsors!

Christopher Barnett, M.D., MPH; Co-chair Oksana A. Shlobin, M.D., FCCP; Co-chair Janet Arp Daniel C. Grinnan, M.D. Denise Lewis, RN, BSN Stephen Mathai, M.D., MHS Betsie Miklos Gerilynn Connors, B.S., RRT,MAACVPR, FAARC Rachel Damico, M.D., Ph.D. Jason M. Elinoff, M.D. Karen Fagan, M.D. Grant Farr, D.O. Mardi Gomberg-Maitland, M.D., MSc Hunter Groninger, M.D., FACP, FAAHPM Shilpa Johri, M.D. Todd M. Kolb, M.D., Ph.D. Katherine Kroner Tunay Kuru, M.D. Janet Pinson, MSN, ACNP Gautam Ramani, M.D. Virginia Steen, M.D. Nargues Weir, M.D. PHA Thanks the Washington, DC Planning Committee and Presenters!

PH Patients and Families Education Forum A Program of the Pulmonary Hypertension Association Medical Education Fund Washington, D.C. October 1, 2016

Jason M. Elinoff, MD Critical Care Medicine Department Mark O. Hatfield Clinical Center National Institutes of Health Where We Are, Where We Are Going, and How Do We Get There?

Disclosure I have no relevant financial disclosures

Disclaimer The content of this presentation does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

Where We Began Adapted from D’Alonzo GE Ann Intern Med 1991 Years From Time of Diagnosis Survival (%) No treatment available Less than 50% of people with PAH lived more than 3 years from the time of diagnosis 100 0

Where We Are Adapted from Benza RL Chest 2012 Years From Time of Diagnosis Survival (%)

Where We Are Adapted from Benza RL Chest 2012 Years From Time of Diagnosis More People Are Living Longer With PAH Survival (%)

Timeline of PAH Drug Development Macitentan Epoprostenol Bosentan Treprostinil subcutaneous Iloprost Treprostinil intravenous Sildenafil Tadalafil Treprostinil inhaled Room temperature stable epoprostenol Ambrisentan Riociguat Treprostinil oral 2015 Selexipag Courtesy of Dr. Harold I. Palevsky

PAH: Therapeutic Targets

Adapted from Humbert et al. NEJM 2004

PAH: Therapeutic Targets Pulmonary artery endothelial cells Adapted from Humbert et al. NEJM 2004

PAH: Therapeutic Targets Pulmonary artery endothelial cells Pulmonary artery smooth muscle cells Adapted from Humbert et al. NEJM 2004

Endothelin Pathway Smooth muscle cell Endothelial cell Endothelin receptor A Vasoconstriction Endothelin receptor B Endothelin production Adapted from Humbert et al. NEJM 2004

Endothelin Pathway Endothelin production Endothelin receptor antagonists (ERAs) Endothelin receptor A Endothelin receptor B Smooth muscle cell Endothelial cell Adapted from Humbert et al. NEJM 2004

Endothelin Pathway 1.Bosentan (Tracleer ® ) 2.Ambrisentan (Letaris ® ) 3.Macitentan (Opsimut ® ) Adapted from Humbert et al. NEJM 2004

Nitric Oxide (NO) Pathway cGMP NO Guanylate cyclase Vasodilation NO production Smooth muscle cell Endothelial cell Adapted from Humbert et al. NEJM 2004

Nitric Oxide (NO) Pathway cGMP NO Guanylate cyclase Phosphodiesterase type 5 PDE5 Inhibitors NO production Smooth muscle cell Endothelial cell Vasodilation Adapted from Humbert et al. NEJM 2004

Nitric Oxide (NO) Pathway cGMP NO Guanylate cyclase Phosphodiesterase type 5 PDE5 inhibitors Guanylate cyclase stimulators NO production Smooth muscle cell Endothelial cell Vasodilation Adapted from Humbert et al. NEJM 2004

Nitric Oxide (NO) Pathway cGMP NO Guanylate cyclase Phosphodiesterase type 5 PDE5 inhibitors Guanylate cyclase stimulators NO production Smooth muscle cell Endothelial cell Vasodilation Adapted from Humbert et al. NEJM 2004

Nitric Oxide (NO) Pathway 1.Sildenafil (Revatio ® ) 2.Tadalafil (Adcirca ® ) 3.Riociguat (Adempas ® ) Adapted from Humbert et al. NEJM 2004

Prostacyclin (PGI 2 ) Pathway Prostacyclin receptor Vasodilation PGI 2 production PGI 2 Smooth muscle cell Endothelial cell Adapted from Humbert et al. NEJM 2004

Prostacyclin receptor Prostacyclin derivatives Prostacyclin receptor agonists PGI 2 production Smooth muscle cell Endothelial cell Vasodilation Prostacyclin (PGI 2 ) Pathway Adapted from Humbert et al. NEJM 2004

Prostacyclin (PGI 2 ) Pathway 1.Epoprostenol (Flolan ®, Veletri ® ) 2.Treprostinil (Remodulin ®, Tyvaso ®, Orenitram ® ) 3.Iloprost (Ventavis ® ) 4.Selexipag (Uptravi ® ) Adapted from Humbert et al. NEJM 2004

Goals of PAH Treatment Improve survival Maintain or improve quality of life Decrease symptoms Improve exercise capacity Minimize side-effects of treatment

Advances In Clinical Trials Patients without an Event (%) Months weeks Hospitalization for worsening PAH Decreased 6 MWD AND worse symptoms needing additional treatment Need for continuous prostacyclin treatment Lung transplant Death

Advances In Clinical Trials Months PlaceboN=574 Selexipag (Uptravi®) N= N Engl J Med 2013 and Patients without an Event (%) Months PlaceboN=250 N=250, 3 mg Macitentan (Opsimut ® ) N=242, 10 mg

Advances In Clinical Trials Months PlaceboN=574 Selexipag (Uptravi ® ) N= Patients without an Event (%) Months PlaceboN=250 N=250, 3 mg Macitentan (Opsimut ® ) N=242, 10 mg Over 700 Patients Participated Over 1000 Patients Participated N Engl J Med 2013 and 2015.

Participants with No Event (%) Weeks 9672 Advances In Clinical Trials

Is Initial Combination Therapy Superior To Either Drug Alone? Participants with No Event (%) Weeks 9672 N Engl J Med 2015 Hospitalization for worsening PAH or Decreased 6 MWD AND severe symptoms (class III/IV) or Lack of long term clinical improvement or Death

Yes, Initial Combination Therapy Is Better Than Either Drug Alone Weeks 9672 Ambrisentan (Letaris ® ) or Tadalafil (Adcirca ® ) N=247 Ambrisentan (Letaris ® ) AND Tadalafil (Adcirca ® ) N=253 Participants with No Event (%) N Engl J Med 2015

General Medical Management Prevent fluid retention (dietary changes, monitoring your weight and use of diuretics) Regular exercise if able (Pulmonary Rehab) Prevent low oxygen levels (oxygen therapy and/or nocturnal CPAP) Use of blood thinners

General Medical Management Immunizations (e.g. influenza and Prevnar/Pneumvax) Avoidance of pregnancy Communication with your other medical providers

More options = more decisions Treatment decisions are individualized and based largely on the severity of your PH Other considerations: Patient preferences Social support Other medical conditions Side effects How Does Your PH Physician Determine The Right Treatment For You?

Variables in the equation -How severe are your symptoms? (i.e. your functional classification) -How is the right side of your heart performing? -Are your symptoms worsening quickly? -Six minute walk distance -Laboratory blood tests Determining Risk…. Part Science & Part Art Courtesy of Dr. Harold I. Palevsky We use data from multiple sources to make final judgments…a key is the experience of the healthcare provider!

“Because that’s where the money is….” Courtesy of Dr. Harold I. Palevsky In PAH – the major determinant of symptom severity, risk of progression & survival is right ventricular function (NOT the pulmonary arterial pressures!)

How Do We Know When To Escalate PAH Therapy? Failure to improve with current therapy Improved, but not enough (symptoms, exercise tolerance, quality of life, etc.) Improved for a period of time, but now deteriorating

How Do We Know When To Escalate PAH Therapy? Other mitigating factors? Diet, abnormal heart rhythm, low blood count (anemia), blood clot in the lung (pulmonary embolism), worsening of other medical conditions Go back to the variables in the equation…. Patient preferences Social support Other medical conditions Side effects Echocardiogram 6 minute walk test Blood tests Catheterization

Taking Aim At New Targets

Pulmonary HTN ↑Pulmonary vascular resistance ↑Mean pulmonary artery pressure Treatment Targets

Increased cell proliferaton Increased cell proliferaton Right Ventricular Adaptation Altered cell metabolism InflammationEstrogen Vasodilation ↓ Pulmonary artery pressure ↓ Pulmonary vascular resistance

Tacrolimus (FK-506) Mutations in the BMPR2 gene are the most common genetic cause of PAH Impaired BMPR2 signaling is very common even in PAH patients who do not have a gene mutation Identified by molecular techniques searching for drugs that activate BMPR2 signaling (“drug repurposing”) Drug Repurposing: “Old” Drugs For New Purposes JCI 2013 and AJRCCM 2015

Tacrolimus (FK-506) Demonstrated promising effects in PH animal models Phase II study – early clinical trial to determine safety and efficacy Target enrollment = 40 patients Stopped early due to slow enrollment at a single center but a multi-center study is planned JCI 2013 and AJRCCM 2015 Drug Repurposing: “Old” Drugs For New Purposes

Anastrazole (Aromatase inhibitor) Used in the treatment of breast cancer Prevents conversion of androgens to estrogens Rationale is to reduce estrogen levels that may contribute to the harmful changes in the pulmonary arteries associated with PAH Drug Repurposing: “Old” Drugs For New Purposes AJRCCM 2016

Drug Repurposing: “Old” Drugs For New Purposes Anastrazole (Aromatase inhibitor) Pilot randomized, placebo-controlled study Primary outcome was change in blood levels of estradiol as well as effect on the right ventricle 12 PAH patients treated with anastrazole and 6 treated with placebo Duration was 3 months

Drug Repurposing: “Old” Drugs For New Purposes Anastrazole (Aromatase inhibitor) Anastrazole reduced blood estrogen levels, increased 6 MWD and did not change measures of right heart function by echo There were no serious side effects and no differences in side effects between the two groups AJRCCM 2016

Trials 2013 Spironolactone (Aldactone) In patients with left heart failure, spironolactone improves blood vessel function, inflammation and survival Spironolactone treatment is beneficial in PH animal models Drug Repurposing: “Old” Drugs For New Purposes

Spironolactone (Aldactone) Baylor University: Effect of spironolactone on blood levels of collagen/fibrosis markers as well as safety and tolerability ® ) Brigham and Women’s Hospital: Effect of ambrisentan (Letaris ® ) + spironolactone on exercise capacity NIH Clinical Center: Effect of spironolactone on exercise capacity, clinical worsening and inflammation NCT , NCT and NCT

Rituximab Depletes immune cells that make antibodies Phase II study in patients with Scleroderma associated PAH Primary outcome is change in pulmonary vascular resistance A subset of patients will undergo cardiac MRI to determine effects on the right ventricle AJRCCM 2016 NCT Drug Repurposing: “Old” Drugs For New Purposes

ASK1 Inhibitor (GS-4997; ARROW Trial) Suppresses of inflammation and cell proliferation Phase II study assessing change in pulmonary vascular resistance Long-term extension study planned New Drugs Targeting New Pathways AJRCCM 2016 NCT

Bardoxolone Methyl (LARIAT Trial) Suppresses inflammation and cell proliferation Phase II, dose finding study assessing change in 6MWD PAH, PH due to interstitial lung disease and PH due to sarcoidosis Long-term extension study planned AJRCCM 2016 NCT New Drugs Targeting New Pathways

Ubenimex (Bestatin™; LIBERTY Study Ubenimex (Bestatin™; LIBERTY Study) Inhibits the inflammatory mediator LTB 4 Used in Japan to treat patients with leukemia Phase II study assessing change in pulmonary vascular resistance Long term extension study is planned AJRCCM 2016 NCT New Drugs Targeting New Pathways

Participating In Clinical Research

Where We Want To Be Adapted from Benza RL Chest 2012 Survival (%) Years From Time of Diagnosis 100 0

Research involving human volunteers with the goal of adding to medical knowledge A clinical research study that follows a specific protocol Two general types of clinical trials: Observational study Interventional study What Is A Clinical Trial?

Observational Study Choose a convenient study population Collect data over time or review data from prior records Look for patterns or associations Generate new hypotheses Interventional Study Carefully selected participants Participants and the researchers may be “blinded” Typically includes a control group to compare to the intervention group Types of Clinical Trials

Generate knowledge that will help us understand, diagnose and/or treat PH now or in the future Without clinical research we are unable to improve our understanding of human disease Early access to new tests or treatments Frequent contact with health care providers What Are The Benefits Of Participating In A Clinical Trial?

Early access to new tests or treatments Side effects from medications or adverse effects from study procedures Frequent contact with health care providers Time investment The test or treatment may be ineffective or even harmful What Are The Risks Of Participating In A Clinical Trial?

How Do I Learn More About Current PH Studies? Ask your PH health care team!

How Do I Learn More About Current PH Studies? or ask your PH specialist!

How Do I Learn More About Current PH Studies? or ask your PH specialist!

Jason M. Elinoff, MD Oksana Shlobin, MD Stephen C. Mathai, MD, MHS Thank You! Questions?