Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
PHA Thanks the Medical Education Fund Sponsors! PHA Thanks the Washington, DC Planning Committee and Presenters! • Christopher Barnett, M.D., MPH; Co-chair • Grant Farr, D.O. • Oksana A. Shlobin, M.D., FCCP; Co-chair • Mardi Gomberg-Maitland, M.D., MSc • Janet Arp • Hunter Groninger, M.D., FACP, FAAHPM • Daniel C. Grinnan, M.D. • Shilpa Johri, M.D. • Denise Lewis, RN, BSN • Todd M. Kolb, M.D., Ph.D. • Stephen Mathai, M.D., MHS • Katherine Kroner • Betsie Miklos • Tunay Kuru, M.D. • Gerilynn Connors, B.S., RRT,MAACVPR, FAARC • Janet Pinson, MSN, ACNP • Gautam Ramani, M.D. • Virginia Steen, M.D. • Nargues Weir, M.D. • • • Rachel Damico, M.D., Ph.D. Jason M. Elinoff, M.D. Karen Fagan, M.D. PH Patients and Families Education Forum A Program of the Pulmonary Hypertension Association Medical Education Fund Washington, D.C. October 1, 2016 Where We Are, Where We Are Going, and How Do We Get There? Jason M. Elinoff, MD Critical Care Medicine Department Mark O. Hatfield Clinical Center National Institutes of Health 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 • • Survival (%) 100 No treatment available Less than 50% of people with PAH lived more than 3 years from the time of diagnosis 0 Years From Time of Diagnosis Adapted from D’Alonzo GE Ann Intern Med 1991 Where We Are Survival (%) 100 0 Years From Time of Diagnosis Adapted from Benza RL Chest 2012 Where We Are Survival (%) 100 More People Are Living Longer With PAH 0 Years From Time of Diagnosis Adapted from Benza RL Chest 2012 Timeline of PAH Drug Development Treprostinil intravenous Ambrisentan Room temperature stable epoprostenol Treprostinil subcutaneous Macitentan Riociguat Sildenafil Bosentan Tadalafil Epoprostenol 1995 2001 2002 2004 2005 Iloprost Courtesy of Dr. Harold I. Palevsky 2007 2009 Treprostinil inhaled 2010 2013 Selexipag 2014 2015 Treprostinil oral PAH: Therapeutic Targets PAH: Therapeutic Targets PAH: Therapeutic Targets 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 Endothelial cell Endothelin production Endothelin receptor A Smooth muscle cell Endothelin receptor B Vasoconstriction Adapted from Humbert et al. NEJM 2004 Endothelin Pathway Endothelial cell Endothelin production Endothelin receptor A Endothelin receptor B Endothelin receptor antagonists (ERAs) Smooth muscle 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 Endothelial cell NO production NO Guanylate cyclase NO cGMP Smooth muscle cell Vasodilation Adapted from Humbert et al. NEJM 2004 Nitric Oxide (NO) Pathway Endothelial cell NO production NO Guanylate cyclase NO cGMP Smooth muscle cell Phosphodiesterase type 5 PDE5 Inhibitors Vasodilation Adapted from Humbert et al. NEJM 2004 Nitric Oxide (NO) Pathway Endothelial cell NO production NO GuanylateGuanylate cyclase cyclase stimulators NO Phosphodiesterase type 5 cGMP Smooth muscle cell PDE5 inhibitors Vasodilation Adapted from Humbert et al. NEJM 2004 Nitric Oxide (NO) Pathway Endothelial cell NO production NO GuanylateGuanylate cyclase cyclase stimulators NO Phosphodiesterase type 5 cGMP Smooth muscle cell PDE5 inhibitors 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 (PGI2) Pathway Endothelial cell PGI2 production Prostacyclin receptor Smooth muscle cell PGI2 Vasodilation Adapted from Humbert et al. NEJM 2004 Prostacyclin (PGI2) Pathway Endothelial cell PGI2 production Prostacyclin Prostacyclin receptor receptor agonists Smooth muscle cell Prostacyclin derivatives Vasodilation Adapted from Humbert et al. NEJM 2004 Prostacyclin (PGI2) 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 Patients without an Event (%) Advances In Clinical Trials 100 90 80 70 60 50 40 30 12-16 weeks 20 10 0 0 6 12 18 Months 24 30 36 • 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 Patients without an Event (%) Macitentan (Opsimut®) N=242, 10 mg N=250, 3 mg 100 90 80 70 60 Placebo N=250 50 40 30 100 90 80 70 60 50 40 30 20 10 0 20 10 0 0 6 12 Selexipag (Uptravi®) N=582 18 Months 24 30 36 Placebo N=574 0 6 12 18 24 30 36 Months N Engl J Med 2013 and 2015. Advances In Clinical Trials Patients without an Event (%) Macitentan (Opsimut®) N=242, 10 mg N=250, 3 mg 100 90 80 70 60 Placebo N=250 50 40 30 20 10 0 100 90 80 70 60 Over 700 Patients Participated 0 6 12 18 Months 24 30 Selexipag (Uptravi®) N=582 36 50 40 30 20 10 0 Placebo N=574 Over 1000 Patients Participated 0 6 12 18 24 30 36 Months N Engl J Med 2013 and 2015. Participants with No Event (%) Advances In Clinical Trials 100 80 60 40 20 0 0 24 48 72 96 120 144 168 192 Weeks Participants with No Event (%) Is Initial Combination Therapy Superior To Either Drug Alone? 100 • Hospitalization for worsening PAH or 80 • Decreased 6 MWD AND severe symptoms (class III/IV) or 60 • Lack of long term clinical improvement or 40 • Death 20 0 0 24 48 72 96 120 144 168 192 Weeks N Engl J Med 2015 Participants with No Event (%) Yes, Initial Combination Therapy Is Better Than Either Drug Alone Ambrisentan (Letaris®) AND Tadalafil (Adcirca®) N=253 100 80 60 Ambrisentan (Letaris®) or Tadalafil (Adcirca®) N=247 40 20 0 0 24 48 72 96 120 144 168 192 Weeks 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 How Does Your PH Physician Determine The Right Treatment For You? • 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 Determining Risk…. Part Science & Part Art • Variables in the equation - How severe are your symptoms? We(i.e. useyour data from multiple sources to functional classification) make final judgments…a key is the - How is the right side of your heart experience of the healthcare provider! performing? - Are your symptoms worsening quickly? - Six minute walk distance - Laboratory blood tests Courtesy of Dr. Harold I. Palevsky “Because that’s where the money is….” In PAH – the major determinant of symptom severity, risk of progression & survival is right ventricular function (NOT the pulmonary arterial pressures!) Courtesy of Dr. Harold I. Palevsky 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…. Echocardiogram 6 minute walk test Blood tests Catheterization Patient preferences Social support Other medical conditions Side effects Taking Aim At New Targets Treatment Targets Pulmonary HTN ↑Pulmonary vascular resistance ↑Mean pulmonary artery pressure Treatment Targets Vasodilation ↓ Pulmonary artery pressure ↓ Pulmonary vascular resistance Increased cell proliferaton Altered cell metabolism Inflammation Estrogen Right Ventricular Adaptation Drug Repurposing: “Old” Drugs For New Purposes 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”) JCI 2013 and AJRCCM 2015 Drug Repurposing: “Old” Drugs For New Purposes 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 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 AJRCCM 2016 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 Drug Repurposing: “Old” Drugs For New Purposes Spironolactone (Aldactone) • In patients with left heart failure, spironolactone improves blood vessel function, inflammation and survival • Spironolactone treatment is beneficial in PH animal models Trials 2013 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 NCT01468571, NCT02253394 and NCT01712620 Drug Repurposing: “Old” Drugs For New Purposes 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 NCT01086540 AJRCCM 2016 New Drugs Targeting New Pathways 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 NCT02234141 AJRCCM 2016 New Drugs Targeting New Pathways 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 NCT02036970 AJRCCM 2016 New Drugs Targeting New Pathways Ubenimex (Bestatin™; LIBERTY Study) • Inhibits the inflammatory mediator LTB4 • Used in Japan to treat patients with leukemia • Phase II study assessing change in pulmonary vascular resistance • Long term extension study is planned NCT01086540 AJRCCM 2016 Participating In Clinical Research Where We Want To Be Survival (%) 100 0 Years From Time of Diagnosis Adapted from Benza RL Chest 2012 What Is A Clinical Trial? • 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 Types of Clinical Trials Observational Study Interventional Study • Choose a convenient study population • Carefully selected participants • Collect data over time or review data from prior records • Participants and the researchers may be “blinded” • Look for patterns or associations • Typically includes a control group to compare to the intervention group • Generate new hypotheses What Are The Benefits Of Participating In A Clinical Trial? • 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 Risks 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 How Do I Learn More About Current PH Studies? Ask your PH health care team! How Do I Learn More About Current PH Studies? How Do I Learn More About Current PH Studies? Thank You! Questions? Jason M. Elinoff, MD Oksana Shlobin, MD Stephen C. Mathai, MD, MHS