Therapeutic Options for PAH ADAANI FROST, MD Director, Pulmonary Hypertension Center Professor of Medicine Baylor College of Medicine Houston, Texas

2 Learning Objectives (CME, CE, CPE) ●At the completion of this educational activity, participants should be able to: - Discuss the improvements made in PAH-specific therapies over the past decade - Discuss data regarding the efficacy, safety, and tolerability of the major classes of PAH-specific therapies - Identify major class-related adverse effects associated with PAH-specific therapies - Identify issues related to drug-drug interactions and other aspects of clinical pharmacology that impact on patient care - List the major points of difference between the individual agents used to treat PAH

Introduction

4 PAH: Definition on Right Heart Catheterization Gaine SP, et al. Lancet. 1998;352: Increased mean pulmonary arterial pressure (mPAP) >25 mm Hg at rest or >30 mm Hg during exercise Normal pulmonary artery wedge pressure (PAWP) <15 mm Hg Increased pulmonary vascular resistance (PVR) >3 Wood units

5 Goals of Management of PAH ●Improve survival ●Prevent worsening ●Improve hemodynamics ●Maintain or improve functional class ●Improve exercise capacity ●Improve daily functioning and quality of life

6 General Measures ●Recommend regular cautious supervised exercise - Maintain skeletal muscle conditioning - Know the pre-determined stopping points (eg, significant dyspnea, chest pain, dizziness) ●Provide prophylaxis for pulmonary infections - Influenza and pneumococcal vaccines ●Maintain hemoglobin levels - Aggressive evaluation for anemia - Monitor for hyperviscosity syndromes in patients with congenital heart disease (eg, Eisenmenger syndrome) Phlebotomy may be indicated in patients with high hematocrit (>63) or with signs of neurologic symptoms Galie N, et al. Eur Heart J. 2004;25:

7 General Measures ●Counsel on avoiding pregnancy - High rate of mortality in patients with PAH - Caution with hormonal birth control methods when on bosentan It renders oral contraceptive less effective, so must add barrier method Ambrisentan does not interfere with oral contraceptives - Bosentan and ambrisentan are pregnancy category X Galie N, et al. Eur Heart J. 2004;25:

8 General Medical Care for PH ●Oxygen supplementation - Maintain O 2 saturation >90% at rest, with supervised exercise, and during sleep - Unless PAH is severe, most patients are only mildly hypoxemic in the absence of intracardiac shunt or concomitant lung disease O 2 supplementation may not alleviate PAH symptoms associated with shunts - Supplemental O 2 for air travel, if indicated - Avoid altitudes above 5000 feet Badesch DB, et al. Chest. 2004;126:35S-62S. Galie N, et al. Eur Heart J. 2004;25:

9 Considerations for Selecting Initial Therapy for PAH ●Severity of symptoms/functional class ●Physical examination (right-heart failure?) ●Rate of progression ●Echocardiogram (RV size and function) ●Cardiopulmonary hemodynamics ●6-minute walk distance/exercise capacity ●BNP/NT-pro-BNP ●Capability of patient to handle parenteral therapy - Parenteral therapy is first choice in very advanced patients ●Other issues - Drug-drug interactions, adverse events, comorbid conditions (eg, diabetes), route of administration, dosing intervals, cost

10 Mechanisms of Action of Therapies for PH Humbert M, et al. N Engl J Med. 2004;351: Nitric oxide cGMP Vasodilation and antiproliferation Endothelial cells Nitric oxide pathway PreproendothelinProendothelin L-arginine NOS Arachidonic acidProstaglandin I 2 cAMP Vasodilation and antiproliferation Vasoconstriction and antiproliferation Endothelin- receptor A Endothelin- receptor B Endothelin pathwayProstacyclin pathway Endothelin-1 Endothelin- receptor antagonists Exogenous nitric oxide Prostacyclin derivates Phosphodiesterase type 5 inhibitor Phosphodiesterase type 5

11 Commonly Reported Clinical Trial Outcomes in PAH ●6-minute walk distance - Primary endpoint in many clinical trials - Easy to administer - Correlates with other outcomes ●Change in NYHA/WHO functional class - Secondary endpoint in many trials ●Improvement in hemodynamics - Requires repeat catheterization

12 Commonly Reported Clinical Trial Outcomes in PAH ●Time to clinical worsening - Combined endpoint being used more frequently - Variation in definition depending on study ●Mortality - Placebo-controlled survival studies not feasible/ethical with modern PAH therapies - Survival data available based on open-label long-term extension studies of placebo-controlled trials

13 Pharmacotherapy for PAH: Routes of Delivery ●Oral therapy - Endothelin receptor antagonists (ERAs) - PDE5 inhibitors - Calcium channel blockers (small minority of patients) ●Inhaled therapy - Prostanoids ●Intravenous/subcutaneous therapy - Prostanoids

14 Treatment Options for Patients Failing Acute Vasoreactivity Testing by NYHA Functional Class Functional Class II Functional Class III Functional Class IV Sildenafil Ambrisentan* Treprostinil sc Treprostinil iv Bosentan † Bosentan ‡ Ambrisentan* ‡ Sildenafil ‡ Epoprostenol iv Iloprost (inhaled) Treprostinil sc Treprostinil iv Epoprostenol iv Bosentan Iloprost (inhaled) Sildenafil Treprostinil sc Treprostinil iv Badesch DB, et al. Chest. 2007;131: Galie N, et al. Presented at ESC *Ambrisentan approved after development of updated guidelines. † Inclusion based on data presented at ESC ‡ Not necessarily in order of preference.

15 Options for Patients Failing to Improve or Deteriorating Under Initial Therapy Badesch DB, et al. Chest. 2007;131: Functional Class III or IV Atrial septostomy and/or Lung transplantation Combination Therapy(?) Prostanoids Endothelin Receptor Antagonists PDE5 Inhibitors

16 Management of PAH Therapy ●Up to 100% of PAH patients will report 1 or more adverse effects of PAH therapy ●Most adverse effects should be managed conservatively ●Since there are limited agents and alternatives, patient risk from adverse event needs to be judged against reduced efficacy of PAH therapy

PAH Therapies in Treatment-Naïve Patients

Calcium Channel Blockers

19 Oral Calcium Channel Blockers in IPAH ●Favorable acute response to vasodilator challenge - Decrease in mPAP of at least 10 mmHg to <40 mm Hg - Increased or unchanged cardiac output ●Patients who fail acute vasodilator challenge should not be treated with calcium channel blockers Badesch DB, et al. Chest. 2004;126:35S-62S.

20 French Registry: Response to Acute Vasodilator Challenge Response (%) Idiopathic n=649. Challenge with vasodilator at time of right heart catheterization. 10.3% Humbert M, et al. Am J Respir Crit Care Med. 2006;173: % 2.6% 0% 3.3% 1.6% 6.8% Familial Connective Tissue Congenital Heart Portal Hypertension Anorexigens HIV >2 Factors

21 Long-Term Response to Calcium Channel Blocker Therapy in IPAH ●Long-term responders to calcium channel blocker therapy (at least 1 year) - Less severe disease at baseline - More pronounced decrease in mPAP during acute challenge - Long-term responders 54% of acute responders 6.8% (95% CI, 4.7% to 8.9%) of patient sample - 5-year survival rate of calcium channel blocker therapy failures: 48% Responders Patients (%) Acute Vasodilator Challenge Long-Term Calcium Channel Blocker Therapy 12.6% 6.8% Sitbon O, et al. Circulation. 2005;111: n=557.

22 Survival on Oral Calcium Channel Blocker Therapy Sitbon O, et al. Circulation. 2005;111: Survival endpoint included those who received transplants or were lost to follow-up Years Failures Cumulative Survival Responders Subjects at Risk (n) Responders Failures Long-Term Calcium Channel Blocker Therapy

Prostanoids Intravenous/Subcutaneous Therapy

24 Prostanoid Intravenous/Subcutaneous Therapy for PAH ●Requires expertise as numerous complications and risks are associated with therapy - Adequate coordinator support for associated problems Adequate patient support for medication preparation Epoprostenol ●First PAH-specific therapy ●Requires continuous intravenous infusion Treprostinil ●Available both as continuous subcutaneous injection or continuous intravenous infusion ●Longer half-life and more chemically stable than epoprostenol Barst RJ, et al. N Engl J Med. 1996;334: Simonneau G, et al. Am J Respir Crit Care Med. 2002;165:

25 Improved Survival With Epoprostenol for IPAH P=0.003 versus conventional therapy (anticoagulants, oral vasodilators, diuretic agents, cardiac glycosides, and supplemental oxygen). Barst RJ, et al. N Engl J Med. 1996;334: Epoprostenol (n=41) Conventional therapy (n=40) Weeks Survival (%)

26 Intravenous Epoprostenol for Severe PAH: 3-Year Survival n=162 consecutive patients with IPAH in NYHA Class III or IV. 3-year survival with IV epoprostenol compared with expected survival from historical controls. *P<0.001 at all time points. McLaughlin VV, et al. Circulation. 2002;106: Months Survival (%) * * * Observed Expected

27 Hemodynamic Variables Improved With Epoprostenol Therapy McLaughlin VV, et al. Circulation. 2002;106: mPAP mRAP Cl PVR Change (mm Hg) Change (L/min/m 2 ) Change (Wood units ) Change (mm Hg) Epoprostenol Epoprostenol Epoprostenol

28 Subcutaneous Treprostinil: Week-12 Change From Baseline in 6-Minute Walk Distance by Dose Quartile Simonneau G, et al. Am J Respir Crit Care Med. 2002;165: Mean Change in 6-Minute Walk Distance (meters) < <8.2 n=470. Chronic study drug infusion initiated at 1.25 ng/ kg/min. At Week 12, the maximum allowable dose was 22.5 ng/kg/min. *P=0.006 for all doses of treprostinil versus placebo <13.8 >13.8 Dose Quartile (ng/kg/min)

29 Long-Term Outcomes With Subcutaneous Treprostinil Barst RJ, et al. Eur Respir J. 2006;28: Patients (%) Discontinue for Deterioration Death n=860. Patients followed for up to 4 years. Switch Therapy Add Therapy Discontinue for Adverse Events 14% 16% 11% 15% 23%

30 SC Treprostinil as Naïve, Add-On, and Transition Therapy Soto FJ, et al. Am J Respir Crit Care Med. 2008;177:A966. Changes in 6-Minute Walk Distance: >1 Year Follow-Up n=52. *P=0.0009; † P=0.01; ‡ P=0.02 versus baseline for each group. Change from baseline 6-MWD (m) Naïve (n=25) Add-On (n=15) Transition (n=13) 120* 128 † 76 ‡

31 Intravenous Treprostinil: Impact on 6-Minute Walk Distance Baseline n=16. *P=0.008 and † P=0.001 versus baseline. Week 6Week 12 Tapson VF, et al. Chest. 2006;129: * 400 † Total 6-Minute Walk Distance (meters)

32 Intravenous Treprostinil: Hemodynamic Changes at 12 Weeks mPAP mRAP Cl PVR Change (mm Hg) Change (L/min/m 2 ) Change (Wood units ) Change (mm Hg) -4.2 Treprostinil -0.8 Treprostinil Treprostinil Tapson VF, et al. Chest. 2006;129: Treprostinil

33 Epoprostenol Pharmacokinetics Half life2.7 minutes Bioavailability100% MetabolismSpontaneous and enzymatic degradation ExcretionUrinary CYP interactionsNone StabilityUnstable at room temperature; requires refrigeration Epoprostenol full prescribing information

34 Treprostinil Pharmacokinetics Half life4 hours Bioavailability~100% MetabolismHepatic ExcretionUrinary CYP interactionsNone known Treprostinil full prescribing information

35 Adverse Events Associated With Prostanoid Injection Therapy ●Common adverse events - Adverse events associated with therapy should be expected (incidence rates >80%) Most adverse events associated with vasodilation - Headache, jaw pain, flushing/skin rash, diarrhea, nausea and vomiting - Catheter infections and injection site reactions (treprostinil) Epoprostenol full prescribing information Treprostinil full prescribing information

36 Epoprostenol and Treprostinil: Common Adverse Effects ●Flushing ●Headache ●Diarrhea, nausea, vomiting ●Jaw pain ●Myalgia ●Hypotension ●Anxiety, nervousness, agitation ●Chest pain ●Dizziness ●Bradycardia ●Abdominal pain ●Dyspnea ●Back pain ●Sweating ●Dyspepsia ●Paresthesia ●Tachycardia ●Delivery site complications Epoprostenol full prescribing information Treprostinil full prescribing information

37 Thrombocytopenia Correlated With Epoprostenol Dose and With RAP Chin KM, et al. Am J Respir Crit Care Med. 2008;177:A260. n=54 current and former epoprostenol-treated patients RAP <10 mmHg RAP mmHg RAP >15 mmHg Platelet Count (1000s) Epoprostenol Dose (ng.kg/min)

38 Epoprostenol-Related Thrombocytopenia Platelet Count Drop >50,000 Noted in Red Platelet Count at Baseline Platelet Count 2-4 Months Platelet Count at 8-12 Months Jacob S. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

39 Catheter Infections Associated With Intravenous Prostacyclins ●Infection rates range from 0.43 to 1.13 infections per 1000 treatment days ●IV treprostinil associated with slightly higher infection rates compared with epoprostenol - Treprostinil also associated with higher incidence of Gram-negative bacteria ●Exposure to Gram-negative pathogens may occur during bathing or showering ●A closed-hub system may decrease bacterial contamination of the hub Doran AK, et al. Int J Clin Pract. 2008;62(suppl 160):5-9.

40 Preventing and Managing Catheter Infections ●Complete guidelines available at ●Use a cuffed and tunneled CVC ●No submersion of catheter in water ●Remove catheter if bacterial infection is documented - Do not use “clear the line” approach ●Use of gloves does not eliminate hand hygiene need ●Do not use topical antibiotics or creams on insertion sites Doran AK, et al. Int J Clin Pract. 2008;62(suppl 160):5-9.

41 Treprostinil SC Infusion Site Pain and Reaction ●Infusion site pain and infusion site reaction (redness and swelling) occur in the majority of patients ●These symptoms were often severe and could lead to treatment with narcotics or discontinuation of treprostinil ●Infusion site pain is not related to dose ●Site pain varies by patient as well as by infusion site ●There are sometimes simply “good” sites and “bad” sites ●Site pain is often the worst 2 to 5 days into a new injection site Treprostinil full prescribing information

42 Treprostinil Site Pain Care: Nonpharmacologic Approaches ●Encourage patients to change a “bad” site right away ●Allow patients to maintain a “good” site for several days ●Try alternative sites such as upper buttocks or backs of upper arms ●Remove any medication droplets on the end of the needle after priming ●For frequent topical medication application, apply thin DuoDERM ® prior to catheter insertion ●Try dry catheter preplacement method before initiating medication ●Change to a more concentrated solution to allow for less volume infusion per hour

Prostanoids Inhalation Therapy

44 Prostanoid Mechanisms of Action Humbert M, et al. N Engl J Med. 2004;351: Newman JH, et al. Circulation. 2004;109: cAMP Vasodilation and antiproliferation Arachidonic acid Prostaglandin I 2

45 Inhaled Prostanoid Therapy for PAH: Iloprost ●Stable prostacyclin analogue ●Effect on PVR approximately equivalent to inhaled NO or oral sildenafil during acute testing ●6 to 9 inhalations daily required - Half-life of 20 to 30 minutes Olschewski H, et al. N Engl J Med. 2002;347: Ghofrani HA, et al. J Am Coll Cardiol. 2004;43:68S-72S. Rubin LJ, et al. Proc Am Thorac Soc. 2006;3:

46 Inhaled Iloprost for Severe PAH: Combined Endpoint Analysis Patients (%) All 16.8%* Non-IPAH 4.9% 20.8% 12.5% n=203. *P=0.07 versus placebo. Non-IPAH group included patients with chronic thromboembolic pulmonary hypertension (n=57). Iloprost Placebo Olschewski H, et al. N Engl J Med. 2002;347: % 4.3% IPAH Improvement of 1 NYHA Class and >10% Increase in 6-Minute Walk Distance

47 Inhaled Iloprost Pharmacokinetics Half life20 to 30 minutes BioavailabilityUndetermined MetabolismHepatic ExcretionUrinary CYP interactionsNone known Iloprost full prescribing information

48 Safety and Tolerability Considerations With Inhaled Iloprost ●Adverse events - Flushing, headache, jaw pain typical of prostanoid therapy - Cough associated with route of delivery ●Warnings and precautions - Risk of hypotension in patients with low systemic blood pressure Iloprost full prescribing information