1. Wednesday, November 15, 2006 Washington, DC Richard M. Silver, MD, Program Chair VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS

2. Treatment Targets for PAH in Systemic Sclerosis Myung H. Park, MD, FACC Assistant Professor of Medicine Director, Pulmonary Vascular Diseases Program University of Maryland Medical Center Baltimore, Maryland

3. VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS DISCLOSURE STATEMENT Myung H. Park, MD, FACC Grants/research support: Actelion Pharmaceuticals US, Inc., CoTherix, Inc., United Therapeutics Consultant: Actelion Pharmaceuticals US, Inc., CoTherix, Inc., Myogen, Inc., Pfizer Inc, United Therapeutics Speakers’ bureau: Actelion Pharmaceuticals US, Inc., Encysive Pharmaceuticals Inc., Pfizer Inc, United Therapeutics Off-label uses for products may be discussed.

4. Definition of Pulmonary Arterial Hypertension Barst, RJ et al. J Am Coll Cardiol. 2004;43:40S- 47S. Pulmonary arterial hypertension: –Mean PAP >25 mm Hg at rest –Mean PAP >30 mm Hg with exercise Normal pulmonary capillary wedge pressure (<15 mm Hg)

5. Incidence of Pulmonary Hypertension Population IncidencePopulation Incidence –Primary 4 : 500,000 –Familial 1 : 30,000,000 Disease Specific IncidenceDisease Specific Incidence –Connective Tissue1 : 10 – 1 : 1,000 –Portopulmonary8 : 1,000 –HIV1 : 5,000 –Anorexigens (>3 mo)1 : 17,000 –Anorexigens (>6 mo)1 : 10,000 –CTEPH1 : 10,000 Chest 2003.

6. Connective Tissue Disease: Major Risk Factor for Development of PAH Connective Tissue Disease (CTD) Most common and severe in CREST –Diffuse scleroderma—up to 33% –Limited scleroderma (CREST)—25%- 30% –SLE—4% to 14% –RA—up to 21% (mild) PH most common cause of death in CREST Identical to iPAH pathology Medical treatment same as for iPAH –But benefits less than for iPAH CREST=Calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia.

7. 2003 WHO Pulmonary Hypertension Diagnostic Classification 1. Pulmonary Arterial Hypertension Idiopathic PAH (Formerly iPAH)Idiopathic PAH (Formerly iPAH) Familial PAHFamilial PAH Related to:Related to: –Connective tissue diseases –HIV –Portal hypertension –Anorexigens –Congenital heart disease Portopulmonary hypertensionPortopulmonary hypertension PAH with venule/cap involvementPAH with venule/cap involvement 2. Pulmonary Venous Hypertension Atrial or ventricular heart diseaseAtrial or ventricular heart disease Valvular heart diseaseValvular heart disease 3. PH With Lung Diseases/Hypoxemia COPDCOPD Interstitial lung diseasesInterstitial lung diseases Sleep-disordered breathingSleep-disordered breathing Developmental abnormalitiesDevelopmental abnormalities 4. PH Due to Chronic Thrombotic and/or Embolic Disease TE obstruction of proximal PATE obstruction of proximal PA TE obstruction of distal PATE obstruction of distal PA Nonthrombotic pulmonary embolismNonthrombotic pulmonary embolism 5. Miscellaneous SarcoidosisSarcoidosis Pulmonary histocytosisPulmonary histocytosis LymphangiomatosisLymphangiomatosis

8. 1 yr: 68% Median survival: 2.8 yrs 3 yr: 48% 5 yr: 34% 0 20 40 60 80100 00.51.01.52.02.53.03.54.04.55.0 Years of follow-up % Surviving Surviving Adapted from: D’Alonzo GE et al. Ann Int Med. 1991;115:343-349. Observed 5-Year Survival Without Treatment in iPAH: National Registry

9. Time (yrs) 123405SSc-PAH iPAH Survival (%) 0.2 0.8 0.41.00.6 0 Log-rank text  2 =4.88 p=0.03 No. at risk: SSc-PAH:2273––– iPAH:33241593– Kawut SM et al. Chest. 2003;123:344-350. Survival Comparison of Patients With SSc- PAH and iPAH With Similar Hemodynamics

10. Vascular Injury Vascular Remodeling and Dysfunction Disease Progression Cardiac Hypertrophy Neurohormonal Imbalance Gaine SP, Rubin LJ. Lancet. 1998;352:719-725. Insult Geneticpredisposition Pulmonary Arterial Hypertension: Understanding the Pathobiology

11. Increased Activity Endothelin-1Angiopoietin-1PAI-1 Growth factors PDGF Reduced Activity Prostacyclin Nitric oxide VIP PAI = plasminogen activator inhibitor. VIP = vasoactive intestinal peptide. Neurohormonal Imbalance in PAH

12. McLaughlin V et al. Circulation. 2006:114.

13. Therapeutic Options for PAH General Tx General Tx Supplemental O 2Supplemental O 2 DiureticsDiuretics CCBCCB WarfarinWarfarin DigitalisDigitalis FDA Approved for PAH Prostanoids –epoprostenol –treprostinil (SC,IV) –inhaled iloprost ERAs –bosentan PDE-5 Inhibitors –sildenafil Investigational Tx Prostanoids –Inhaled treprostinil –Oral treprostinil ERAs –sitaxsentan –ambrisentan PDE-5 Inhibitor –tedalafil

14. ACCP Grading System for Recommendations Net Benefit to Patient (adjusted for risk and based on clinical assessment) SubstantialIntermediateSmall/WeakNoneConflictingNegative Quality of Evidence Good AABDID Fair ABCDID Low BCCIID Expert Opinion E/AE/BE/CIIE/D Good: Evidence is based on good randomized controlled trials or meta-analysis Fair: Evidence is based on other controlled trials or other RTCs with minor flaws Low: Evidence is based on non-randomized, case-control, or other observational studies Expert Opinion: Evidence is based on consensus of carefully selected panel of experts. There are no published studies that meet the criteria for inclusion in the literature review. McCrory DC et al. Chest 2004;126.

15. Therapy for PAH Functional class II/III/IV General Care Oral anticoagulants (B for iPAH, E/C for other PAH) + diuretics + oxygen (E/A) + digoxin Acute Vasoreactivity Testing (A for iPAH, E/C for PAH) Functional Class IIIFunctional Class IV Sustained Response Oral CCB (B for iPAH, E/B for other PAH) Continue CCB Chronic IV epoprostenol (A) bosentan (B) treprostinil (B) Chronic IV iloprost (C) Endothelin receptor antagonists bosentan (A) or Chronic IV epoprostenol (A) or Prostanoid Analogues SC treprostinil (B), Inhaled iloprost (B), beraprost (l) PDE-5 Inhibitors (sildenafil) (C) Atrioseptostomy Lung Transplantation YesNo Positive Negative No improvement or deterioration Badesch D et al. Chest. 2004;126.

16. Therapy for PAH Functional class II/III/IV General Care Oral anticoagulants (B for iPAH, E/C for other PAH) + diuretics + oxygen (E/A) + digoxin Acute Vasoreactivity Testing (A for iPAH, E/C for PAH) Functional Class IIIFunctional Class IV Sustained Response Oral CCB (B for iPAH, E/B for other PAH) Continue CCB Chronic IV epoprostenol (A) bosentan (B) treprostinil (B) Chronic IV iloprost (C) Endothelin receptor antagonists bosentan (A) or Chronic IV epoprostenol (A) or Prostanoid Analogues SC treprostinil (B), Inhaled iloprost (B), beraprost (l) PDE-5 Inhibitors (sildenafil) (C) Atrioseptostomy Lung Transplantation YesNo Positive Negative No improvement or deterioration Badesch D et al. Chest. 2004;126.

17. Idiopathic PAH –Improved survival reported with oral anticoagulation in iPAH 1, –In situ microscopic thrombosis documented in patients with iPAH –RV failure and venous stasis increases risk of pulmonary thromboembolism –Recommended target INR1.5-2.5 but varies from center to center PAH associated with other diseases - controversial –Consider risk/benefit ratio Scleroderma – risk of increased GI bleeding higher Consider if right ventricle is enlarged and systolic dysfunction present Badesch D et al. Chest. 2004;126. 1 Rich S et al. N Engl J Med.1992;327. Anticoagulation Therapy for Pulmonary Arterial Hypertension

18. Conventional Therapies Diuretics –Reduce peripheral edema, intravascular volume, and venous pressure –Avoid excessive diuresis –Combination of loop diuretics and spironolactone may be beneficial Digoxin –May increase contractility in refractory right heart failure –Can be useful in patients with atrial tachyarrhythmia Oxygen –Supplemental oxygen to maintain oxygen saturation >90% at all times –Hypoxemia is a potent vasoconstrictor Badesch D, et al. Chest. 2004;126

19. Therapy for PAH Functional class II/III/IV General Care Oral anticoagulants (B for iPAH, E/C for other PAH) + diuretics + oxygen (E/A) + digoxin Acute Vasoreactivity Testing (A for iPAH, E/C for PAH) Functional Class IIIFunctional Class IV Sustained Response Oral CCB (B for iPAH, E/B for other PAH) Continue CCB Chronic IV epoprostenol (A) bosentan (B) treprostinil (B) Chronic IV iloprost (C) Endothelin receptor antagonists bosentan (A) or Chronic IV epoprostenol (A) or Prostanoid Analogues SC treprostinil (B), Inhaled iloprost (B), beraprost (l) PDE-5 Inhibitors (sildenafil) (C) Atrioseptostomy Lung Transplantation YesNo Positive Negative No improvement or deterioration Badesch D et al. Chest. 2004;126.

20. Correlation of Acute Response to Vasodilator to Long-Term Response to CCB in iPAH Analyzed acute vasoreactivity testing in 557 patients with iPAH Acute vasodilator used: PGI 2 (n=150) or NO (n=407) Acute responder: fall in both mPAP and PVR >20% from baseline – “20/20 criterion”. –70 patients (12.6%) demonstrated acute response Long term CCB responder: –NYHA I/II after  1 year on oral CCB without need for prostanoids and/or ERA –Only half of acute responders (6.8% of total) maintained response long-term Sitbon O et al. Circulation. 2005;111.

21. Disease Acute responseLong-term iPAH13.4%7.5% Anorectin11.8%7.9% CTD10%2% HIV1.6% PortoPH1.3%0.7% CHD0% Familial PH0% PVOD12%0% All worsened on CCBs Sitbon O et al. ATS 2004. Long-term Response to CCB by Disease

22. Therapy for PAH Functional class II/III/IV General Care Oral anticoagulants (B for iPAH, E/C for other PAH) + diuretics + oxygen (E/A) + digoxin Acute Vasoreactivity Testing (A for iPAH, E/C for PAH) Functional Class IIIFunctional Class IV Sustained Response Oral CCB (B for iPAH, E/B for other PAH) Continue CCB Chronic IV epoprostenol (A) bosentan (B) treprostinil (B) Chronic IV iloprost (C) Endothelin receptor antagonists bosentan (A) or Chronic IV epoprostenol (A) or Prostanoid Analogues SC treprostinil (B), Inhaled iloprost (B), beraprost (l) PDE-5 Inhibitors (sildenafil) (C) Atrioseptostomy Lung Transplantation YesNo Positive Negative No improvement or deterioration Badesch D et al. Chest. 2004;126.

23. 13.3 Baseline: epoprostenol 271.5 m; conventional 240.0 m. Adapted from Badesch D et al. Ann Intern Med. 2000;132:425-434. Median change from baseline (m) -40 -20 0 20 40 60 80 -7.0 -14.0 -36.0 48.5 63.5 Week 1Week 6Week 12 Epoprostenol (n=56) Conventional (n=55) p=0.003 p  0.001 Epoprostenol Improves 6-Minute Walk Test in PAH Due to Scleroderma

24. Time (yrs) Kaplan-Meier survival estimates 0.2 1.0 0.4 0 0.6 0.8 CHD Scleroderma 02345617 Other iPAH p=0.002 Kuhn KP et al. Am J Respir Crit Care Med. 2003;167:580-586. Survival With Long-term Epoprostenol by Etiology No. at risk: PAH4940261611921 CHD118631000 SSc1911752000 Other129544100

25. Challenges Implementing Epoprostenol Therapy Development of tolerance Many side effects (diarrhea, flushing, headache, neuropathy) Only approved for advanced stages of disease (Class III to IV) Cost (average cost $50,000-150,000 per year) Need for continuous delivery system –Risk associated with catheter placement –Line related complications (infection, thrombosis, pump failure)

26. Treprostinil (Remodulin ® ) SC Analog of epoprostenol Lasts longer – more stable molecule (~4 hours vs 3-5 minutes for epoprostenol) Room temperature stable – do not need ice packs Rapid and complete absorption subcutaneously – bioavailability 100% Change pump every 3 days with SC (instead of every day with epoprostenol)

27. Treprostinil Sodium Injection: Change in Exercise vs Treprostinil Dose at Week 12 -4 ± 12 (N=34) +7 ± 10 (N=52) +15 ± 7 (N=58) +36 ± 9 (N=58) (2.5 ± 0.2) (16.2 ± 0.4) (9.4 ± 0.2) (5.6 ± 0.1) Mean ± SE Change from Baseline (meters) (Mean ± SE) ng/kg/min Simonneau G et al, Am J Respir Crit Care Med. 2002;165. N=470

28. Limitations of SC Treprostinil Site pain is major impediment –Affects 85% –Not dose dependent –Treatments Local measures: ice, heat, lidocaine NSAIDs, narcotics, gabapentin PLOgel –Patient education and support imperative for treatment success pain erythema induration pain erythema induration

29. Open-Label Transition Study Results 6-Minute Walk Test Results: IV REMODULIN vs Flolan*. NO Significant Change From Baseline Baseline on Flolan 12 weeks on REMODULIN 438 m + 16 m 439 m + 16 m P=NS N=27 *Data expressed as mean ± standard error. Safety results: 27 of 31 patients completed the study; 4 patients transitioned back to Flolan (3 due to leg pain, 1 with worsening PAH symptoms in setting of pneumonia). The most frequent adverse events were: extremity pain (71%), headache (45%), diarrhea (26%), and jaw pain (23%). One patient had syncope; 4 reported worsening dyspnea during titration. Gomberg-Maitland M, et al. Am J Respir Crit Care Med. 2005;172:1586-1589.

30. Inhaled Iloprost Indicated for inhalation via the I-neb™ AAD ® system only 6-9 inhalations daily during waking hours –No more than once every two hours Dose: maximum of 2.5 or 5 mcg per treatment Side effects (headache, flushing, diarrhea) –Cough, Syncope Advantage: Do not need a central line Disadvantage: Compliance

31. Olschewski H et al. N Engl J Med. 2002;347. Effect of Inhaled Iloprost on Walk Distance 36 meters 36 meter difference

32. Proliferation vascular smooth muscle fibroblasts Fibrosis fibroblast proliferation  extracellular matrix proteins  collagenase production Inflammation  vascular permeability neutrophil / mast cell activation promotes cellular adhesion  cytokine production Hypertrophy cardiac/vascular Endothelin Is A Key Pathogenic Mediator Vasoconstriction direct or via facilitation of other vasoconstrictor systems (renin angiotensin system, sympathetic) Clozel. Ann Med. 2003:35;1-5. ET

33. Endothelin Is a Key Mediator in PAH and PAH Secondary to Other Diseases Stewart et al., Ann Inter Med,1991; Vancheeswaran et al., J. Rheum, 1994; Yoshibayashi et al., Circulation, 1991 Congenital Heart Disease Non-PHPH 0 1 2 3 4 5 P<0.05 Delta ET-LI (PV-RV) (pg/ml) iPAH IrET-1 (pg/ml) Non-PAHPAH 0 2 4 6 8 10 Scleroderma Concentration of ET-1(pg/ml) 4 6 8 10 LcSSc PAH LcSSc Non-PAH P<0.05

34. Clozel M et al. J Pharmacol Exp Ther. 1994;270:228. Bosentan: Chemical Structure First Synthesis: December 1991 Pharmacokinetic Profile Orally active dual endothelin receptor antagonist Bioavailability is ~50% and is not affected by food. Metabolized by the liver (CYP3A4 and 2C9) and eliminated via the bile.

35. Bosentan (Tracleer ® ): BREATHE-1 Randomized, double-blind, placebo- controlled 16 week study 213 patients with NYHA Class III or IV PAH –Idiopathic PAH (70%) –PAH associated with connective tissue disease (30%) Gender M / F: 22% / 78% Baseline 6MWD: 330 ± 74 meters WHO FC III / IV: 94% / 6% Mean PAP: 53 ± 17 mm Hg Rubin LJ et al. N Engl J Med. 2002;346.

36. Adapted from Rubin LJ et al for the BREATHE Study Group. N Engl J Med. 2002;346:896-903, and Channick RN et al. Lancet. 2001;358:1119-1123. Data on file. Bosentan (n=37) Placebo (n=15)  walk distance (m) -22 -8 15 36 -30 -20 -10 0 10 20 30 40 Placebo Bosentan Bosentan (n =144) Placebo (n=69) SSc Pooled All BREATHE-1 Bosentan and SSc-PAH Walk Test Change From Baseline to Study End

37. BREATHE-1 SSc PATIENTS Time to Clinical Worsening* *Shortest time to death, premature withdrawal, hospitalization due to PAH worsening, or initiation of prostacyclin therapy. 100 25 50 75 0 Time (Wks) 048121618 Event-Free (%) Bosentan (n = 33) Placebo (n = 14)90%79%

38. Bosentan Indication PAH with WHO Class III (or IV) symptoms “to improve exercise capacity and decrease the rate of clinical worsening” Caveat: Response may take time - up to 2 to 3 months –Patients should be informed –Should be used with caution in Class IV patients and not without right heart catheterization to document presence of PAH

39. Bosentan Monitoring Increase in liver enzymes –Seen in about 10-12% of patients –LFTs checked baseline and monthly –Dose related and reversible Confirm elevation with another test Stop if ALT/AST >3 ULN – evaluate for concomitant medication use Consider reintroduction after resolution Stop treatment if associated with clinical symptoms (eg, jaundice, fever, nausea, vomiting) Dose 62.5 mg BID oral for 4 weeks. Titrate to 125 mg BID if LFTs stable.

40. Side Effect Bosentan Other side effects –Mild anemia –Teratogenic –Mild edema Drug interactions –May decrease efficacy of hormonal contraception; barrier method advised –Contraindicated with glyburide and cyclosporine

41. Differences in ET Receptors ET A –Located on smooth muscle cells –Mediate vasoconstriction ET B –Found on both endothelial and smooth muscle cells –Smooth muscle cells: mediates vasoconstriction –Endothelial cells: mediates vasodilation and clearance of ET-1

42. Selective vs Non-selective ERA? What Role Does ET B Receptor Play? Controversial Increased ET B receptor density in PH – spatial distribution not clear –Congenital heart disease (Am J Respir Crit Care Med 2002;165) –Chronic thromboembolic PH (Circulation 2002;105) –Scleroderma

43. Other ERAs Sitaxsentan: once daily specific ERA blocker –Phase III trials completed 1 –Marketing application filed with the FDA, approval pending –Significant warfarin interaction – need to decrease dose by 80% –Less liver toxicity Ambrisentan: once-daily specific ERA blocker (less than sitaxsentan) –Phase II trial showed ? less liver toxicity (3.1%), functional and hemodynamic improvements 2 –Phase III trials underway 1. Barst RJ, et al. Am J Respir Crit Care Med. 2004;169:441-447. 2. Galie N, et al. J Am Coll Cardiol. 2005;46:529-535.

44. N278 Age Mean: 49 y (range: 18-81 ) Gender 68 (25%) men; 209 (75%) women Primary Diagnosis iPAH: n=175 (63%) PAH secondary to CTD: n=84 (30%) PAH with surgical repair of congenital heart lesions: n=18 (6%) Mean 6-MWD distance 344 m mPAP 53 mm Hg Functional Classification Class I: n=1 (0.4%) Class II: n=107 (39%) Class III: n=154 (56%) Class IV: n=9 (3%) Dose 20, 40, 80 mg sildenafil or placebo in 1:1:1:1 Galie N et al. N Engl J Med. 2005:353:2148-2157. Sildenafil for PAH: SUPER Study

45. -30 -20 -10 0 10 20 30 40 50 6070 Week 4 Week 8 Week 12  from baseline (m) Placebo Sildenafil 20 mg Sildenafil 40 mg Sildenafil 80 mg *p<0.0001 * * * 45 m 46 m 50 m n=278. Adapted from Galie N et al. N Engl J Med. 2005;353:38-47. SUPER-1: Change in 6-MWD From Baseline to 12 Weeks

46. PAH Determinants of Risk Lower Risk Determinants of Risk Higher Risk No Clinical evidence of RV failure Yes GradualProgressionRapid IIWHO classIV Longer (>400 m)6MW distanceShorter (<300 m) Minimally elevatedBNPVery elevated Minimal RV dysfunction Echocardiographic findings Pericardial effusion, significant RV dysfunction Normal/near normal RAP and CI HemodynamicsHigh RAP, low CI McLaughlin VV and McGoon M. Circulation. 2006;114:1417-1431.

47. Summary Multiple pathogenic pathways contribute to CTD-associated PAHMultiple pathogenic pathways contribute to CTD-associated PAH –  prostacyclin and  NO cause  vasodilatation, and  smooth muscle proliferation –  ET-1 production causes  vasoconstriction,  inflammation,  fibrosis,  cellular proliferation Current targeted therapy has been demonstrated to improve clinical outcomes:Current targeted therapy has been demonstrated to improve clinical outcomes: –ERAs –PDE5 inhibitors –IV, SQ, or inhaled prostacyclin/prostanoid analogues New treatment approaches are focusing on:New treatment approaches are focusing on: –novel targets –improving delivery systems for current treatments –combination therapy to target multiple pathogenic pathways