The document discusses chronic thromboembolic pulmonary hypertension (CTEPH) and its pathophysiology. It describes the core pathologic process as an imbalance between prothrombotic factors and disturbed thrombus resolution, leading to in situ thrombosis over thromboembolic lesions. It also discusses the BENEFIT trial which found that treatment with bosentan improved exercise capacity and hemodynamics in inoperable CTEPH patients. The CHEST trial then evaluated riociguat, a soluble guanylate cyclase stimulator, in inoperable or recurrent CTEPH patients and found improvements in pulmonary vascular resistance and other outcomes.

1. DRUGS FOR CTEPH Dr. Marco Morsolini, MD Research Doctorate in Experimental Surgery and Microsurgery University of Pavia School of Medicine Division of Cardiac Surgery Foundation I.R.C.C.S. “San Matteo” Hospital – Pavia – Italy

2. PATHOPHYSIOLOGY

3. PATHOPHYSIOLOGY

6. “… the development of these hypertensive changes may explain the deterioration which these patients experience preoperatively over time…” ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

9. “… thrombotic material can provide the basis elements for the pultaceous core of atherosclerotic plaques, whereas it has not been observed in the hypertensive non-thromboembolic arteries…” ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

12. “… patients with plexiform lesions failed to show dramatic hemodynamic improvement despite successful PEA, suggesting that plexiform lesions were probably responsible for persistent pulmonary hypertension…” ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

15. Right bronchial artery Right mammary artery Before After Right thoracic artery ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

16. Right intercostal artery Right frenic artery Before After ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

20. EARLY DIAGNOSIS EARLY TREATMENT

22. JAMIESON CLASSIFICATION L.M.E.L. - 65 yrs M - Oct 2004 - PEA #119 mPAP 39  19 (-51%) CO 4.4  5.4 (+23%) PVR 665  222 (-66%) G.A.C. - 52 yrs F - Jul 2003 - PEA #96 mPAP 48  27 (-44%) CO 2.1  4.2 (+100%) PVR 1638  381 (-77%) B.A. - 43 yrs F - May 2009 - PEA #233 mPAP 49  19 (-61%) CO 3.3  5.0 (+52%) PVR 1067  224 (-79%)

23. Exclusively distal lesions MEDICAL THERAPY ! OPERABILITY ASSESSMENT

24. SURVIVAL OF UNTREATED PATIENTS

25. Higher operability rate PH RECURRENCY AFTER PEA More Jamieson type III PEAs MEDICAL THERAPY ! Higher PH recurrence after PEA

27. Pre-operative V/Q scan Pre-operative right pulmonary angiogram Pre-operative RHC mPAP 50 CI 1.4 PVR 1241 RVEF 9 PRE-OPERATIVE LONG LASTING DISEASE

30. PH MEDICAL THERAPY Pulmonary hypertension is a rare disease… … but not an orphan disease at all!

32. CTEPH MEDICAL THERAPY No drugs are currently approved for CTEPH Further clinical trials are needed

33. CTEPH MEDICAL THERAPY PHASE II STUDIES Author Drug Study Design Patients WHO Treatment Results McLaughlin (1999) Epoprostenol Observational 3 III-IV 8-16 months Hemodynamic and exercise tolerance improvement Higenbottam (1998) Epoprostenol Iloprost (i.v.) Observational 39 II-IV 1-4 years Survival improvement (if SV O 2 < 60%) Olschewski (2002) Iloprost (inhaled) Controlled 33 III-IV 12 weeks No improvement Nagaya (2002) Beraprost (oral) Open 16 II-III 8-12 weeks Exercise tolerance improvement Vizza (2001) Beraprost (oral) Open 3 II-IV 12 months Exercise tolerance improvement

34. BENEFiT TRIAL – PHASE III –

36. BENEFiT TRIAL Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34

37. Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34 BENEFiT TRIAL

38. *Analysis excluded patients judged operable by the Operability Evaluation Committee (n=11) † Analysis excluded patients with missing baseline or post-baseline assessment(s) (n=9 for pulmonary vascular resistance [PVR] analysis; n=6 for 6-min walk distance [6MWD] analysis) mPAP = mean pulmonary artery pressure mRAP = mean right atrial pressure NT-proBNP = N-terminal pro-brain natriuretic peptide; PEA = pulmonary endarterectomy; TPR = total pulmonary resistance; WHO = World Health Organization. Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34 BENEFiT TRIAL

39. BENEFiT TRIAL Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34

40. Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34 BENEFiT TRIAL

41. Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34 BENEFiT TRIAL

42. RESULTS AFTER PEA p < 0.01 Pre-op 3m 1y 3y 5y 7y 10y

44. NEW PERSPECTIVES

45. RATIONALE RIOCIGUAT Soluble guanylate-cyclase stimulator CHEST STUDY Ch ronic Thrombo e mbolic Pulmonary Hypertension sGC- S timulator T rial riociguat

47. STUDY DESIGN CHEST STUDY Ch ronic Thrombo e mbolic Pulmonary Hypertension sGC- S timulator T rial 2 weeks 2 weeks 2 weeks 2 weeks 2.0 mg tid 1.5 mg tid 1 mg tid ∑ : 16 weeks V2 V1 V3 V4 V5 V7 V7 V7 V7 V7 0.5 mg tid 1.5 mg tid 1.0 mg tid 2.0 mg tid 2.5 mg tid 2.5 mg tid