1. Bosentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and post- pulmonary endarterectomy pulmonary hypertension A pre-defined subgroup analysis of the randomised, placebo controlled trial: BENEFiT Lang I, Ghofrani A, Hoeper MM, Mayer E, Pepke-Zaba J, Rubin LJ, Jaïs X, Jansa P, D’Armini AM, Simonneau G

2. BENEFIT investigators  Australia: A Keogh, K McNeil, T Williams, E Gabbay  Austria: I Lang  Belgium: M Delcroix, R Naeije  Canada: J Granton, S Provencher, S Mehta, F Rubens, R Levy  Czech Republic: P Jansa  France: X Jaïs, V Cottin  Germany: M Hoeper, D Prüfer, A Ghofrani  Italy: N Galiè, AM D'Armini, M Confanolieri, C Albera  Netherlands: A Boonstra, RJ Snijder, P Bresser  Poland: A Torbicki  Spain: J Barbera  UK: J Pepke-Zaba, A Peacock  USA: H Kim, V Tapson, R Frantz

3. ‘Venice’ clinical classification of pulmonary hypertension (PH) 5.Miscellaneous  Sarcoidosis 1.PAH  Idiopathic PAH (IPAH)  Familial PAH  Associated PAH (APAH)  Connective tissue disease  Congenital systemic-to- pulmonary shunts  Portal hypertension  HIV infection  Drugs and toxins  Other  Associated with significant venous or capillary involvement  Persistent pulmonary hypertension of the newborn 2.PH associated with left heart disease 3.PH associated with respiratory disease  COPD  Interstitial lung diseases 4.PH due to chronic thrombotic and/or embolic disease  CTEPH Adapted from Simonneau G, et al. J Am Coll Cardiol 2004; 43:5S-12S.

4. Chronic thromboembolic pulmonary hypertension (CTEPH) Organised thrombotic material in pulmonary arteries

5. Operable Inoperable Pulmonary endarterectomy (PEA) is the treatment of choice for CTEPH  Surgically accessible thrombi  Acceptable operative risk  Small vessel disease  Unacceptable operative risk  Mismatch between haemodynamics and extent of occlusions  Recurrent PH

6. Rationale for the use of bosentan, a dual endothelin receptor antagonist  Up-regulation of endothelin receptors distal to the ligation in pulmonary arteries in animal models of CTEPH 1  Increased expression of ET B receptors on vascular smooth muscle cells 2  Increased systemic production of endothelin 2  Positive findings from open-label studies 3,4 1 Kim et al. Exp Lung Res 2000; 2 Bauer et al. Circulation 2002; 3 Hoeper et al. Chest 2005; 4 Hughes et al. Eur Respir J 2006

7. BENEFiT: study objectives  To demonstrate the efficacy of bosentan in patients with inoperable CTEPH or persistent / recurrent PH post-PEA  To evaluate the safety and tolerability of bosentan in this patient population

8. BENEFiT: study design Prospective, double-blind, randomised, placebo- controlled, multicentre study Baseline randomisation Screening Placebo Bosentan 62.5 mg bid 16 weeks 3 weeks Bosentan 125 mg bid 4 weeks12 weeks Placebo

9. BENEFiT: endpoints  Independent co-primary endpoints : PVR at rest at week 16 expressed as a percent of the baseline value (type-1 error = 0.01) and/or Change from baseline to week 16 in 6MWD (type-1 error = 0.04)  Other endpoints included change from baseline to week 16 in: Other haemodynamic parameters Borg dyspnoea index Plasma levels of the biomarker NT-pro-BNP

10. BENEFiT: summary of key results  Clinically relevant improvement in cardiac haemodynamics: PVR decreased (p < 0.0001) Cardiac index increased NT-pro-BNP decreased  No effect on exercise capacity (p = 0.5449)  Improvement in Borg dyspnoea index  Safety and tolerability: Consistent with previous controlled trials with bosentan in PAH

11. Overall population: bosentan significantly reduced PVR 60% 70% 80% 90% 100% 110% Treatment effect:  22.0% (95% CL:  29.6,  13.5) p<0.0001; Wilcoxon test Placebo n = 75 Bosentan n = 75 % of baseline PVR at week 16 (geometric means)

12. BENEFiT subgroup analysis  The purpose of this analysis was to compare the treatment effects between the subgroups of patients who had inoperable CTEPH (n=113) vs. those who had previously undergone PEA (n=44)

13. Bosentan reduced PVR 60% 70% 80% 90% 100% 110% % of baseline PVR at week 16 (geometric means) Persistent/Recurrent PH Inoperable CTEPH n = 22n = 20n = 53n = 55 Treatment effect:  32.5% (95% CL:  44.4,  18.1) Treatment effect:  17.5% (95% CL:  27.0,  6.7) Placebo Bosentan

14. Change in 6MWD Treatment effect:  11.5 m (95% CL:  39.6, 16.6) Treatment effect: +8.8 m (95% CL:  22.5, 40.0) 15 10 5 0 55  10 Persistent/Recurrent PH Inoperable CTEPH Change in 6MWD (m) at week 16 n = 22 n = 21n = 57 n = 55 Placebo Bosentan

15. Borg dyspnoea index improved Persistent/Recurrent PH Inoperable CTEPH Placebo Bosentan n = 22n = 21n = 57n = 55 Treatment effect: +0.1 (95% CL:  0.9, 1.2) Treatment effect:  0.8 (95% CL:  1.6,  0.1)  0.8  0.6  0.4  0.2 0 0.2 0.4 0.6 Change at week 16

16. Similar effect of bosentan observed between treatment groups for other endpoints Endpoint Persistent/Recurrent PH Inoperable CTEPH Cardiac index, L/min/m 2 0.25 (–0.08, 0.57) 0.31 (0.12, 0.50) mPAP, mmHg –6.4 (–11.2, –1.7) –1.0 (–3.9, 1.9) NT-pro-BNP, ng/L –526 (–1054, 2) –654 (–1170, –138) Mean treatment effect (95% CL)

17. Conclusions  Similar treatment effect observed in both patients with inoperable CTEPH and those with persistent/recurrent PH after PEA  In both groups, bosentan treatment resulted in:  Improved haemodynamics  Decreased PVR  Positive treatment effect observed for cardiac index,  mPAP and NT-pro-BNP