Copyright © 2011 Actelion Pharmaceuticals Ltd SERAPHIN: RESULTS FROM A LANDMARK STUDY

SERAPHIN: Creating a robust morbidity and/or mortality primary endpoint Committee for adjudication of events Measurable definition of PAH worsening (6-MWD & FC) Inclusion of a 3 rd criterion for PAH worsening (need for new treatment(s) for PAH) Complexity & robustness Dana Point 1 SERAPHIN 2 1.McLaughlin VV, et al. J Am Coll Cardiol 2009; 54:S SERAPHIN Study Protocol AC TTCW Secondary endpoint – time driven One criteria to define PAH worsening Morbidity/mortality as primary endpoint – event driven Morbidity/mortality as primary endpoint – event driven

SERAPHIN: A landmark study in PAH DrugStudyDurationPrimary endpointNo. of patients Bosentan Study-351 1,2 12 wks6-MWD32 BREATHE wks6-MWD213 EARLY 4 26 wksPVR, 6-MWD185 Ambrisentan ARIES-1 5,6 12 wks6-MWD202 ARIES-2 5,7 12 wks6-MWD192 SildenafilSUPER wks6-MWD277 Tadalafil PHIRST 9 16 wks6-MWD405 MacitentanSERAPHIN wks* Time to first morbidity/mortality event 742 *Mean study drug exposure 1. Channick RN, et al. Lancet Badesch D, et al. Curr Ther Res Rubin LJ, et al. N Engl J Med Galiè N, et al. Lancet Galiè N, et al. Circulation Oudiz R, et al. Chest Oudiz RJ, et al. J Am Coll Cardiol Galiè N, et al. N Engl J Med Galiè N, et al. Circulation NCT

1. Galiè N, et al. Eur Heart J 2009; 30: Actelion data on file. *Estimated from Galiè N, et al. (2009) Meta-analysis of RCTs in PAH 3 † Treatment exposure up to April 2012 Exposure to macitentan (SERAPHIN) compared with all other PAH drugs combined Treatment exposure (patient weeks) Macitentan in SERAPHIN ≈ 71,000 †2 All PAH studies 47,000* 1 20,00040,00060, ,000

The SERAPHIN study: Objectives and endpoints Objective: To study long-term efficacy and safety of macitentan in PAH using an event-driven trial design Primary endpoint –Time to the first morbidity and/or mortality event up to end of double-blind treatment Secondary endpoints –6-minute walk distance (6-MWD) at month 6 –WHO functional class (FC) at month 6 –Time to death due to PAH or hospitalisation for PAH –All-cause mortality –Safety and tolerability Pulido T et al. NEJM 2013; 369:809-18

Macitentan 10 mg o.d. Macitentan 3 mg o.d. Placebo Time (months) Treatment period Randomisation EOT (discontinuation of study drug) EOS (285 confirmed morbidity/mortality events) 742 patients were randomised 1:1:1 between May 2008 and December 2009 Screening 28 days weeks 99.5 weeks 85.3 weeks Mean exposure SERAPHIN A long-term, event-driven RCT in PAH EOS: end of study EOT: end of treatment

Robust nature of the primary endpoint = only clinically relevant events are captured Morbidity/mortality as primary endpoint is considered more clinically relevant as it reflects the true progression of PAH SERAPHIN morbidity and/or mortality primary endpoint OR Other worsening of PAH All events adjudicated by a blinded clinical events committee OR Time to 1st morbidity and/or mortality event All-cause death Atrial septostomy Lung transplantation Initiation of i.v. or s.c. prostanoids Other worsening of PAH Pulido T et al. NEJM 2013; 369:809-18

SERAPHIN primary endpoint: Other worsening of PAH AND A decrease in 6-MWD of at least 15%, confirmed by 2 tests on different days Worsening of PAH symptoms, which must include either: An increase in FC, or Appearance or worsening of symptoms of RHF Worsening of PAH symptoms, which must include either: An increase in FC, or Appearance or worsening of symptoms of RHF Need for new PAH treatment(s): Oral or inhaled prostanoids Oral PDE-5 inhibitors ERA after study discontinuation Intravenous diuretics Need for new PAH treatment(s): Oral or inhaled prostanoids Oral PDE-5 inhibitors ERA after study discontinuation Intravenous diuretics Other worsening of PAH All events adjudicated by a blinded clinical events committee Pulido T et al. NEJM 2013; 369:809-18

Demographics and baseline characteristics All patients n = 742 Placebo n = 250 Macitentan 3 mg n = 250 Macitentan 10 mg n = 242 Female sex, % Age, years, mean ± SD 45.6 ± ± ± ± 15.0 Time from diagnosis, years, mean ± SD 2.7 ± ± ± ± MWD, m, mean ± SD 360 ± ± ± ± 93 WHO FC, %* I/II III/IV Background PAH therapy, % PDE-5 inhibitors Oral/inhaled prostanoids All patients, n = 739; placebo, n = 249; macitentan 3 mg, n = 248; macitentan 10 mg, n = 242 Pulido T et al. NEJM 2013; 369:809-18

Patient demographics: PAH aetiology Actelion data on file. *Simple shunt at least 1 year post-surgical repair Total number of patients: 742

Risk reduction of primary endpoint event vs placebo Primary endpoint: Morbidity and/or mortality up to end of treatment Time from treatment start (months) Patients without the event (%) Macitentan 10 mg Macitentan 3 mg Placebo Patients at risk Treatment difference3 mg10 mg Hazard ratio (HR) Log-rank p-value0.0108< Macitentan 10 mg: 45% Macitentan 3 mg: 30% Pulido T et al. NEJM 2013; 369:809-18

Morbidity and/or mortality in patients on background PAH therapy Macitentan 10 mg: 38% Patients without the event (%) Time from treatment start (months) Macitentan 10 mg Macitentan 3 mg Placebo Patients at risk Treatment difference3 mg10 mg Hazard ratio (HR) Log-rank p-value Risk reduction of primary endpoint event vs placebo Macitentan 3 mg: 17% Pulido T et al. NEJM 2013; 369:809-18

Morbidity and/or mortality in patients not on background PAH therapy Macitentan 10 mg: 55% Time from treatment start (months) Patients without the event (%) Macitentan 10 mg Macitentan 3 mg Placebo Patients at risk Treatment difference3 mg10 mg Hazard ratio (HR) Log-rank p-value Risk reduction of primary endpoint event vs placebo Macitentan 3 mg: 47% Pulido T et al. NEJM 2013; 369:809-18

Secondary endpoint: Death due to PAH and/or hospitalisation for PAH Patients without the event (%) Time from treatment start (months) Patients at risk Macitentan 10 mg Macitentan 3 mg Placebo Macitentan 3 mg: 33% Treatment difference3 mg10 mg Hazard ratio (HR) Log-rank p-value0.0146< Risk reduction of death due to PAH or hospitalisation for PAH event vs placebo Macitentan 10 mg: 50% Pulido T et al. NEJM 2013; 369:809-18

Secondary endpoint: Change from baseline to month 6 in WHO FC p = 0.04 p = Patients on macitentan 3 mg had a 54% greater chance to improve FC status Patients on macitentan 10 mg had a 74% greater chance to improve FC status Pulido T et al. NEJM 2013; 369:809-18

Treatment-emergent adverse events Adverse event, n (%) Placebo n = 249 Macitentan 3mg n = 250 Macitentan 10mg n = 242 Patients with ≥ 1 AE240 (96.4)240 (96.0)229 (94.6) PAH87 (34.9)75 (30.0)53 (21.9) Peripheral oedema45 (18.1)40 (16.0)44 (18.2) Upper respiratory tract infection33 (13.3)50 (20.0)37 (15.3) Right ventricular failure56 (22.5)37 (14.8)32 (13.2) Headache22 (8.8)33 (13.2)33 (13.6) Nasopharyngitis26 (10.4)37 (14.8)34 (14.0) Dizziness27 (10.8)24 (9.6)26 (10.7) Cough30 (12)20 (8.0)21 (8.7) Bronchitis14 (5.6)20 (8.0)28 (11.6) Anaemia8 (3.2)22 (8.8)32 (13.2) Dyspnoea22 (8.8)26 (10.4)28 (7.4) Pulido T et al. NEJM 2013; 369:809-18

Adverse events and laboratory abnormalities previously associated with ERAs Placebo n = 249 Macitentan 3 mg n = 250 Macitentan 10 mg n = 242 Mean treatment duration, weeks, mean ± SD 85 ± ± ± 52 ALT or AST > 3 x ULN, % (n/N) 4.5 (11/244)3.6 (9/247)3.4 (8/236) ALT or AST > 3 x ULN and bilirubin > 2 x ULN, % (n/N) 1.7 (4/237)2.1 (5/241)1.7 (4/230) Haemoglobin ≤ 8 g/dl, % (n/N) 0.4 (1/237)1.7 (4/241)4.3 (10/230) Peripheral oedema, % (n/N)18.1 (45/249)16.0 (40/250)18.2 (44/242) Up to 28 days after study drug discontinuation Pulido T et al. NEJM 2013; 369:809-18

Summary I Macitentan 10 mg significantly reduced the risk of morbidity and/or mortality events up to 45% vs placebo Treatment effect with macitentan 10 mg was consistent in patients on or not on background PAH therapy Macitentan also significantly improved clinically important secondary endpoints including 6-MWD, WHO FC and PAH-related death or hospitalisation

Summary II Rates of transaminase elevations and oedema were similar in placebo and macitentan groups A greater decrease in haemoglobin levels was observed in the active treatment groups –This laboratory abnormality has been reported in other clinical trials investigating ERAs The most common adverse events, not associated with PAH and reported at a higher incidence than placebo, were headache, nasopharyngitis and anaemia