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Seraphin : results from a landmark study

Seraphin : results from a landmark study. SERAPHIN: Creating a robust morbidity and/or mortality primary endpoint. Inclusion of a 3 rd criterion for PAH worsening (need for new treatment(s) for PAH). Complexity & robustness. Measurable definition of PAH worsening (6-MWD & FC).

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Seraphin : results from a landmark study

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  1. Seraphin: resultsfrom a landmarkstudy

  2. SERAPHIN: Creating a robust morbidity and/or mortality primary endpoint Inclusion of a 3rd criterion for PAH worsening (need for new treatment(s) for PAH) Complexity & robustness Measurable definition of PAH worsening (6-MWD & FC) Committee for adjudication of events One criteria to define PAH worsening Morbidity/mortality as primary endpoint – event driven Secondary endpoint – time driven Dana Point1 SERAPHIN2 TTCW • McLaughlin VV, et al. J Am Coll Cardiol 2009; 54:S97-107. • SERAPHIN Study Protocol AC-055-302.

  3. SERAPHIN: A landmark study in PAH 1. Channick RN, et al. Lancet 2001. 2. Badesch D, et al. Curr Ther Res 2002. 3. Rubin LJ, et al. N Engl J Med 2002. 4. Galiè N, et al. Lancet 2008. 5. Galiè N, et al. Circulation 2008. 6. Oudiz R, et al. Chest 2006. 7. Oudiz RJ, et al. J Am Coll Cardiol 2009. 8. Galiè N, et al. N Engl J Med 2005. *Mean study drug exposure 9. Galiè N, et al. Circulation 2009. 10. www.clinicaltrials.gov, NCT00660179.

  4. Exposure to macitentan (SERAPHIN) compared with all other PAH drugs combined All PAH studies 47,000*1 Macitentan in SERAPHIN ≈ 71,000†2 0 20,000 40,000 60,000 80,000 Treatment exposure (patient weeks) *Estimated from Galiè N, et al. (2009) Meta-analysis of RCTs in PAH3 †Treatment exposure up to April 2012 1. Galiè N, et al. Eur Heart J 2009; 30:394-403. 2. Actelion data on file.

  5. 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

  6. SERAPHINA long-term, event-driven RCT in PAH 742 patients were randomised 1:1:1 between May 2008 and December 2009 Mean exposure 103.9 weeks Macitentan 10 mg o.d. 99.5 weeks Macitentan 3 mg o.d. 85.3 weeks Placebo Time (months) 5 10 15 0 Screening 28 days Treatment period Randomisation EOS (285 confirmed morbidity/mortality events) EOT(discontinuation of study drug) EOS: end of study EOT: end of treatment Pulido T et al. NEJM 2013; 369:809-18

  7. SERAPHIN morbidity and/or mortality primary endpoint 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 All-cause death OR Atrialseptostomy All events adjudicated by a blinded clinical events committee OR Time to 1st morbidity and/or mortality event Lung transplantation OR Initiation of i.v. or s.c.prostanoids OR Other worsening of PAH Other worsening of PAH OR Pulido T et al. NEJM 2013; 369:809-18

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

  9. Demographics and baseline characteristics 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

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

  11. Primary endpoint: Morbidity and/or mortality up to end of treatment Risk reduction of primaryendpoint event vs placebo 100 80 Macitentan 10 mg: 45% • Macitentan 3 mg: 30% 60 Patients without the event (%) 40 Macitentan 10 mg 20 Macitentan 3 mg Placebo 0 0 6 12 18 24 30 36 Patients at risk Time from treatment start (months) 242 208 187 1711559141 250 213 188 166 147 80 32 250 188 160 135 122 64 23 Pulido T et al. NEJM 2013; 369:809-18

  12. Morbidity and/or mortality in patients on background PAH therapy Macitentan 10 mg: 38% 100 80 • Risk reduction of primaryendpoint event vs placebo 60 • Macitentan 3 mg: 17% Patients without the event (%) 40 Macitentan 10 mg 20 Macitentan 3 mg Placebo 0 0 6 12 18 24 30 36 Patients at risk Time from treatment start (months) • 154 134 119 107 97 53 24 • 139 125 107 91 51 19 • 122 106 90 80 40 10 Pulido T et al. NEJM 2013; 369:809-18

  13. Morbidity and/or mortality in patients not on background PAH therapy Macitentan 10 mg: 55% 100 Risk reduction of primaryendpoint event vs placebo 80 Macitentan 3 mg: 47% 60 Patients without the event (%) 40 Macitentan 10 mg 20 Macitentan 3 mg Placebo 0 0 6 12 18 24 30 36 Time from treatment start (months) Patients at risk 88 746864583817 86 746359562913 96 665445422413 Pulido T et al. NEJM 2013; 369:809-18

  14. Secondary endpoint: Death due to PAH and/or hospitalisation for PAH Macitentan 3 mg: 33% 100 Risk reduction of death due to PAH or hospitalisation for PAH event vs placebo 80 Macitentan 10 mg: 50% 60 Patients without the event (%) 40 Macitentan 10 mg 20 Macitentan 3 mg Placebo 0 0 6 12 18 24 30 36 Patients at risk Time from treatment start (months) 242 2031831661528639 250 208 181 159 144 77 31 250 188 165 132 119 62 22 Pulido T et al. NEJM 2013; 369:809-18

  15. Secondary endpoint: Change from baseline to month 6 in WHO FC p = 0.006 p = 0.04 • 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

  16. Treatment-emergent adverse events Pulido T et al. NEJM 2013; 369:809-18

  17. Adverse events and laboratory abnormalities previously associated with ERAs Up to 28 days after study drug discontinuation Pulido T et al. NEJM 2013; 369:809-18

  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

  19. 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

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