The use of ERA after SERAPHIN, COMPASS-2 and AMBITION Marius M Hoeper

Grade I recommendation and high level of evidence only for initial mono-therapy Initial monotherapy is still standard of care in current guidelines Galie N et al. J Am Coll Cardiol 2013;62:D60-72

The future of combination therapy Is monotherapy still adequate? Sequential or up-front? Are all drugs the same?

Is monotherapy still adequate?

Macitentan reduced morbidity/mortality events in treatment-naive patients 20 40 80 100 60 12 18 24 30 36 6 Patients without the event (%) Risk reduction of primary endpoint event vs placebo Macitentan 10 mg: 55% Macitentan 3 mg: 47% Treatment difference 3 mg 10 mg Hazard ratio (HR) 0.53 0.45 Log-rank p-value 0.007 <0.001 Macitentan 10 mg Macitentan 3 mg Placebo Time from treatment start (months) Patients at risk 88 74 68 64 58 38 17 Macitentan 10 mg 86 74 63 59 56 29 13 Macitentan 3 mg 96 66 54 45 42 24 13 Placebo Pulido T, et al. N Engl J Med 2013; 369: 809-18.

SERAPHIN: Adding macitentan to pre-treated, stable FC II/III patients improved outcome Patients without the event (%) 12 18 24 30 36 20 40 80 100 60 6 Pulido T et al. N Engl J Med 2013;369:809-18 Risk reduction of primary endpoint event vs placebo Macitentan 10 mg: 38% Treatment difference 10 mg Hazard ratio (HR) 0.62 Log-rank p-value 0.009 Macitentan 10 mg Placebo Time from treatment start (months) Patients at risk 154 134 119 107 97 53 24 Macitentan 10 mg 154 122 106 90 80 40 10 Placebo Pulido T, et al. N Engl J Med 2013; 369: 809-18.

SERAPHIN – Patient characteristics All patients n = 742 Placebo n = 250 Macitentan 3 mg n = 250 Macitentan 10 mg n = 242 Female sex, % 77 74 75 80 Age, years, mean ± SD 45.6 ± 16.1 46.7 ± 17.0 44.5 ± 16.3 45.5 ± 15.0 6-MWD, m, mean ± SD 360 ± 100 352 ± 111 364 ± 96 363 ± 93 PVR, dyn.sec/cm5 1026 ± 696.7 996 ± 784.3 1044 ± 624.2 1040 ± 672.5 WHO FC, % I/II III/IV 53 47 52 48 56 44 50 Background PAH therapy, % PDE-5 inhibitors Oral/inhaled prostanoids 64 61 5 62 60 3 66 7 6 Pulido T et al. N Engl J Med 2013;369:809-18

SERAPHIN – primary endpoint Death 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 Need for new PAH treatment(s): Oral or inhaled prostanoids Oral PDE-5 inhibitors ERA after study discontinuation Intravenous diuretics AND Other worsening of PAH All events adjudicated by a blinded clinical events committee OR Atrial septostomy Time to 1st morbidity or mortality event OR Lung transplantation OR Initiation of i.v. or s.c. prostanoids OR Other worsening of PAH OR Pulido T et al. N Engl J Med 2013;369:809-18

Conclusions from SERAPHIN Patients with PAH presenting in FC II/III benefit from macitentan, regardless of them being treatment-naïve or pre- treated with a PDE5i Monotherapy with PDE5i may no longer be appropriate for patients with PAH

Up-front or sequential?

AMBITION – Objective “The primary objective of this study is to compare the difference between two treatment strategies; first-line combination therapy (with ambrisentan 10mg od and tadalafil 40mg od) vs. monotherapy (with ambrisentan 10 mg od or tadalafil 40 mg od) in subjects with PAH. This will be assessed by time to first clinical failure (TtCF) event.”

AMBITION – Study design Combination arm: AMB + TAD PAH Patients N = 610 (n=500 PAS) Randomized 2:1:1 to Combination arm or Monotherapy arm Monotherapy arm: AMB + PBO Group OR Monotherapy arm: TAD + PBO Group 105 events in PAS: primary endpoint AMB: ambrisentan TAD: tadalafil PBO: placebo

AMBITION – Dose titration Clinic Visits Every 12 Weeks Safety Visits Every 4 Weeks 10 mg ABS 40 mg TAD 5 mg ABS 40 mg TAD (n=302) 5 mg ABS 20 mg TAD 610 PAH Subjects Randomized 2:1:1 Combination or Monotherapy Sham (PBO) Up-titration 10 mg ABS PBO TAD Screening (n=152) 5 mg ABS PBO TAD 40 mg TAD PBO ABS Sham (PBO) Up-titration (n=151) 20 mg TAD PBO ABS Week - 4 EOS (~4 weeks after 1st dB lock) Visit: Week 0 (Randomization) Week 4 Week 8 Week 16 Week 24 FAV (~28 days after 105 Clinical Failure Events Reached) Peak/trough Evaluation (6MWD) Evaluation of Secondary Efficacy Endpoints 105 Clinical Failure Events: Primary Endpoint Ambrisentan (ABS) Tadalafil (TAD) Placebo (PBO) FAV: Final Assessment Visit EOS: End of Study

These events trigger combination therapy according to AMBITION – Primary endpoint („time to clinical failure“) Adapted to reflect current clinical practice Time to clinical failure is defined as the time from randomization to the first occurrence of: Death (all-cause) Hospitalization for worsening PAH (adjudicated) Non-elective hospitalization for worsening PAH Lung or heart/lung transplant Atrial septostomy Initiation of parenteral prostanoid therapy Disease progression (adjudicated) >15% decrease from baseline in 6MWD combined with WHO class III or IV symptoms (at two consecutive post-baseline clinic visits separated by ≥14 days) Unsatisfactory long-term clinical response (adjudicated, all criteria required) Receiving randomized treatment for at least 6 months A decrease from baseline in 6MWD at two consecutive post-baseline clinic visits separated by ≥14 days Sustained WHO class III or IV symptoms for ≥6 months These events trigger combination therapy according to the goal-oriented approach recommended in current guidelines The monotherapy arms in AMBITION represent standard of care, i.e. sequential combination therapy if treatment goals are not met

GSK Press release 08.09.2014

Combination vs pooled monotherapy AMBITION did show improved outcome (TTCF) with upfront combination therapy Combination vs pooled monotherapy Galie N et al. ERS 2014

AMBITION – adverse events Combination therapy Ambrisentan monotherapy Tadalafil monotherapy Peripheral edema 46% 33% 28% Headache 42% 35% Nasal congestion 21% 15% 12% Anemia 6% GSK, press release 29.08.2014

The implications of SERAPHIN and AMBITION Combination therapy with an ERA and a PDE-5i is probably going to become standard of care for patients with newly diagnosed PAH presenting in functional class II or III Evidence to support this concept has been generated by both the SERAPHIN and AMBITION study Both trials suggest that the concept of goal-oriented therapy may no longer valid for the initial PAH therapy (but continues to be relevant for further treatment decisions)

Are all drugs the same? ERA

Macitentan reduced the number of morbidity/mortality events HR 0.55, p<0.001 HR 0.7, p=0.01 6MWD 10 mg vs placebo +22 m (p=0.008) Months Pulido T et al. N Engl J Med 2013;369:809-18

Ambrisentan + Tadalafil provides better long-term results than Tadalafil monotherapy GSK Press release 08.09.2014

COMPASS-II: Adding bosentan to sildenafil did not improve outcome www.clinicaltrials.gov

Sildenafil plasma concentrations are reduced by bosentan therapy Sildenafil 100 mg alone X 4 weeks bosentan 62.5 mg bid 4 weeks bosentan 125 mg bid Sildenafil AUC dropped by 69% when bosentan was co-administered at 125 mg bid for 4 weeks Paul GA et al. Br J Pharmacol 2005;60:107-12

Which ERAs will be used in the future? Long-term efficacy has been demonstrated for ambrisentan (in combination with tadalafil) and macitentan, but not for bosentan Where available and reimbursed, ambrisentan or macitentan are expected to become the preferred ERAs for treatment-naïve patients Based on previous studies (BREATHE-I, EARLY), bosentan is still a valuable option when other ERAs are not available/not reimbursed, as well as in bosentan pre-treated patients with a satisfying clinical response

Functional class IV

NYHA FC III (n=8) or IV (n=11) Upfront triple combo therapy: i.v. epoprostenol + bosentan + sildenafil 19 incident (i.e. newly diagnosed) patients with Idiopathic (n=9) or heritable (n=10) PAH Mean age 39 ± 14 years (18 – 63) NYHA FC III (n=8) or IV (n=11) Severe haemodynamics: CI < 2.0 L/min/m2 or PVR > 1000 d.s.cm-5 Sitbon O, et al. Eur Respir J. 2014;43:1691-7

Upfront triple combination therapy: Effect on haemodynamics Prospective, observational analysis of idiopathic or heritable PAH patients (n = 19) treated with upfront combination therapy (epoprostenol, bosentan and sildenafil) Baseline 4-month Last visit (32 ± 19 months) RAP (mmHg) 11.9 ± 5.2 4.9 ± 4.9* 5.2 ± 3.5* mPAP (mmHg) 65.8 ± 13.7 45.7 ± 14.0* 44.4 ± 13.4* PCWP (mmHg) 8.4 ± 3.5 6.7 ± 3.2 7.9 ± 2.8 CI (l/min/m2) 1.66 ± 0.35 3.49 ± 0.69* 3.64 ± 0.65* PVR (d.s.cm-5) 1718 ± 627 564 ± 260* 492 ± 209* Heart rate (bpm) 92.3 ± 10.7 83.9 ± 9.8* 79.9 ± 13.4* Mean BP (mmHg) 92.1 ± 12.5 80.1 ± 11.7* 84.9 ± 19.4 SvO2 (%) 51.0 ± 8.5 69.7 ± 5.2* 72.2 ± 4.0* *p < 0.01 versus baseline n = 18 Sitbon O, et al. Eur Respir J. 2014; Epub ahead of print.

Sitbon O, et al. Eur Respir J. 2014;43:1691-7

Initial therapy for WHO-FC IV Despite lack of robust evidence, up-front triple combination therapy (ERA + PDEi or sGC + IV PCA) may be the best approach to FC IV patients (and FC III patients with severe haemodynamic impairment)

Conclusions Up-front or early combination therapy is expected to become standard of care for patients with PAH ERA + PDE5i for patients in FC II/III ERA + PDE5i + IV/SC PCA in FC IV (or severe FC III) The future role of new drugs such as Riociguat or Selexipag in PAH still needs to be defined

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