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

3. 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

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

5. Is monotherapy still adequate?

7. Macitentan reduced morbidity/mortality events in treatment-naive patients20 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
Macitentan 10 mg
Macitentan 3 mg
Placebo
Pulido T, et al. N Engl J Med 2013; 369:

8. 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
Macitentan 10 mg
Placebo
Pulido T, et al. N Engl J Med 2013; 369:

9. 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

10. 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

11. 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

12. Up-front or sequential?

13. 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.”

14. 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

15. 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

16. 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

17. GSK Press release

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

19. 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

20. 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)

21. Are all drugs the same?
ERA

22. 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

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

24. COMPASS-II: Adding bosentan to sildenafil did not improve outcome

25. 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

26. 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

27. Functional class IV

28. 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

29. 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.

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

31. 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)

32. 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

33. Thank you!