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
Galie N et al. J Am Coll Cardiol 2013;62:D60-72
The future of combination therapy
1. Is monotherapy still adequate?
2. Sequential or up-front?
3. Are all drugs the same?
Is monotherapy still adequate?
Macitentan reduced morbidity/mortality
events in treatment-naive patients
Patients without the event (%)
100
Risk reduction of primary
endpoint event vs placebo
80
Macitentan 10 mg:
Macitentan 3 mg:
55%
47%
Treatment difference
3 mg
10 mg
60
40
20
Macitentan 10 mg
Hazard ratio (HR)
0.53
0.45
Macitentan 3 mg
Log-rank p-value
0.007
<0.001
Placebo
0
0
Patients at risk
88
86
96
6
12
18
24
30
36
Time from treatment start (months)
74
74
66
68
63
54
64
59
45
58
56
42
38
29
24
17
13
13
Macitentan 10 mg
Macitentan 3 mg
Pulido T,Placebo
et al. N Engl J Med 2013; 369: 809-18.
SERAPHIN: Adding macitentan to pre-treated,
stable FC II/III patients improved outcome
Pulido T et al. N Engl J Med 2013;369:809-18
Patients without the event (%)
100
80
Risk reduction of primary
endpoint event vs placebo
60
Macitentan 10 mg:
38%
Treatment difference
10 mg
40
20
Macitentan 10 mg
Hazard ratio (HR)
0.62
Log-rank p-value
0.009
Placebo
0
0
6
12
18
24
30
Patients at risk Time from treatment start (months)
154
134
119
107
97
53
154
122
106
90
80
40
36
24 Macitentan 10 mg
10 Pulido
Placebo
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
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
1044 ± 624.2
1040 ± 672.5
Female sex, %
PVR, dyn.sec/cm5
1026 ± 696.7 996 ± 784.3
WHO FC, %
I/II
53
52
56
50
III/IV
47
48
44
50
64
62
66
64
61
60
62
62
5
3
7
6
Background PAH therapy, %
PDE-5 inhibitors
Oral/inhaled prostanoids
Pulido T et al. N Engl J Med 2013;369:809-18
SERAPHIN – primary endpoint
OR
AND
OR
OR
AND
All events
adjudicated
by a blinded
clinical
events
committee
OR
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 pretreated 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
AMB: ambrisentan
TAD: tadalafil
PBO: placebo
105 events in PAS:
primary endpoint
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)
These
events trigger combination therapy according to
 Hospitalization for worsening PAH (adjudicated)
 Non-elective
hospitalizationapproach
for worsening PAH
the
goal-oriented
recommended in
 Lung or heart/lung transplant
current guidelines
 Atrial septostomy
 Initiation of parenteral prostanoid therapy
The monotherapy arms in AMBITION represent
 >15% decrease from baseline in 6MWD combined with WHO class III or IV
standard
of (at
care,
i.e. sequential
combination
symptoms
two consecutive
post-baseline clinic
visits separated bytherapy
≥14 days)
 Unsatisfactory long-term
clinical response
(adjudicated,
all criteria
if treatment
goals
are not
metrequired)
 Disease progression (adjudicated)
 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
GSK Press release 08.09.2014
AMBITION – adverse events
Combination
therapy
Ambrisentan
monotherapy
Tadalafil
monotherapy
Peripheral
edema
46%
33%
28%
Headache
42%
33%
35%
Nasal
congestion
21%
15%
12%
Anemia
15%
6%
12%
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
 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)
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*
RAP (mmHg)
*p < 0.01 versus baseline
n = 18
Sitbon O, et al. Eur Respir J. 2014; Epub ahead of print.
FC I/II
Patients (n)
20
18
16
14
12
10
8
6
4
2
0
FC III
FC IV
18
17
10
8
1
Baseline 4 months* Last visit*
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
Thank you!