Marius M Hoeper

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

Galie N et al. J Am Coll Cardiol 2013;62:D60-72

Grade I recommendation and high level of

evidence only for initial mono-therapy

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

Macitentan 10 mg: 55%

00

20

40

80

100

60

12 18 24 30 366

Pat

ien

ts w

ith

ou

t th

e ev

ent

(%)

Macitentan 10 mg

Macitentan 3 mg

Placebo

Treatment difference 3 mg 10 mg

Hazard ratio (HR) 0.53 0.45

Log-rank p-value 0.007 <0.001

Risk reduction of primaryendpoint event vs placebo

Macitentan 3 mg: 47%

Patients at risk

88 74 68 64 58 38 17 Macitentan 10 mg86 74 63 59 56 29 13 Macitentan 3 mg96 66 54 45 42 24 13 Placebo

Time from treatment start (months)

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

Pulido T, et al. N Engl J Med 2013; 369: 809-18.

Macitentan 10 mg: 38%

Pat

ien

ts w

ith

ou

t th

e ev

ent

(%)

0 12 18 24 30 360

20

40

80

100

60

6

Macitentan 10 mg

Placebo

Treatment difference 10 mg

Hazard ratio (HR) 0.62

Log-rank p-value 0.009

Risk reduction of primaryendpoint event vs placebo

Patients at risk

154 134 119 107 97 53 24 Macitentan 10 mg154 122 106 90 80 40 10 Placebo

Time from treatment start (months)

Pulido T et al. N Engl J Med 2013;369:809-18

SERAPHIN – Patient characteristics

All patientsn = 742

Placebon = 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

50

Background PAH therapy, %

PDE-5 inhibitors

Oral/inhaled prostanoids

64

61

5

62

60

3

66

62

7

64

62

6

Pulido T et al. N Engl J Med 2013;369:809-18

SERAPHIN – primary endpoint

Pulido T et al. N Engl J Med 2013;369:809-18

Time to 1st morbidity

or mortality

event

Death

Atrial septostomy

Lung transplantation

Initiation of i.v. or s.c. prostanoids

OR

OR

OR

OROther worsening

of PAH

All events adjudicated by a blinded

clinical events

committee

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

AND

Other worsening of PAH

OR

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 thedifference 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

Monotherapy arm: AMB + PBO Group

Randomized 2:1:1 to Combination arm or Monotherapy arm

Monotherapy arm: TAD + PBO Group

105 events in PAS:

primary endpoint

PAH Patients

N = 610

(n=500 PAS)

OR

AMB: ambrisentan

TAD: tadalafil

PBO: placebo

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

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

Pulido T et al. N Engl J Med 2013;369:809-18

Months

HR 0.7, p=0.01HR 0.55, p<0.001

6MWD 10 mg vs placebo +22 m (p=0.008)

GSK Press release 08.09.2014

Ambrisentan + Tadalafil provides better long-term results than Tadalafil monotherapy

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

www.clinicaltrials.gov

Sildenafil plasma concentrations are reduced by bosentan therapy

Paul GA et al. Br J Pharmacol 2005;60:107-12

X

Sildenafil 100 mg alone

4 weeks bosentan 62.5 mg bid

4 weeks bosentan 125 mg bid

Sildenafil AUC dropped by 69% when bosentanwas co-administered at 125 mg bid for 4 weeks

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

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

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

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-monthLast 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

Baseline 4 months* Last visit*02468

101214161820

8

1

10

17 18

FC I/II FC III FC IV

Pa

tie

nts

(n

)

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)

Initial therapy for WHO-FC IV

Conclusions

Up-front or early combination therapy is expected to become standard of care for patients with PAHERA + PDE5i for patients in FC II/IIIERA + 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!