Copyright © 2011 Actelion Pharmaceuticals Ltd
SERAPHIN: RESULTSFROM A LANDMARKSTUDY
SERAPHIN: Creating a robust morbidity and/or mortality primary endpoint
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Dana Point1 SERAPHIN21. McLaughlin VV, et al. J Am Coll Cardiol 2009; 54:S97-107.
2. SERAPHIN Study Protocol AC-055-302.
TTCW
Secondary endpoint – time drivenSecondary endpoint – time driven
One criteria to define PAH worseningOne criteria to define PAH worsening
SERAPHIN: A landmark study in PAH
Drug Study Duration Primary endpoint No. of patients
Bosentan
Study-3511,2 12 wks 6-MWD 32
BREATHE-13 16 wks 6-MWD 213
EARLY4 26 wks PVR, 6-MWD 185
AmbrisentanARIES-15,6 12 wks 6-MWD 202
ARIES-25,7 12 wks 6-MWD 192
Sildenafil SUPER-18 12 wks 6-MWD 277
Tadalafil PHIRST9 16 wks 6-MWD 405
Macitentan SERAPHIN10 96 wks*Time to first morbidity/mortality event
742
*Mean study drug exposure
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.
9. Galiè N, et al. Circulation 2009. 10. www.clinicaltrials.gov, NCT00660179.
1. Galiè N, et al. Eur Heart J 2009; 30:394-403.2. Actelion data on file.
*Estimated from Galiè N, et al. (2009) Meta-analysis of RCTs in PAH3
†Treatment exposure up to April 2012
Exposure to macitentan (SERAPHIN) compared with all other PAH drugs combined
Treatment exposure (patient weeks)
Macitentan in SERAPHIN ≈ 71,000†2
All PAH studies 47,000*1All PAH studies 47,000*1
20,000 40,000 60,0000 80,000
The SERAPHIN study: Objectives and endpoints
Pulido T et al. NEJM 2013; 369:809-18
Pulido T et al. NEJM 2013; 369:809-18
Macitentan 10 mg o.d.
Macitentan 3 mg o.d.
Placebo
Time (months)
Treatment period
Randomisation EOT(discontinuation of
study drug)
0 5 10 15
EOS (285 confirmed
morbidity/mortality events)
742 patients were randomised 1:1:1 between May 2008 and December 2009
Screening28 days
103.9 weeks
99.5 weeks
85.3 weeks
Mean exposure
SERAPHINA long-term, event-driven RCT in PAH
EOS: end of studyEOT: end of treatment
• 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
SERAPHIN morbidity and/or mortality primary endpoint
OR
OR
OR
OROther worsening
of PAH
All events adjudicated by a
blinded clinical events
committee
OR
Time to 1st morbidity and/or mortality event
All-cause death
Atrial septostomy
Lung transplantation
Initiation of i.v. or s.c. prostanoids
Other worsening of PAH
Pulido T et al. NEJM 2013; 369:809-18
SERAPHIN primary endpoint: Other worsening of PAH
AND
AND
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
Other worsening
of PAH
All events adjudicated by a
blinded clinical events
committee
Pulido T et al. NEJM 2013; 369:809-18
Demographics and baseline 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
Time from diagnosis, years, mean ± SD 2.7 ± 4.0 2.6 ± 3.7 3.0 ± 4.5 2.6 ± 3.6
6-MWD, m, mean ± SD 360 ± 100 352 ± 111 364 ± 96 363 ± 93
WHO FC, %*
I/II
III/IV
53
4752
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
6All 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
Patient demographics: PAH aetiology
Actelion data on file.*Simple shunt at least 1 year post-surgical repair
Total number of patients: 742
Risk reduction of primaryendpoint event vs placebo
Primary endpoint: Morbidity and/or mortality up to end of treatment
Time from treatment start (months)
Pat
ien
ts w
ith
ou
t th
e ev
ent
(%)
00
20
40
80
100
60
12 18 24 30 366
Macitentan 10 mg
Macitentan 3 mg
Placebo
Patients at risk
242 208 187 171 155 91 41250 213 188 166 147 80 32250 188 160 135 122 64 23
Treatment difference 3 mg 10 mg
Hazard ratio (HR) 0.704 0.547
Log-rank p-value 0.0108 < 0.0001
Macitentan 10 mg: 45%
Macitentan 3 mg: 30%
Pulido T et al. NEJM 2013; 369:809-18
Morbidity and/or mortality in patients on background PAH therapy
Macitentan 10 mg: 38%
Pat
ien
ts w
ith
ou
t th
e ev
ent
(%)
Time from treatment start (months)0 12 18 24 30 36
0
20
40
80
100
60
6
Macitentan 10 mg
Macitentan 3 mg
Placebo
Patients at risk154 134 119 107 97 53 24164 139 125 107 91 51 19165 122 106 90 80 40 10
Treatment difference 3 mg 10 mg
Hazard ratio (HR) 0.83 0.62
Log-rank p-value 0.2672 0.0094
Risk reduction of primaryendpoint event vs placebo
Macitentan 3 mg: 17%
Pulido T et al. NEJM 2013; 369:809-18
Morbidity and/or mortality in patients not on background PAH therapy
Macitentan 10 mg: 55%
Time from treatment start (months)0
0
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
Patients at risk88 74 68 64 58 38 1786 74 63 59 56 29 1396 66 54 45 42 24 13
Treatment difference 3 mg 10 mg
Hazard ratio (HR) 0.53 0.45
Log-rank p-value 0.0067 0.0007
Risk reduction of primaryendpoint event vs placebo
Macitentan 3 mg: 47%
Pulido T et al. NEJM 2013; 369:809-18
Secondary endpoint: Death due to PAH and/or hospitalisation for PAH
Pat
ien
ts w
ith
ou
t th
e ev
ent
(%)
Time from treatment start (months)Patients at risk
242 203 183 166 152 86 39250 208 181 159 144 77 31250 188 165 132 119 62 22
00
20
40
80
100
60
12 18 24 30 366
Macitentan 10 mg
Macitentan 3 mg
Placebo
Macitentan 3 mg: 33%
Treatment difference 3 mg 10 mg
Hazard ratio (HR) 0.669 0.500
Log-rank p-value 0.0146 < 0.0001
Risk reduction of death due to PAH or hospitalisation for PAH event vs placebo
Macitentan 10 mg: 50%
Pulido T et al. NEJM 2013; 369:809-18
Secondary endpoint: Change from baseline to month 6 in WHO FC
p = 0.04
p = 0.006
• 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
Treatment-emergent adverse events
Adverse event, n (%)Placebon = 249
Macitentan 3mgn = 250
Macitentan 10mgn = 242
Patients with ≥ 1 AE 240 (96.4) 240 (96.0) 229 (94.6)
PAH 87 (34.9) 75 (30.0) 53 (21.9)
Peripheral oedema 45 (18.1) 40 (16.0) 44 (18.2)
Upper respiratory tract infection 33 (13.3) 50 (20.0) 37 (15.3)
Right ventricular failure 56 (22.5) 37 (14.8) 32 (13.2)
Headache 22 (8.8) 33 (13.2) 33 (13.6)
Nasopharyngitis 26 (10.4) 37 (14.8) 34 (14.0)
Dizziness 27 (10.8) 24 (9.6) 26 (10.7)
Cough 30 (12) 20 (8.0) 21 (8.7)
Bronchitis 14 (5.6) 20 (8.0) 28 (11.6)
Anaemia 8 (3.2) 22 (8.8) 32 (13.2)
Dyspnoea 22 (8.8) 26 (10.4) 28 (7.4)
Pulido T et al. NEJM 2013; 369:809-18
Adverse events and laboratory abnormalities previously associated with ERAs
Placebon = 249
Macitentan 3 mg n = 250
Macitentan 10 mgn = 242
Mean treatment duration, weeks, mean ± SD
85 ± 54 100 ± 51 104 ± 52
ALT or AST > 3 x ULN, % (n/N)
4.5 (11/244) 3.6 (9/247) 3.4 (8/236)
ALT or AST > 3 x ULN and bilirubin > 2 x ULN, % (n/N)
1.7 (4/237) 2.1 (5/241) 1.7 (4/230)
Haemoglobin ≤ 8 g/dl, % (n/N)
0.4 (1/237) 1.7 (4/241) 4.3 (10/230)
Peripheral oedema, % (n/N) 18.1 (45/249) 16.0 (40/250) 18.2 (44/242)
Up to 28 days after study drug discontinuation
Pulido T et al. NEJM 2013; 369:809-18
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
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