Copyright © 2011 Actelion Pharmaceuticals Ltd SERAPHIN: RESULTS FROM A LANDMARK STUDY

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


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


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


Demographics and baseline characteristics

All patientsn = 742

Placebon = 250

Macitentan 3 mg n = 250


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


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%



Morbidity and/or mortality in patients on background PAH therapy


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



Log-rank p-value 0.2672 0.0094




Morbidity and/or mortality in patients not on background PAH therapy


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



Log-rank p-value 0.0067 0.0007




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




Log-rank p-value 0.0146 < 0.0001

Risk reduction of death due to PAH or hospitalisation for PAH event vs placebo



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


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)


Adverse events and laboratory abnormalities previously associated with ERAs

Placebon = 249


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


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

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Copyright © 2011 Actelion Pharmaceuticals Ltd SERAPHIN: RESULTS FROM A LANDMARK STUDY