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OPSUMIT® (macitentan) was studied in SERAPHIN, the largest long-term, outcomes-based pivotal trial of an ERA in PAH1

Long-term outcomes data in both monotherapy AND combination therapy1,2

Trial design1,2:

The effect of OPSUMIT® on disease progression in patients with PAH (WHO Group I) was studied in SERAPHIN, a large (N=742), event-driven, multicenter, long-term (average treatment duration 2 years), randomized, double-blind, placebo-controlled phase 3 trial. At study baseline, 36% of patients were not using PAH-specific background therapy and 64% were using stable background therapy for at least 3 months with PDE5 inhibitors or inhaled/oral prostanoids.*

Trial demographics1,3:

  • Patients had predominantly WHO FC II (52%) and FC III (46%) symptoms
  • Etiologies included IPAH/HPAH (57%), PAH-CTD (31%), PAH-CHD with repaired shunts (8%), PAH associated with drugs and toxins (3%), and PAH-HIV (1%)
  • Mean patient age was 46 years, and 77% of patients were female
  • 25% of patients were recently diagnosed (<6 months) and 75% were previously diagnosed (≥6 months)

Trial demographics1

742

Patients were randomized

OPSUMIT® 10 mg: n=242
Macitentan 3 mg: n=250
Placebo: n=250

Macitentan 3 mg is not an approved dose.

Monotherapy and
combination therapy1,3

2-1-mono-combo-chart-mobile

*Patients were treated with OPSUMIT® monotherapy or in combination with phosphodiesterase type 5 inhibitors or inhaled prostanoids.1

REPAIR study

EXPLORE ANALYSIS

7-Year Data

EXPLORE ANALYSIS

SERAPHIN: Primary endpoint in overall study population†

OPSUMIT® (macitentan) significantly reduced the risk of disease progression by 45% vs placebo1

The primary endpoint in the SERAPHIN trial was time to the first occurrence of death, a significant morbidity event, defined as atrial septostomy, lung transplantation, initiation of IV or SC prostanoids, or clinical worsening of PAH (defined as all of the following: a sustained ≥15% decrease from baseline in 6MWD,‡ worsening of PAH symptoms,§ and need for additional PAH treatment) during double-blind treatment plus 7 days.1,2

Kaplan-Meier estimates of risk of first primary endpoint event in SERAPHIN1,2

Primary SERAPHIN endpoint: Kaplan-Meier estimates of risk of disease progression

Summary of primary endpoint events1

  OPSUMIT® 10 mg
(n=242), n (%)		 Placebo
(n=250), n (%)
Patients with a primary endpoint event‖ 76 (31.4) 116 (46.4)
Component as first event
Worsening PAH 59 (24.4) 93 (37.2)
Death 16 (6.6) 17 (6.8)
Initiation of IV/SC prostanoids 1 (0.4) 6 (2.4)

The beneficial effect of OPSUMIT® was primarily attributable to a reduction in clinical worsening events (defined as all of the following: a sustained ≥15% decrease from baseline in 6MWD,† worsening of PAH symptoms [a decline in WHO FC], and need for additional PAH treatment).


‖No patients experienced an event of lung transplantation or atrial septostomy in the placebo or OPSUMIT® 10 mg treatment groups.

OPSUMIT® can be started as monotherapy or in combination with PDE5 inhibitors or inhaled prostanoids.1*

*Patients were treated with OPSUMIT® monotherapy or in combination with phosphodiesterase type 5 inhibitors or inhaled prostanoids.1

Combination therapy exploratory subgroup analysis in SERAPHIN trial

The combination therapy data below represent an exploratory analysis. Results should be interpreted with caution.

Kaplan-Meier estimates of risk of primary endpoint event when OPSUMIT® was added to stable PAH-specific background therapy1,3

At baseline, 64% of enrolled patients were treated with a stable dose of PAH-specific background therapy (61% PDE5 inhibitors; 6% inhaled or oral prostanoids).1*

*Patients were treated with OPSUMIT® monotherapy or in combination with phosphodiesterase type 5 inhibitors or inhaled prostanoids.1

Kaplan-Meier estimates of risk of first primary endpoint event1,3,4

Combination therapy exploratory analysis: estimates of risk of first primary endpoint event graph

Not adjusted for multiplicity.

Summary of primary endpoint events in patients treated with PAH-specific background therapy4

  OPSUMIT® 10 mg
(n=154), n (%)		 Placebo
(n=154), n (%)
Patients with a primary endpoint event‖ 50 (32.5) 68 (44.2)
Component as first event
Worsening PAH 39 (25.3) 58 (37.7)
Death 10 (6.5) 6 (3.9)
Initiation of IV/SC prostanoids 1 (0.6) 4 (2.6)

‖No patients experienced an event of lung transplantation or atrial septostomy in the placebo or OPSUMIT® 10 mg treatment groups.

Common adverse reactions in the combination therapy exploratory subgroup5#

  OPSUMIT® 10 mg
n=154		 Placebo
n=153
Anemia 16.2% 4.6%
Nasopharyngitis 11.0% 10.5%
Bronchitis 11.0% 5.9%
Headache 13.6% 10.5%
Diarrhea 13.0% 9.8%

#More frequent than placebo by ≥3%.

Combination therapy exploratory subgroup safety2,5

  • The safety profile of OPSUMIT® as part of a combination therapy regimen was consistent with that of OPSUMIT® in the overall SERAPHIN population
  • The incidence of peripheral edema, a known ERA-related adverse event, was similar in OPSUMIT®- and placebo-treated patients receiving background therapy (19.5% and 23.5%, respectively)
  • Treatment discontinuations due to adverse events in patients receiving background therapy were similar in those receiving OPSUMIT® and those receiving placebo (9.1% and 11.8%, respectively)

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SERAPHIN PAH-related hospitalization results

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PAH-related hospitalization

OPSUMIT® (macitentan) reduced the risk of PAH-related hospitalization1,2

A key secondary endpoint in SERAPHIN was death due to PAH or PAH-related hospitalization.

There was a 50% reduction in the risk of PAH-related hospitalization vs placebo in the overall population.†

Kaplan-Meier estimates of risk of first key secondary endpoint event1,2

Key secondary SERAPHIN endpoint: risk of PAH-related hospitalization graph

Summary of death due to PAH and hospitalization due to PAH1,2

  OPSUMIT®
 10 mg
(n=242), 
n (%) 		Placebo
(n=250), n (%)
Death due to PAH or hospitalization for PAH 50 (20.7) 84 (33.6)
Component as first event
Death due to PAH 5 (2.1) 5 (2.0)
Hospitalization for PAH 45 (18.6) 79 (31.6)

Exploratory subgroup analysis: Combination therapy results

The combination therapy data below represent an exploratory analysis. Results should be interpreted with caution.

Kaplan-Meier estimates of risk of first key secondary endpoint event when OPSUMIT® was added to stable PAH-specific background therapy6

  • At baseline, 64% of enrolled patients were treated with a stable dose of PAH-specific background therapy (61% PDE5 inhibitors; 6% inhaled or oral prostanoids). Patients were treated with OPSUMIT® monotherapy or in combination with phosphodiesterase type 5 inhibitors or inhaled prostanoids.1

Kaplan-Meier estimates of risk of first key secondary endpoint event6

Combination therapy exploratory analysis: combination therapy results graph

Summary of death due to PAH and hospitalization due to PAH6

  OPSUMIT®
 10 mg
(n=154), 
n (%) 		Placebo
(n=154), n (%)
Death due to PAH or hospitalization for PAH 37 (24.0) 49 (31.8)
Component as first event
Death due to PAH 2 (1.3) 2 (1.3)
Hospitalization for PAH 35 (22.7) 47 (30.5)

Common adverse reactions in the combination therapy exploratory subgroup5#

  OPSUMIT®
10 mg
n=154		 Placebo
n=153
Anemia 16.2% 4.6%
Nasopharyngitis 11.0% 10.5%
Bronchitis 11.0% 5.9%
Headache 13.6% 10.5%
Diarrhea 13.0% 9.8%

#More frequent than placebo by ≥3%.

Combination therapy exploratory subgroup safety2,5,6

  • The safety profile of OPSUMIT® as part of a combination therapy regimen was consistent with that of OPSUMIT® in the overall SERAPHIN population
  • The incidence of peripheral edema, a known ERA-related adverse event, was similar in OPSUMIT®- and placebo-treated patients receiving background therapy (19.5% and 23.5%, respectively)
  • Treatment discontinuations due to adverse events in patients receiving background therapy were similar in those receiving OPSUMIT® and those receiving placebo (9.1% and 11.8%, respectively)

†All randomized patients.

Not adjusted for multiplicity.

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OPSUMIT® (macitentan): Additional endpoints from the SERAPHIN trial

SERAPHIN included secondary and exploratory endpoints from baseline to Month 6

Change from baseline in 6MWD at Month 61,2

At Month 6, 6MWD had increased by a mean of 12.5 m in the group receiving OPSUMIT® 10 mg (n=242); 6MWD decreased by a mean of 9.4 m in the placebo group (n=249) (placebo-corrected mean increase of 22.0 m; 97.5% CI, 3.0-41.0; P=0.0078).

Change in 6MWD at Month 6

Additional endpoints from SERAPHIN: improvements in 6MWD at month 6

Changes from baseline in WHO FC1,2

At Month 6, 22% of patients in the OPSUMIT® 10 mg group (n=242) experienced improvement of at least 1 WHO FC vs 13% of patients in the placebo group (n=249) P=0.006.

% Patients with improvement of at least
 1 WHO FC at Month 6

Additional endpoints from SERAPHIN: improvements in WHO FC

Change from baseline in measures of hemodynamics at Month 61,7,8

Exploratory hemodynamic substudy within SERAPHIN (OPSUMIT®: n=57, placebo: n=67).

PVR

37%

median reduction
in PVR vs
placebo

(95% CI, 22-49)

Mean PVR at BL
for OPSUMIT®:
924 ± 532 dyn•sec/cm**

 

Cardiac Index

0.6

L/min/m2
median increase
in cardiac index vs placebo

(95% CI, 0.3-0.9)

Mean cardiac index
at BL for OPSUMIT®:
2.55 ± 0.85 L/min/m2**

Not adjusted for multiplicity.

**Plus-minus values are mean ± standard deviation.

SERAPHIN PAH-related hospitalization results

View the Data

View SERAPHIN PAH-CTD subgroup data

See the Data

PAH associated with connective tissue disease (PAH-CTD)

PAH: A potential complication of CTD affecting up to approximately 1 in 10 patients9

PAH is a well-known complication in some patients with CTD10:

  • PAH affects approximately 3% to 13% of patients with CTD and 5% to 12% of patients with systemic sclerosis (SSc)9,11
  • Patients with PAH-SSc have a worse prognosis than most other PAH-associated disease populations12

Exploratory subgroup analysis: Disease progression in patients with PAH-CTD

Overall, in SERAPHIN, OPSUMIT® (macitentan) reduced the risk of disease progression by 45% vs placebo (HR 0.55; 97.5% CI, 0.39-0.76; P<0.0001).1 In the SERAPHIN trial, 31% of the overall patient population had PAH-CTD.1

The information below represents an exploratory subgroup analysis. Results should be interpreted with caution.

POST HOC ANALYSIS: Time to first disease progression event in patients with PAH-CTD13,14

Exploratory subgroup analysis: Time to first disease progression event in patients with PAH-CTD

Summary of primary endpoint events in patients with PAH-CTD13

  OPSUMIT® 10 mg
(n=73), n (%)		 Placebo
(n=82), n (%)
Patients with a primary endpoint event* 20 (27.4) 31 (37.8)
Component as first event
Worsening PAH 16 (21.9) 25 (30.5)
Death 3 (4.1) 5 (6.1)
Initiation of IV/SC prostanoids 1 (1.4) 1 (1.2)

*No patients experienced an event of lung transplantation or atrial septostomy in the placebo or OPSUMIT® 10 mg treatment groups.


Differences in PAH-CTD subgroup baseline characteristics compared with SERAPHIN overall population2,13

  • Larger percentage of female patients (92% vs 76.5%)
  • Older average age (49.7 years vs 45.6 years)
  • Larger percentage of patients with WHO FC II symptoms (58.5% vs 52.4%)
  • Lower percentage of patients with WHO FC Ill symptoms (39.3% vs 45.6%)
  • Shorter time from diagnosis (mean 2.0 years vs 2.7 years)

Adverse reactions in the PAH-CTD subgroup different from the overall population13††

  OPSUMIT® 10 mg
n=73		 Placebo
n=82
Upper respiratory tract infection 23.3% 13.4%
Urinary tract infection 12.3% 6.1%
Skin ulcer 9.6% 3.7%
Sinusitis 6.8% 1.2%
Lower respiratory tract infection 5.5% 1.2%
Nausea 8.2% 4.9%

††Only adverse reactions occurring ≥3% on OPSUMIT® compared with placebo and placebo-corrected difference of ≥3% in the PAH-CTD subgroup vs the overall population are shown here.

Eight (9.8%) patients receiving placebo and 8 (11.0%) patients receiving OPSUMIT® 10 mg in the PAH-CTD subgroup discontinued treatment due to adverse reactions, compared with approximately 11% for both the placebo and OPSUMIT® in the overall population.2,13

Exploratory subgroup analysis: PAH-related hospitalization

Overall, in SERAPHIN, OPSUMIT® reduced the risk of PAH-related hospitalization by 50% vs placebo (HR 0.50; 97.5% CI, 0.34-0.75; P<0.0001).1

The information below represents an exploratory subgroup analysis. Results should be interpreted with caution.

POST HOC ANALYSIS: Time to PAH-related death or hospitalization in patients with PAH-CTD13,15

Exploratory subgroup analysis: Time to PAH-related death or hospitalization in patients with PAH-CTD

PAH-CTD Subgroup: Summary of death due to PAH and hospitalization due to PAH13

  OPSUMIT® 10 mg
(n=73), n (%)		 Placebo
(n=82), n (%)
Death due to PAH or hospitalization for PAH 13 (17.8) 22 (26.8)
Component as first event
Death due to PAH 1 (1.4) 1 (1.2)
Hospitalization for PAH 12 (16.4) 21 (25.6)

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SERAPHIN PAH-related hospitalization results

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†All randomized patients.
‡Confirmed by a 6-minute walk test performed on a different day within 2 weeks.
§Worsening of PAH included at least one of the following: Advancing to a higher FC from baseline (or no change in WHO FC IV) and signs of right heart failure that does not respond to oral diuretic treatment.
Not adjusted for multiplicity.
#More frequent than placebo by ≥3%.
**Plus-minus values are mean ± standard deviation.

6MWD=6-minute walk distance; BL=baseline; CI=confidence interval; CTD=connective tissue disease; ERA=endothelin receptor antagonist; FC=Functional Class; HPAH=heritable PAH; HR=hazard ratio; IPAH=idiopathic PAH; IV=intravenous; PAH=pulmonary arterial hypertension; PAH-CHD=PAH associated with congenital heart disease; PAH-CTD=PAH associated with connective tissue disease; PAH-HIV=PAH associated with human immunodeficiency virus; PAH-SSc=PAH associated with systemic sclerosis; PDE5i=phosphodiesterase type 5 inhibitor; PVR=pulmonary vascular resistance; SC=subcutaneous; SERAPHIN=Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve CliNical Outcome; WHO=World Health Organization.
References: 1. OPSUMIT® (macitentan) full Prescribing Information. Actelion Pharmaceuticals US, Inc. 2. Pulido T, Adzerikho I, Channick RN, et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818 and suppl 1-21. doi:10.1056/NEJMoa1213917. 3. US Dept of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research. Opsumit® (macitentan) NDA 204410. Accessed July 30, 2024. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000MedR.pdf 4. Data on file. Actelion Pharmaceuticals US, Inc. 5. Jansa P, Pulido T. Macitentan in pulmonary arterial hypertension: a focus on combination therapy in the SERAPHIN trial. Am J Cardiovasc Drugs. 2018;18:1-11. 6. Data on file. Actelion Pharmaceuticals US, Inc. 7. Galiè N, Jansa P, Pulido T, et al. SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension. Eur Heart J. 2017;38(15):1147-1155. 8. Data on file. Actelion Pharmaceuticals US, Inc. 9. Chung L, Liu J, Parsons L, et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest. 2010;138:1383-1394. 10. Khanna D, Gladue H, Channick R, et al. Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum. 2013;65:3194-3201. 11. Humbert M, Kovacs G, Hoeper MM, et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Heart J. 2022;43(38):3618-3731. 12. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 suppl):D34-D41. 13. Data on file. Actelion Pharmaceuticals US, Inc. 14. Data on file. Actelion Pharmaceuticals US, Inc. 15. Data on file. Actelion Pharmaceuticals US, Inc.

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