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Macitentan REMS

Important Safety Information
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Important Safety
Information
Prescribing
Information
For Patients

Macitentan REMS

The REPAIR study: Effects of macitentan on RV structure and function in pulmonary arterial hypertension¹

VIEW THE SERAPHIN CLINICAL DATA to learn more about a large, outcomes-based pivotal trial in PAH.

Important Considerations¹

Data are based on a single-arm, open-label clinical trial and not on a randomized, placebo-controlled clinical trial
CMR parameters have not been accepted as primary endpoints for pivotal studies in PAH, so these data are hypothesis generating and further research is needed for a better understanding of the significance of CMR parameters as proxy for disease progression
The open-label design and study size of the REPAIR study limited subgroup analyses
OPSUMIT® (macitentan) is an ERA indicated for the treatment of PAH (WHO Group I) (FC II-III) to reduce the risks of disease progression and hospitalization for PAH²
This study was funded by Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson

REPAIR was a 52-week, prospective, multicenter, single-arm, open-label, phase 4 study

Study objectives

To evaluate the effect of OPSUMIT® on RV and hemodynamic properties in patients with PAH
- Primary endpoints were assessed at Week 26
To evaluate the safety and tolerability of OPSUMIT® in patients with symptomatic PAH
- Patients’ median exposure time was 52 weeks

Study population

Primary interim analysis set: n=42*
Final analysis set: n=71†‡
Safety set: n=87^§ǁ

Inclusion criteria

18 to 74 years of age
Idiopathic or heritable PAH, PAH related to CTD, drug use or toxin exposure, or simple congenital systemic-to-pulmonary shunts at least 2 years after repair (RHC required to confirm diagnosis)
Patients who are PAH-treatment naïve or receiving a stable background PDE-5i for at least 3 months, have a 6MWD of ≥150 m, and a WHO FC I-III

Exclusion criteria^¶

Prior use of ERAs, stimulators of soluble guanylate cyclase, or prostacyclin/prostacyclin analogs

The primary endpoints in REPAIR were RVSV (assessed by CMR) and PVR (measured by RHC)¹

Primary endpoints: Change from baseline to Week 26
RVSV assessed by CMR
PVR measured by RHC

Secondary endpoints: Change from baseline to Week 26
RVESV, RVEDV, RVEF, and RV mass assessed by CMR
6MWD
WHO FC

The single-arm, open-label design and study size of the REPAIR study limited subgroup analyses.

Patient demographics¹

Baseline characteristics (finals analysis set, n=71)

Female patients

80.3^%

(n=57)

Median age

45
years

WHO FC^#

1.4^%

(n=1)

II:

47.9^%

(n=34)

III:

50.7^%

(n=36)

6MWD (mean)

411.2
meters

Etiology

Monotherapy and combination therapy

The single-arm, open-label design and study size of the REPAIR study limited subgroup analyses.

RVSV and PVR at Week 26

The primary interim analysis set (n=42) was declared positive and enrollment was stopped at Week 26 as both primary endpoints (RVSV and PVR) were met
The final analysis set (n=71) was consistent with the primary interim analysis set

Primary interim analysis set
(n=42)

RVSV

15.2 mL
increase

Change from baseline
to Week 26^††
LS mean (96% CL)
15.2 (9.3-21.0) mL
Baseline (mean±SD):
50.7±17.5 mL

PVR

REPAIR study primary endpoint: PVR primary interim analysis set, 37% decrease

Week 26/baseline ratio^‡‡
Geometric mean (99% CL)
0.63 (0.54-0.74) dyn·sec/cm⁵
Baseline (mean±SD):
900.2±457.6 dyn·sec/cm⁵

Final analysis set
(n=71)

RVSV

12.0 mL
increase

Change from baseline
to Week 26^††
LS mean (96% CL)
12.0 (8.4-15.6) mL
Baseline (mean±SD):
52.2±17.2 mL

PVR

REPAIR study primary endpoint: PVR final analysis set, 38% decrease

Week 26/baseline ratio^‡‡
Geometric mean (99% CL)
0.62 (0.56-0.69) dyn·sec/cm⁵
Baseline (mean±SD):
974.6±679.0 dyn·sec/cm⁵

CMR parameters have not been accepted as primary endpoints for pivotal studies in PAH, so these data are hypothesis generating and further research is needed for a better understanding of the significance of CMR parameters as proxy for disease progression.

Observations of RV stroke volume, ejection fraction, and mass at Week 26^{1^§§}

Final analysis set (n=70)
Change from baseline to Week 26^‖‖ in RV parameters
LS mean (95% CL)

RVESV
(mL)

–16.1

(–20.0 to –12.2)
Baseline (mean±SD):
90.2±40.6

RVEDV
(mL)

–6.2

(–12.8 to 0.4)
Baseline (mean±SD):
149.8±49.1

RVEF^¶¶
(%)

+10.6

(7.9 to 13.3)
Baseline (mean±SD):
37.7±14.3

RV mass
(g)

–10.5

(–14.0 to –7.1)
Baseline (mean±SD):
110.4±47.5

Observations of 6MWD and WHO FC at Week 26¹

Exercise capacity at Week 26 (n=71)

	Baseline (mean±SD)	Change from baseline to Week 26^## LS mean (95% CL)
6MWD (m)	411.2±120.5	35.6 (19.0-52.3)

FC at Week 26 (n=70)

Zero patients worsened in WHO FC.

Baseline WHO FC^#: WHO FC I, 1 (1.4%);
WHO FC II, 34 (48.6%); WHO FC III, 35 (50.0%).

Secondary efficacy analyses were performed with no correction for multiple testing; thus, these analyses are of an exploratory nature.

Safety and tolerability in the REPAIR study

Adverse events observed in the safety set (n=87)

Treatment-emergent adverse events

Patients with ≥1 treatment-emergent adverse event in ≥10% of patients, n (%)	75 (86.2)
Peripheral edema	19 (21.8)
Headache	18 (20.7)
Dizziness	12 (13.8)
Cough	10 (11.5)
Hemoglobin decreased	10 (11.5)
Upper respiratory tract infection	10 (11.5)
Myalgia	9 (10.3)

Adverse events leading to discontinuation of study treatment

Patients with ≥1 adverse event leading to discontinuation of study treatment, n (%)	7 (8.0)
Aspartate aminotransferase increased	2 (2.3)
Transaminases increased	2 (2.3)
Hypersensitivity	1 (1.1)
Liver function test increased	1 (1.1)
Edema peripheral	1 (1.1)

Select treatment-emergent serious adverse events***

Patients with ≥1 treatment-emergent serious adverse event, n (%)	14 (16.1)
Pneumonia	3 (3.4)
Acute myocardial infarction	2 (2.3)
Pulmonary arterial hypertension	2 (2.3)
Pulmonary embolism	2 (2.3)
Sepsis	2 (2.3)
Cardiac arrest (1 death recorded was the result of a fatal cardiac arrest, which occurred after the patient experienced a pulmonary embolism)	1 (1.1)

Laboratory abnormalities of ALT/AST ≥3 x the ULN were reported for 5 (5.8%) patients in the safety set¹

*Primary results were based on the interim analysis set: Prespecified set of the first 42 patients who received at least 1 dose of OPSUMIT® and had valid measurements for both primary endpoints at baseline and at Week 26.

^†71 patients with both RVSV and PVR measures at baseline and Week 26.

^‡Final analysis set: All enrolled patients who received at least 1 dose of OPSUMIT® and had valid measurement for both primary endpoints at baseline and at Week 26.

^§87 patients received ≥1 dose of OPSUMIT®.

^ǁSafety set: All screened patients who received at least 1 dose of OPSUMIT®.

^¶Reference supplemental methods for a complete list of the exclusion criteria.

^#OPSUMIT® is only indicated in WHO FC II and III.

**Only simple congenital systemic-to-pulmonary shunts at ≥2 years postsurgical repair.

^††Adjusted change using an ANCOVA model with a factor for PAH-targeted background therapy and a covariate for baseline parameter value.

^‡‡Adjusted change using an ANCOVA model with a factor for PAH-targeted background therapy and a covariate for baseline log PVR.

^§§Not adjusted for multiplicity.

^ǁǁAnalyzed using an ANCOVA with a factor for PAH-targeted background therapy and a covariate for baseline parameter value.

^¶¶From pulmonary artery flow.

^##From ANCOVA model on parameter change from baseline with factors for PAH-targeted treatment strategy, baseline WHO FC, and parameter at baseline as a covariate.

***Reference supplemental table 6 for a complete list of treatment-emergent serious adverse events.

6MWD=6-minute walk distance; ALT=alanine aminotransferase; ANCOVA=analysis of covariance; AST=aspartate aminotransferase; CL=confidence limit; CMR=cardiac magnetic resonance; CTD=connective tissue disease; ERA=endothelin receptor antagonist; FC=Functional Class; IPAH=idiopathic PAH; LS=least squares; PAH=pulmonary arterial hypertension; PAH-CTD=PAH associated with connective tissue disease; PDE-5i=phosphodiesterase type 5 inhibitor; PVR=pulmonary vascular resistance; REPAIR=Right vEntricular remodeling in Pulmonary ArterIal hypeRtension; RHC=right heart catheterization; RV=right ventricular; RVEDV=RV end-diastolic volume; RVEF=RV ejection fraction; RVESV=RV end-systolic volume; RVSV=RV stroke volume; ULN=upper limit of normal; WHO=World Health Organization.

References: 1. Vonk Noordegraaf A, Channick R, Cottreel E, et al. The REPAIR study: Effects of macitentan on RV structure and function in pulmonary arterial hypertension. JACC Cardiovasc Imaging. 2021;S1936-878X(21)00635-5 and suppl 1-15. doi:10.1016/j.jcmg.2021.07.027 2. OPSUMIT® [prescribing information]. Actelion Pharmaceuticals US, Inc.

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The REPAIR study: Effects of macitentan on RV structure and function in pulmonary arterial hypertension1

Important Considerations1

REPAIR was a 52-week, prospective, multicenter, single-arm, open-label, phase 4 study

Study objectives

Study population

Inclusion criteria

Exclusion criteria¶

The primary endpoints in REPAIR were RVSV (assessed by CMR) and PVR (measured by RHC)1

The single-arm, open-label design and study size of the REPAIR study limited subgroup analyses.

Patient demographics1

Baseline characteristics (finals analysis set, n=71)

Etiology

Monotherapy and combination therapy

The single-arm, open-label design and study size of the REPAIR study limited subgroup analyses.

RVSV and PVR at Week 26

Primary interim analysis set(n=42)

Final analysis set (n=71)

CMR parameters have not been accepted as primary endpoints for pivotal studies in PAH, so these data are hypothesis generating and further research is needed for a better understanding of the significance of CMR parameters as proxy for disease progression.

Observations of RV stroke volume, ejection fraction, and mass at Week 261§§

Final analysis set (n=70)Change from baseline to Week 26‖‖ in RV parameters LS mean (95% CL)

Observations of 6MWD and WHO FC at Week 261

Exercise capacity at Week 26 (n=71)

FC at Week 26 (n=70)

Secondary efficacy analyses were performed with no correction for multiple testing; thus, these analyses are of an exploratory nature.

Safety and tolerability in the REPAIR study

Treatment-emergent adverse events

Adverse events leading to discontinuation of study treatment

Select treatment-emergent serious adverse events***

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SERAPHIN PAH-related hospitalization results

View SERAPHIN PAH-CTD subgroup data

The REPAIR study: Effects of macitentan on RV structure and function in pulmonary arterial hypertension¹

Important Considerations¹

Exclusion criteria^¶

The primary endpoints in REPAIR were RVSV (assessed by CMR) and PVR (measured by RHC)¹

Patient demographics¹

Primary interim analysis set
(n=42)

Final analysis set
(n=71)

Observations of RV stroke volume, ejection fraction, and mass at Week 26^{1^§§}

Final analysis set (n=70)
Change from baseline to Week 26^‖‖ in RV parameters
LS mean (95% CL)

Observations of 6MWD and WHO FC at Week 26¹