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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 part of Johnson & Johnson Innovative Medicine

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

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 PDE5 inhibitor for at least 3 months, have a 6MWD of ≥150 m, and a WHO FC I-III

Study population

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

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.

REPAIR Primary Endpoints: 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

7-Year Data

VIEW RESULTS

Safety and Tolerability

LEARN MORE

*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; PDE5i=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® (macitentan) full 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

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

Patient demographics1

Baseline characteristics (finals analysis set, n=71)

Etiology

Monotherapy and combination therapy

REPAIR Primary Endpoints: RVSV and PVR at Week 26

Primary interim analysis set(n=42)

Final analysis set (n=71)

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)

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***

7-Year Data

Safety and Tolerability

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

Important Considerations¹

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