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

OPSUMIT® was associated with an increase in RVSV and a decrease in PVR at Week 261

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)

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)

Average age

 

45
years

WHO FC#

I:

1.4%

(n=1)

II:

47.9%

(n=34)

III:

50.7%

(n=36)

6MWD (mean)

 

411.2
meters

Etiology

5-1-etiology-mobile

Monotherapy and combination therapy

5-1-monotherapy-mobile

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. RVSV was increased by 15.2 mL and PVR was decreased by 37%
  • The final analysis set (n=71) was consistent with the primary interim analysis set. RVSV was increased by 12 mL and PVR decreased by 38% at Week 26

Primary interim analysis set
(n=42)

5-1-RVSV-mobile.png

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

5-1-PVR-37.jpg

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)

5-1-RVSV-mobile.png

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

5-1-PVR-38.jpg

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.

Changes were observed in RVESV, RVEDV, RVEF, and RV mass at Week 261§§

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

Changes from baseline were seen in 6MWD and WHO FC1

  • Exercise capacity: 35.6 m increase in 6MWD
  • FC: No patients had worsened

Exercise capacity at Week 26 (n=71)

Baseline
(mean±SD)
Change from baseline
to Week 26##
LS mean (95% CL)
6MWD (m)411.2±120.535.6 (19.0-52.3)

FC at Week 26 (n=70)

5-1-WHO-Pie-mobile

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 edema19 (21.8)
Headache18 (20.7)
Dizziness12 (13.8)
Cough10 (11.5)
Hemoglobin decreased10 (11.5)
Upper respiratory tract infection10 (11.5)
Myalgia9 (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 increased2 (2.3)
Transaminases increased2 (2.3)
Hypersensitivity1 (1.1)
Liver function test increased1 (1.1)
Edema peripheral1 (1.1)

Select treatment-emergent serious adverse events***

Patients with ≥1 treatment-emergent serious adverse event, n (%)14 (16.1)
Pneumonia3 (3.4)
Acute myocardial infarction2 (2.3)
Pulmonary arterial hypertension2 (2.3)
Pulmonary embolism2 (2.3)
Sepsis2 (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

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IMPORTANT SAFETY INFORMATION

BOXED WARNING: EMBRYO-FETAL TOXICITY

  • Do not administer OPSUMIT® to a pregnant female because it may cause fetal harm.
  • Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception.
  • For all female patients, OPSUMIT® is available only through a restricted program called the OPSUMIT® Risk Evaluation and Mitigation Strategy (REMS).

INDICATION

OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.

Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).

CONTRAINDICATIONS

Pregnancy: OPSUMIT® may cause fetal harm when administered to a pregnant woman. OPSUMIT® is contraindicated in females who are pregnant. If OPSUMIT® is used during pregnancy, advise the patient of the potential risk to a fetus.

Hypersensitivity: OPSUMIT® is contraindicated in patients with a history of a hypersensitivity reaction to macitentan or any component of the product.

WARNINGS AND PRECAUTIONS

Embryo-fetal Toxicity and OPSUMIT® REMS Program

Due to the risk of embryo-fetal toxicity, OPSUMIT® is available for females only through a restricted program called the OPSUMIT® REMS Program. For females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests.

Notable requirements of the OPSUMIT® REMS Program include:

  • Prescribers must be certified with the program by enrolling and completing training.
  • All females, regardless of reproductive potential, must enroll in the OPSUMIT® REMS Program prior to initiating OPSUMIT®. Male patients are not enrolled in the REMS.
  • Females of reproductive potential must comply with the pregnancy testing and contraception requirements.
  • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSUMIT®.

Hepatotoxicity

  • ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the SERAPHIN study >3 x ULN was 3.4% for OPSUMIT® vs 4.5% for placebo, and >8 x ULN was 2.1% vs 0.4%, respectively. Discontinuations for hepatic adverse events were 3.3% for OPSUMIT® vs 1.6% for placebo.
  • Obtain liver enzyme tests prior to initiation of OPSUMIT® and repeat during treatment as clinically indicated.
  • Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching).
  • If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT®. Consider re-initiation of OPSUMIT® when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

Fluid Retention

  • Peripheral edema and fluid retention are known consequences of PAH and ERAs. In the pivotal PAH study SERAPHIN, edema was reported in 21.9% of the OPSUMIT® group vs 20.5% for placebo.
  • Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment. In a small study of pulmonary hypertension due to left ventricular dysfunction, more patients in the OPSUMIT® group developed significant fluid retention and had more hospitalizations due to worsening heart failure compared to placebo. Postmarketing cases of edema and fluid retention occurring within weeks of starting OPSUMIT®, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported.
  • Monitor for signs of fluid retention after OPSUMIT® initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause and the possible need to discontinue OPSUMIT®.

Hemoglobin Decrease

  • Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and in clinical studies with OPSUMIT®. These decreases occurred early and stabilized thereafter.
  • In the SERAPHIN study, OPSUMIT® caused a mean decrease in hemoglobin (from baseline to 18 months) of about 1.0 g/dL vs no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT® group vs 3.4% for placebo. Decreases in hemoglobin seldom require transfusion.
  • Initiation of OPSUMIT® is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.

Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)

Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue OPSUMIT®.

Decreased Sperm Counts

OPSUMIT®, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility.

ADVERSE REACTIONS

Most common adverse reactions (more frequent than placebo by ≥3%) were anemia (13% vs 3%), nasopharyngitis/pharyngitis (20% vs 13%), bronchitis (12% vs 6%), headache (14% vs 9%), influenza (6% vs 2%), and urinary tract infection (9% vs 6%).

DRUG INTERACTIONS

  • Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of OPSUMIT® with strong CYP3A4 inducers should be avoided.
  • Strong inhibitors of CYP3A4 like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of OPSUMIT® with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment.
  • Moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole and amiodarone are predicted to increase macitentan exposure. Avoid concomitant use of OPSUMIT® with moderate dual inhibitors of CYP3A4 and CYP2C9.
  • Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSUMIT® should also be avoided.

INDICATION

OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.

Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).

Please see full Prescribing Information, including BOXED WARNING.

cp-113979v5

*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; HCP=healthcare professional; HPAH=heritable PAH; IPAH=idiopathic PAH; LS=least squares; PAH=pulmonary arterial hypertension; PAH-CHD=PAH associated with congenital heart disease; 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; SERAPHIN=Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve CliNical Outcome; 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.

EXPAND +

IMPORTANT SAFETY INFORMATION

BOXED WARNING: EMBRYO-FETAL TOXICITY

  • Do not administer OPSUMIT® to a pregnant female because it may cause fetal harm.
  • Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception.
  • For all female patients, OPSUMIT® is available only through a restricted program called the OPSUMIT® Risk Evaluation and Mitigation Strategy (REMS).

INDICATION

OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.

Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).