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POST HOC ANALYSIS: TRIPLE-COMBINATION SUBGROUP

GRIPHON—The FIRST and ONLY COMPLETED PAH Outcomes Trial That Included Patients Treated With TRIPLE-Combination Therapy1,2

In an exploratory post hoc subgroup analysis, UPTRAVI® was associated with a: 37% RELATIVE RISK REDUCTION OF DISEASE PROGRESSION IN PATIENTS TREATED WITH UPTRAVI® + ERA + PDE-5i VS PLACEBO3*

Time to first disease progression event
Patients without an event in the triple combination subgroup mobile curve
37% risk reduction HR 0.63 (95% CI: 0.44, 0.90)

The treatment effect was established early and maintained over the entire treatment period*

Baseline patient characteristics

  • 33% (n=376) of all patients in GRIPHON were receiving an ERA and a PDE-5i at baseline (31% FC II and 68% FC III)†
  • Etiology in triple-combination subgroup: IPAH/HPAH (64%), PAH-CTD (26%), PAH-CHD (5%), other (5%)‡
  • Time from diagnosis: UPTRAVI® (4 years), placebo (3.6 years)

Summary of primary endpoint events in patients receiving ERA + PDE-5i at baseline

Events in patients receiving ERA + PDE-5i at baseline (triple combination) mobile table

Adverse reactions in triple-combination subgroup occurring more frequently with UPTRAVI® compared with placebo by ≥3%

Adverse reactions in triple-combination subgroup notably different from overall population mobile table

2022 ESC/ERS Guidelines: UPTRAVI® is the only prostacyclin pathway therapy to receive the highest-class recommendation (Class I, Level B) for sequential triple- and dual-combination therapy4

Patients receiving an ERA and a PDE-5i at baseline were a prespecified subgroup for evaluation of the GRIPHON primary endpoint; however, the more detailed analyses described on this page are exploratory and post hoc. Sample size should be considered and results should be interpreted with caution.

In an exploratory post hoc subgroup analysis, UPTRAVI® was associated with a: 64% RELATIVE RISK REDUCTION OF DISEASE PROGRESSION IN FC II PATIENTS ALREADY RECEIVING ERA + PDE-5i VS PLACEBO3*

Time to first disease progression event in FC II patients receiving ERA + PDE-5i at baseline
Patients without an event in the FC II triple combination subgroup mobile curve
64% risk reduction HR 0.36 (95% CI: 0.14, 0.91)

Baseline patient characteristics

  • 10% (n=115) of all patients in GRIPHON were FC II and receiving an ERA and a PDE-5i at baseline
  • Etiology in FC II triple-combination subpopulation: IPAH/HPAH (70%), PAH-CTD (18%), PAH-CHD (6%), other (6%)‡
  • Time from diagnosis in FC II patients: UPTRAVI® (4.3 years), placebo (3.6 years)

Summary of primary endpoint events in FC II patients receiving ERA + PDE-5i at baseline

Events in FC II patients receiving ERA + PDE-5i at baseline (triple combination) mobile table

Adverse reactions in FC II triple-combination subgroup occurring more frequently with UPTRAVI® compared with placebo by ≥3%

Adverse reactions in FC II triple-combination subgroup notably different from overall population mobile table

2022 ESC/ERS Guidelines: UPTRAVI® is the only prostacyclin pathway therapy to receive the highest-class recommendation (Class I, Level B) for sequential triple- and dual-combination therapy4

Patients receiving an ERA and a PDE-5i at baseline were a prespecified subgroup for evaluation of the GRIPHON primary endpoint; however, the more detailed analyses described on this page are exploratory and post hoc. Sample size should be considered and results should be interpreted with caution.

In an exploratory post hoc subgroup analysis, UPTRAVI® was associated with a: 26% RELATIVE RISK REDUCTION OF DISEASE PROGRESSION IN FC III PATIENTS ALREADY RECEIVING ERA + PDE-5i VS PLACEBO3*

Time to first disease progression event in FC III patients receiving ERA + PDE-5i at baseline
Patients without an event in the FC III triple combination subgroup mobile curve
26% risk reduction HR 0.74 (95% CI: 0.50, 1.10)

Baseline patient characteristics

  • 22% (n=255) of all patients in GRIPHON were FC III and receiving an ERA and a PDE-5i at baseline
  • Etiology in FC III triple-combination subpopulation: IPAH/HPAH (61%), PAH-CTD (29%), PAH-CHD (5%), other (4%)‡
  • Time from diagnosis in FC III patients: UPTRAVI® (3.9 years), placebo (3.6 years)

Summary of primary endpoint events in FC III patients receiving ERA + PDE-5i at baseline

Events in FC III patients receiving ERA + PDE-5i at baseline (triple combination) mobile table

Adverse reactions in FC III triple-combination subgroup occurring more frequently with UPTRAVI® compared with placebo by ≥3%

Adverse reactions in FC III triple-combination subpopulation notably different from overall population mobile table

2022 ESC/ERS Guidelines: UPTRAVI® is the only prostacyclin pathway therapy to receive the highest-class recommendation (Class I, Level B) for sequential triple- and dual-combination therapy4

Patients receiving an ERA and a PDE-5i at baseline were a prespecified subgroup for evaluation of the GRIPHON primary endpoint; however, the more detailed analyses described on this page are exploratory and post hoc. Sample size should be considered and results should be interpreted with caution.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Concomitant use of strong inhibitors of CYP2C8 (eg, gemfibrozil) with UPTRAVI® is contraindicated.

Hypersensitivity to the active substance or to any of the excipients is contraindicated.

WARNINGS AND PRECAUTIONS

Pulmonary Edema with Pulmonary Veno-Occlusive Disease (PVOD)

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

ADVERSE REACTIONS

Adverse reactions more frequent compared to placebo (≥3%) seen with UPTRAVI® Tablets are headache (65% vs 32%), diarrhea (42% vs 18%), jaw pain (26% vs 6%), nausea (33% vs 18%), myalgia (16% vs 6%), vomiting (18% vs 9%), pain in extremity (17% vs 8%), flushing (12% vs 5%), arthralgia (11% vs 8%), anemia (8% vs 5%), decreased appetite (6% vs 3%), and rash (11% vs 8%).

These adverse reactions are more frequent during the dose titration phase.

Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI® Tablets and in none of the patients on placebo.

DRUG INTERACTIONS

CYP2C8 Inhibitors

Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant use of UPTRAVI® with strong inhibitors of CYP2C8 is contraindicated.

Concomitant administration of UPTRAVI® with clopidogrel, a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7–fold. Reduce the dosing of UPTRAVI® to once daily in patients on a moderate CYP2C8 inhibitor.

CYP2C8 Inducers

Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI® dose, up to twice, when co-administered with rifampin. Reduce UPTRAVI® when rifampin is stopped.

DOSAGE AND ADMINISTRATION

Recommended Dosage

Recommended starting dose is 200 mcg twice daily for UPTRAVI® Tablets. Tolerability may be improved when taken with food. Increase by 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If dose is not tolerated, reduce to the previous tolerated dose.

Patients With Hepatic Impairment

For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of UPTRAVI® Tablets is 200 mcg once daily. Increase by 200 mcg once daily at weekly intervals, as tolerated. Avoid use of UPTRAVI® in patients with severe hepatic impairment (Child-Pugh class C).

Co-administration With Moderate CYP2C8 Inhibitors

When co-administered with moderate CYP2C8 inhibitors (eg, clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI® to once daily.

Dosage Strengths

UPTRAVI® tablet strengths:
200, 400, 600, 800, 1000, 1200, 1400, and 1600 mcg.

Additional Important Safety Information for UPTRAVI® IV

Use UPTRAVI® for injection in patients who are temporarily unable to take oral therapy.

Administer UPTRAVI® for injection twice daily by intravenous infusion at a dose that corresponds to the patient’s current dose of UPTRAVI® Tablets (see Table 1 in full Prescribing Information). Administer UPTRAVI® for injection as an 80-minute intravenous infusion.

Adverse Reactions: Infusion-site reactions (infusion-site erythema/redness, pain and swelling) were reported with UPTRAVI® for injection.

INDICATION

UPTRAVI® (selexipag) is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

Effectiveness of UPTRAVI® Tablets was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms.

Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), and PAH associated with congenital heart disease with repaired shunts (10%).

Please see full Prescribing Information for UPTRAVI®.

cp-126160v5

*Not adjusted for multiplicity.

†Included 6 patients with WHO FC IV symptoms at baseline.

‡Other=drugs and toxins (4%) and HIV (1%) in overall population; drugs and toxins (4%) and HIV (3%) in FC II patients; drugs and toxins (4%) and HIV (<1%) in FC III patients.

§Hazard ratio based on primary endpoint events up to the end of treatment.

‖Treatment period defined as 7 days after last intake of UPTRAVI® or placebo.

Class I recommendation definition: evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective. Level B evidence definition: data derived from a single randomized clinical trial or large nonrandomized studies. The 2022 ESC/ERS Guidelines recommend adding UPTRAVI® for patients without cardiopulmonary comorbidities who are at intermediate-low risk despite receiving ERA/PDE-5i therapy. In these patients, switching from a PDE-5i to riociguat may be considered. In patients who present as intermediate-high or high risk on oral therapies, also consider adding UPTRAVI® or switching from a PDE-5i to riociguat if it is not feasible to add IV or SC prostacyclin analogs.

6MWD=6-minute walk distance; CI=confidence interval; ERA=endothelin receptor antagonist; ERS=European Respiratory Society; ESC=European Society of Cardiology; FC=Functional Class; GRIPHON=Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial HypertensiON; HIV=human immunodeficiency virus; HPAH=heritable PAH; HR=hazard ratio; IPAH=idiopathic PAH; IV=intravenous; PAH-CHD=PAH associated with congenital heart disease with repaired shunts; PAH-CTD=PAH associated with connective tissue disease; PDE-5i=phosphodiesterase type-5 inhibitor; SC=subcutaneous; WHO=World Health Organization.

References: 1. UPTRAVI® (selexipag) full Prescribing Information. Actelion Pharmaceuticals US, Inc. 2. Ruopp NF, Cockrill BA. Diagnosis and treatment of pulmonary arterial hypertension: a review. JAMA. 2022;327(14):1379-1391. 3. Coghlan JG, Channick R, Chin K, et al. Targeting the prostacyclin pathway with selexipag in patients with pulmonary arterial hypertension receiving double combination therapy: insights from the randomized controlled GRIPHON study. Am J Cardiovasc Drugs. 2018;18(1):37-47. 4. 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.