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POST HOC ANALYSIS: CTD SUBGROUP

GRIPHON—The Largest PAH-CTD Subpopulation in a Randomized Controlled PAH Trial (n=334)1

In an exploratory post hoc subgroup analysis, UPTRAVI® was associated with a: 41% RELATIVE RISK REDUCTION OF DISEASE PROGRESSION IN PAH-CTD PATIENTS TREATED WITH UPTRAVI® VS PLACEBO1*

Time to first disease progression event in patients with PAH-CTD
Percent of patients without an event in the PAH-CTD subgroup analysis mobile curve
41% risk reduction HR 0.59 (95% CI: 0.41, 0.85)

Baseline patient characteristics

  • 29% (n=334) of all patients in GRIPHON had PAH-CTD
  • PAH-CTD subtypes: PAH-SSc (51%, n=170), PAH-SLE (24.5%, n=82), PAH-MCTD/CTD-Other (24.5%, n=82)†
  • 46% of patients in the PAH-CTD subgroup were FC II and 53% were FC III
  • 28% were receiving PDE-5i monotherapy, 23% were not receiving PAH background therapy, 20% were receiving ERA monotherapy, and 29% were receiving an ERA + PDE-5i at baseline
  • Time from diagnosis: UPTRAVI® (1.6 years), placebo (1.7 years)
  • Average age: UPTRAVI® (52 years), placebo (53 years)

Summary of primary endpoint events in patients with PAH-CTD

Events in patients with PAH-SSc mobile table

Adverse reactions in the PAH-CTD subpopulation occurring more frequently with UPTRAVI® compared with placebo by ≥3%

Adverse reactions in the PAH-SSc subgroup notably different from the overall population mobile table

PAH-CTD was a prespecified subgroup for evaluation of the primary endpoint; however, the more detailed analyses described here are 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: 44% RELATIVE RISK REDUCTION OF DISEASE PROGRESSION IN PAH-SSc PATIENTS TREATED WITH UPTRAVI® VS PLACEBO1*

Time to first disease progression event in patients with PAH-SSc
Percent of patients without an event in the PAH-SSc subgroup analysis mobile curve
44% risk reduction HR 0.56 (95% CI: 0.34, 0.91)

Baseline patient characteristics

Of the 334 patients with PAH-CTD in GRIPHON, 51% (n=170) had PAH-SSc.

  • 34% FC II, 65% FC III, and 2% FC I or FC IV
  • 78% of patients were receiving PAH background therapy (36% receiving an ERA + PDE-5i, 23% receiving a PDE-5i only, and 18% receiving an ERA only)
  • Time from diagnosis: UPTRAVI® (1.5 years), placebo (1.6 years)
  • Average age: UPTRAVI® (59 years), placebo (61 years)

Summary of primary endpoint events in patients with PAH-SSc

Events in patients with PAH-SSc mobile table

Adverse reactions in the PAH-SSc subpopulation occurring more frequently with UPTRAVI® compared with placebo by ≥3%

Adverse reactions in the PAH-SSc subgroup notably different from the overall population mobile table

This subgroup analysis was post hoc and exploratory in nature. 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.

†Due to smaller patient numbers and corresponding number of primary endpoint events, PAH-MCTD and PAH-CTD-Other patients were presented as a single group.

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

6MWD=6-minute walk distance; CI=confidence interval; CTD=connective tissue disease; ERA=endothelin receptor antagonist; FC=Functional Class; GRIPHON=Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial HypertensiON; HR=hazard ratio; PAH-CTD=PAH associated with connective tissue disease; PAH-MCTD/CTD-Other=PAH associated with mixed connective tissue disease and CTD-Other; PAH-SLE=PAH associated with systemic lupus erythematosus; PAH-SSc=PAH associated with systemic sclerosis; PDE-5i=phosphodiesterase type-5 inhibitor.

Reference: 1. Gaine S, Chin K, Coghlan G, et al. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. Eur Respir J. 2017;50(2):1602493. doi:10.1183/13993003.02493-2016