SUMMARY

• In the phase 3 GRIPHON study evaluating the long-term efficacy and safety of UPTRAVI in 1156 patients with pulmonary arterial hypertension (PAH), renal and urinary disorders were reported at baseline as previous or concomitant diseases in 59 (10.3%) and 76 (13.1%) patients in the UPTRAVI and placebo groups, respectively. Patients with severe renal impairment (SRI; estimated creatinine clearance [CrCl] <30 mL/min or serum creatinine >2.5 mg/dL) were excluded and no specific subgroup analysis of patients with renal impairment was conducted.^1,2
• During the GRIPHON study, a total of 41 (7.1%) patients receiving UPTRAVI and 26 (4.5%) patients receiving placebo experienced at least 1 adverse event (AE) denoting ‘renal disorders’. A total of 10 (1.7%) patients on UPTRAVI experienced a serious AE denoting ‘renal disorders’ compared to 7 (1.2%) patients on placebo. The serious AEs (SAEs) had a fatal outcome for 2 patients in the UPTRAVI group and 3 patients in the placebo group. Three patients (0.5%) on UPTRAVI and 3 patients (0.3%) on placebo discontinued the study due to renal disorder AEs.²
• In a phase 1 pharmacokinetic (PK) study, exposure to selexipag and its metabolite, ACT333679, increased 1.7-fold and 1.6-fold, respectively, in patients with SRI compared with healthy patients.³
• An additional citation is added in the REFERENCES section for your review.⁴

CLINICAL DATA

GRIPHON

GRIPHON was a randomized, double-blind, placebo-controlled phase 3 study conducted in 1156 adult patients with symptomatic PAH in which the median length of study drug exposure was 70.7 weeks for patients on UPTRAVI (n=574) and 63.7 weeks for patients on placebo (n=582). UPTRAVI was initiated at 200 mcg twice daily (BID) and up titrated weekly in increments of 200 mcg BID until the individual highest tolerated dose was reached (ranging from 200 to 1600 mcg BID). Of note, patients with SRI (estimated CrCl <30 mL/min or serum creatinine >2.5 mg/dL) were excluded from participating in the study. Please visit http://www.clinicaltrials.gov for additional information on GRIPHON, including inclusion and exclusion criteria (identifier NCT01112306).¹

Concomitant Renal Disorders at Baseline

During the GRIPHON study, renal and urinary disorders were reported at baseline as previous or concomitant diseases in 59 (10.3%) and 76 (13.1%) patients in the UPTRAVI and placebo groups, respectively. The most frequent types of previous or concomitant renal disorders at baseline are summarized in Table: Most Frequently Occurring Previous or Concomitant Renal Disorders at Baseline in the GRIPHON Study.²

AEs Denoting Renal Disorders

During the GRIPHON study, a total of 41 (7.1%) patients receiving UPTRAVI and 26 (4.5%) patients receiving placebo experienced at least 1 AE denoting ‘renal disorders’. The overall incidence of terms denoting ‘renal disorders’, reported by more than 1 patient receiving either UPTRAVI or placebo during GRIPHON, is provided in Table: Incidence of Renal Disorders and Related Terms in GRIPHON, Reported as an AE by >1 Patient Receiving Either UPTRAVI or Placebo.²

All patients with renal disorder AEs had 1 or more of the following confounding factors at baseline: serum creatinine >133 μmol/L, CrCl <60 mL/min, medical history of diabetes, and renal dysfunction. In total, 13/27 patients in the UPTRAVI group and 10/15 patients in the placebo group with renal dysfunction AEs (renal failure, acute renal failure, renal impairment, increased blood creatinine) had serum creatinine >133 μmol/L and/or CrCl <60 mL/min at baseline. Furthermore, many of these AEs occurred in the context of comorbid illnesses that can affect renal function (e.g., hemodynamic compromise due to PAH disease progression, sepsis, and hypovolemic shock) or were reported in patients receiving concomitant medications known to potentially affect renal function (e.g., diuretics).

SAEs and Discontinuations Due to Renal Disorder AEs

The overall proportion of patients with renal disorder SAEs and those who discontinued UPTRAVI due to renal disorder AEs is summarized in Table: Patients With SAEs Denoting Renal Disorders (and Related Terms) and Discontinuations Due to Renal Disorder AEs in GRIPHON.²

Overall, acute renal failure was reported as an SAE for 6 (1%) patients in each group. Of these, 5 patients in the UPTRAVI group and 2 patients in the placebo group, respectively, had comorbid right ventricular failure or PAH worsening. The SAEs had a fatal outcome for 2 patients in the UPTRAVI group and 3 patients in the placebo group.

Creatinine Laboratory Abnormalities

A marked increase in creatinine (defined as >1.5 × upper limit of normal [ULN] or 1.5 × baseline) was reported for 5.4% (30/554) of patients in the UPTRAVI group and 6.0% (34/564) in the placebo group, with 1 patient in each of the 2 groups having creatinine increased to >3 × ULN or 3 × baseline.²

Phase 1 Study

AC-065-105 was a single-center, open-label, single-dose, phase 1 study investigating the PK, tolerability, and safety of a single dose of selexipag 400 mcg in 8 patients with SRI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) compared with 8 healthy patients with normal renal function (eGFR ≥90 mL/min/1.73 m²).³

PK Results

Selexipag was absorbed with a median time to reach maximum plasma concentration (t_max) of 2.0 h and 1.5 h in SRI and healthy patients, respectively. A 1.7-fold increase in exposure (maximum plasma concentration [C_max] and area under plasma concentration-time curve from 0 to infinity [AUC_0-∞]) to selexipag was observed in patients with SRI compared with healthy patients.³ For more information regarding the PK parameters of selexipag and ACT­333679 in healthy patients and patients with SRI, see Table: Plasma PK Variables of Selexipag and ACT-333679 in Healthy Patients and Patients With SRI After Administration of a Single Dose of 400 mcg Selexipag.

Tolerability and Safety

A total of 17 AEs were reported by 10 patients: 8 AEs by 5 patients (62.5%) with SRI and 9 AEs by 5 healthy patients (62.5%). Headache was the most frequently reported AE and was reported by 4 patients (50%) in each group. All AEs were of mild or moderate intensity and resolved without sequelae not requiring treatment.³

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 7 April 2024.