SUMMARY

• In GRIPHON, UPTRAVI or placebo was initiated at 200 mcg twice daily (BID) and increased weekly in increments of 200 mcg BID, as tolerated, up to a maximum dose of 1600 mcg BID. This dose adjustment phase spanned the first 12 weeks of treatment.¹
• To determine the highest tolerable dose, the dose was reduced by 200 mcg BID when an intolerable dose was reached.¹
• The observed benefit of UPTRAVI in the GRIPHON study was similar regardless of the dose achieved when patients were titrated to their highest tolerated dose.^1–3
• An analysis of the SPHERE registry showed that the median maintenance dose of UPTRAVI was 1100 mcg BID (n=729). In the overall pulmonary arterial hypertension (PAH) population (n=759), the median duration of UPTRAVI titration was 8.1 weeks, with 671 (88.4%) patients titrating at speeds slower than 200 mcg BID per week and 88 (11.6%) patients titrating at speeds equal to or faster than 200 mcg BID per week.^4,5

CLINICAL DATA

Information From the UPTRAVI Clinical Development Program

Phase 1 Data

The pharmacokinetics (PK) of selexipag and its active metabolite are dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1800 mcg BID. In a phase 1, singlecenter, randomized, double-blind, placebo-controlled, parallel-group, uptitration study, 16 healthy male patients were started on UPTRAVI 400 mcg BID (n=12) or placebo (n=4) for 3 days. The dose was then uptitrated every third day by 200 mcg BID to a maximum dose of 1800 mcg BID. Prior to each uptitration to the next dose, available safety data were reviewed. The study was terminated per protocol after the 1800 mcg BID dose level, because >50% of patients (7/9 patients remaining on treatment) showed moderate drug-related adverse events (AEs) which, in part, required treatment. Based on this termination, doses up to and including 1600 mcg BID were considered well tolerated and this dose was identified as the maximum tolerated dose (MTD).⁶

Phase 2 Data

Study NS-304/-02 was a multicenter, double-blind, placebo-controlled, randomized, parallelgroup, proof-of-concept, phase 2 study assessing the safety, tolerability, PK, and preliminary efficacy of UPTRAVI in patients with PAH (N=43). Patients were started on UPTRAVI 200 mcg BID (n=33) or matching placebo (n=10) on day 1. The dose was then uptitrated to 400 mcg BID on day 3, to 600 mcg BID on day 7 and to 800 mcg BID on day 21. A slower uptitration schedule was allowed up to day 35 to allow for a MTD (up to 800 mcg BID). Among UPTRAVI-treated patients, 14 (42.4%) were on a final dosage of 800 mcg BID, 7 (21.2%) were on 600 mcg BID, 6 (18.2%) were on 400 mcg BID and 4 (12.1%) were on 200 mcg BID. The MTD could not be determined for 2 patients due to premature treatment discontinuation.⁷

AC-065C202 was a phase 2, multicenter, single-blind run-in, double-blind, randomized, placebo-controlled, parallel-group study assessing the activity of UPTRAVI on Raynaud’s phenomenon (RP) attack frequency in patients with systemic sclerosis-associated RP (N=74). UPTRAVI was titrated from 200 to 1600 mcg BID, at 3-day intervals, until unmanageable AEs associated with prostacyclin developed. Overall, 83.3% of patients in the UPTRAVI group (n=36) had an individual maintenance dose (IMD) ≤800 mcg BID (median IMD [interquartile range (IQR)]: 600 [200-800] mcg BID). Among the placebo group (n=38), 71.1% of patients had the placebo equivalent of an IMD of 1600 mcg BID.⁸

Phase 3 GRIPHON Study

The GRIPHON phase 3 study (Prostacyclin [PGI₂] Receptor agonist In Pulmonary arterial HypertensiON; AC-065A302) was a multicenter, double-blind, parallel-group, placebo-controlled event-driven trial evaluating the efficacy and safety of oral UPTRAVI in adult patients with World Health Organization (WHO) Group 1 PAH. Patients were randomized 1:1 to UPTRAVI or placebo (see Figure: GRIPHON Study Design).¹

Dosing of UPTRAVI or placebo in GRIPHON was initiated at 200 mcg BID and increased weekly by 200 mcg BID, as tolerated, up to a maximum dose of 1600 mcg BID. This dose adjustment phase spanned the first 12 weeks of treatment. To determine the highest tolerable dose, this phase employed dose reduction by 200 mcg BID when an intolerable dose was reached (see Figure: GRIPHON Study Titration and Dosing).^1,3 After 12 weeks, patients entered the maintenance phase of the study. Starting at week 26, doses could be increased at scheduled visits; dose reductions were allowed at any time. For each patient, the IMD was the dose the patient received for the longest duration until end of treatment (EOT; ie, last intake of double-blind treatment with UPTRAVI or placebo plus 7 days). For the majority (81.7%) of UPTRAVI-treated patients, the IMD represented the highest tolerated dose in the titration phase.²

Patients were categorized into 1 of 3 prespecified dose groups: low (200 and 400 mcg BID), medium (600, 800, and 1000 mcg BID) or high (1200, 1400, and 1600 mcg BID).^1,3 The proportion of patients in the low-, medium-, and high-dose groups was 23.2%, 31.2%, and 42.9%, respectively. Baseline characteristics did not appear to influence the highest tolerated dose of UPTRAVI. Additionally, the effect of UPTRAVI on the time to first morbidity or mortality event was consistent across the 3 prespecified dose groups.²

Phase 4 Data

SPHERE (SelexiPag: tHe usErs dRug rEgistry) is a United States (US)-based, multicenter, prospective, real-world, observational selexipag drug registry that reports the real-word outcomes of UPTRAVI treatment in routine clinical practice. Of the total 829 patients with pulmonary hypertension (WHO Group I-V) enrolled in SPHERE, 759 had PAH (WHO Group I), of whom 387 and 372 were newly (starting UPTRAVI ≤60 days before enrollment) and previously (starting UPTRAVI >60 days before enrollment) initiated on UPTRAVI, respectively.⁴

In 729 of 759 patients with PAH, the median maintenance dose of UPTRAVI was 1100 mcg BID (range, 1003200 mcg). In the overall PAH population (n=759), the median duration of UPTRAVI titration was 8.1 weeks (range, 1.126.9 weeks), with 671 (88.4%) patients (newly initiated, n=338 [87.3%]; previously initiated, n=333 [89.5%]) titrating at speeds slower than 200 mcg BID per week and 88 (11.6%) patients (newly initiated, n=49 [12.7%]; previously initiated, n=39 [10.5%]) titrating at speeds equal to or faster than 200 mcg BID per week. Of the 759 patients with PAH, 114 (15.0%), 238 (31.4%), and 310 (40.8%) patients received a BID maintenance dose of UPTRAVI 200-400 mcg, 600-1000 mcg, and >1200 mcg, respectively, whereas 97 (12.8%) patients received a different or an unrecorded UPTRAVI dose.^4,5

Information Regarding Dosing in Patients With Hepatic and Renal Impairment

Two prospective, open‐label studies evaluated the PK of selexipag and its active metabolite ACT‐333679 in healthy patients and in patients with mild, moderate, and severe hepatic impairment or severe renal function impairment (SRFI). A single dose of 200 mcg or 400 mcg was administered. The PK parameters were derived from plasma concentrationtime profiles. The data suggests that the starting dose of selexipag 200 mcg needs no adjustments in patients with mild or moderate hepatic impairment or SRFI. The small number of patients in this study limited the interpretation of the PK of selexipag in patients with severe hepatic impairment.⁹

Real-world Evidence

Kung et al (2018)¹⁰ presented dosing trends for UPTRAVI in real-world practice. Data were analyzed retrospectively from dosing and shipment records from specialty pharmacies. Patients were included if they had at least 6 months of exposure to UPTRAVI and 6 shipments. The time point of 6 months was selected as patients were likely to have finished titration and to have reached their maintenance dose. At the time of the analysis, 2490 patients were exposed to UPTRAVI for at least 6 months and had corresponding shipment data. At the time of the first maintenance shipment, 15.6%, 33.9%, and 50.5% of patients were receiving doses in the low-, medium-, and high-dose groups, respectively. More patients reached doses in the high-dose group. This is similar to GRIPHON, in which 23%, 31%, and 43% of patients reached maintenance doses in the low-, medium-, and high-dose groups. The overall median time to reach maintenance dose was 83 days which suggests that clinicians may be titrating UPTRAVI slower than on a weekly basis.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 25 June 2024.