SUMMARY

• In the pivotal phase 3 study, GRIPHON (Prostacyclin [PGI₂] Receptor agonist In Pulmonary arterial HypertensiON), UPTRAVI 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.¹
• SPHERE (SelexiPag: tHe usErs dRug rEgistry) registry study showed that the median maintenance dose of UPTRAVI was 1100 mcg BID in 729 of 759 patients with pulmonary arterial hypertension (PAH). In the overall 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; 97 (12.8%) patients received a different or an unrecorded UPTRAVI dose, the specific outcomes of which are not available.^2,3
• EXPOSURE (EXPloratory Observational Study of Uptravi in Real-lifE) is an ongoing, Europe and Canada-based, multicenter, prospective, observational study of PAH patients initiating PAH-specific therapy. Three dose groups were defined (low, medium, and high) in the study based on patients’ individualized dose (ID) at the end of titration. Overall, 6% (n=36) of patients received doses outside of the defined groups, for reasons that were not captured in EXPOSURE.^4,5
• A real-world, retrospective, observational cohort study evaluating adult patient outcomes across UPTRAVI dose ranges in the United States (US) using the Komodo closed-claims database reported the UPTRAVI dosage adjustments in varied patterns, across all the ID strata. Increase in maintenance dose by ≥200 mcg occurred ≥1 time in 112 (67.1%) patients in the low-ID group, 91 (48.1%) in the medium-ID group, and 75 (27.0%) in the high-ID group (standardized mean difference [SMD], 0.69). Decrease in the maintenance dose by ≥200 mcg occurred ≥1 time in 93 (55.7%) patients in the low-ID group, 79 (41.8%) in the medium-ID group, and 58 (20.9%) in the high-ID group (SMD, 0.46).⁶
• A retrospective study examining real-world dosing patterns of UPTRAVI, and the effect of prior prostacyclin pathway agent (PPA) use on UPTRAVI dosing and discontinuation reported that the mean time to reach the individualized maintenance dose was 14 weeks (greater than that specified in the protocol outlined in the GRIPHON study [12 weeks]). The median time to reach the individualized maintenance dose was 56 days in the ≤weekly cohort and 86 days in the >weekly cohort.⁷
• Another retrospective study examining real-world dosing patterns of UPTRAVI reported that the overall median time to reach the maintenance dose was 83 days, suggesting that clinicians may be titrating UPTRAVI slower than on a weekly basis.⁸
• Additional studies are included in the REFERENCES section for your review.^9-13 
• Administration of doses not specified in the UPTRAVI product label is not recommended.

CLINICAL DATA

GRIPHON Study

In the pivotal phase 3 study, GRIPHON, UPTRAVI was initiated at 200 mcg 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. To determine the highest tolerable dose, the dose was reduced by 200 mcg BID when an intolerable dose was reached.¹

Alternative Dosing and Titration Schedule

SPHERE Registry

SPHERE (SelexiPag: tHe usErs dRug rEgistry) is a US-based, multicenter, prospective, observational, real-world registry. Adult patients (≥18 years of age) receiving UPTRAVI in routine clinical practice were enrolled from November 2016 to March 2020 and followed for up to 18 months. The study provided data on the realworld outcomes of UPTRAVI treatment in the US along with information regarding patient demographics and disease characteristics in the enrolled population.²

Of the total 829 patients with pulmonary hypertension (PH; World Health Organization [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.²

In 729 of 759 patients, the median maintenance dose of UPTRAVI was 1100 mcg BID (range, 100-3200 mcg). In the overall PAH population (n=759), the median duration of UPTRAVI titration was 8.1 weeks (range, 1.1-26.9 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. One hundred and fourteen (15.0%), 238 (31.4%), and 310 (40.8%) patients received a BID maintenance dose of UPTRAVI 200-400 mcg, 6001000 mcg, and >1200 mcg, respectively, whereas 97 (12.8%) patients received a different or an unrecorded UPTRAVI dose, the specific outcomes of which are not available.^2,3

Four-Strata Risk Assessment of EXPOSURE Study

EXPOSURE (EXPloratory Observational Study of Uptravi in Real-lifE) is an ongoing, Europe and Canada-based, multicenter, prospective, observational study of PAH patients initiating PAH-specific therapy. Adult patients with Group I PH initiating a new PAH-specific therapy within 1 month of or at enrollment were enrolled from September 2017 to November 2022 and followed for up to 3 years. This study provided data on real-world characteristics, treatment patterns, and outcomes of patients with PAH, categorized by risk status when initiated with UPTRAVI.⁴

Of the 698 patients enrolled with PAH, 163 did not have sufficient data to allow for risk evaluation, leaving 535 patients for baseline risk assessment calculations. Patients with available baseline data were grouped into low (n=76), intermediate-low (n=168), intermediate-high (n=182), or high risk (n=109) of 1-year mortality according to the European Society of Cardiology and the European Respiratory Society (ESC/ERS) 4-strata method.^4,5

There were 3 defined dose groups based on patients’ ID at the end of titration: low (200 or 400 mcg BID), medium (600, 800 or 1000 mcg BID), and high dose (1200, 1400, or 1600 mcg BID). A total of 36 patients received doses outside of the defined dose groups for reasons not captured in EXPOSURE: 9 patients in the low risk group received alternative doses (50 mcg [n=1], 300 mcg [n=5], 500 mcg [n=2], and 2000 mcg [n=1] BID); 6 in the intermediate-low risk group (300 mcg [n=3] and 700 mcg [n=3] BID); 7 in the intermediate-high risk group (300 mcg [n=1], 500 mcg [n=2], 700 mcg [n=3], and 1500 mcg [n=1] BID); 4 in the high risk group (100 mcg [n=2], 300 mcg [n=1], and 700 mcg [n=1] BID). Overall, patients received 50 mcg (n=1), 100 mcg (n=5), 300 mcg (n=12), 500 mcg (n=6), 700 mcg (n=9), 900 mcg (n=1), 1500 mcg (n=1), and 2000 mcg (n=1) BID.^4,5

Alternative Titration Schedule

Real-World Evidence

Burger et al (2024)⁶ conducted a real-world, retrospective, observational cohort study to evaluate patient outcomes across UPTRAVI dose ranges in the US using the Komodo closed-claims database between December 15, 2015, and June 30, 2022. Eligibility criteria included adult patients treated with UPTRAVI during the study period and had ≥1 inpatient or 2 outpatient records with an International Classification of Diseases, Ninth or Tenth Revision (ICD-9/ ICD-10) diagnosis code for PH (on separate days, with ≥1 PH diagnosis prior to UPTRAVI initiation). The index date was UPTRAVI ID date defined as receipt of the first maintenance UPTRAVI dose pack used for >60 consecutive days.

A total of 1186 eligible patients with PAH were included in the study, of whom 634 (53.5%) completed the titration phase and reached their UPTRAVI ID, and categorized into high- (43.8%), medium- (29.8%), and low- (26.3%) ID strata. Across all ID strata, adjustments in UPTRAVI dosing occurred in varied patterns. In the high-ID group, a higher proportion of patients remained at their initial ID with fewer dose adjustments over time compared with the low- and medium-ID groups. The UPTRAVI maintenance dose was adjusted in 121 (72.5%), 117 (61.9%), and 96 (34.5%) patients in the low-, medium-, and high-ID group patients, respectively (SMD, 0.63). An increase in the maintenance dose by ≥200 mcg occurred ≥1 time in 112 (67.1%) patients in the low-ID group, 91 (48.1%) patients in the medium-ID group, and 75 (27%) patients in the high-ID group (SMD, 0.69). A decrease in maintenance dose by ≥200 mcg occurred ≥1 time in 93 (55.7%) patients in the low-ID group, 79 (41.8%) patients in the medium-ID group, and 58 (20.9%) patients in the high-ID group (SMD, 0.46).⁶ The details on UPTRAVI dose adjustments are summarized in the Table: UPTRAVI Dose Adjustments - Overall and According to Initial ID Reached.

Palevsky et al (2020)⁷ conducted a retrospective study using de-identified specialty pharmacy data from January 01, 2016 to March 29, 2019, to examine real-world dosing patterns of UPTRAVI and the effect of prior PPA use on UPTRAVI dosing and discontinuation. Adult patients (≥18 years old) who attained their individualized maintenance doses were included. These patients were further categorized into 2 cohorts (based on dosing pattern and PPA use), which each had 2 subcategories ([≤weekly cohort: patients who received titration ≤8 days/200 mcg BID; >weekly cohort: patients who received titration >8 days/200 mcg BID] and [prior-use cohort: patients with a history of PPA use; naïve cohort: patients without a history of PPA use]).

Of the 3931 patients who attained their individualized maintenance doses, 2869 (73%) were female, and the mean (±standard deviation [SD]) age was 57.9 (±14.8) years. The mean time to reach the individualized maintenance dose was 14 weeks (greater than that specified in the protocol outlined in the GRIPHON study [12 weeks]).

The ≤weekly and >weekly cohorts included 550 (14%) and 3381 (86%) patients, respectively. The median time to reach the individualized maintenance dose was 56 days in the ≤weekly cohort and 86 days in the >weekly cohort. The median time to reach the individualized maintenance dose for patients on low, medium, and high individualized maintenance doses were 73, 83, and 89 days, respectively. Results pertaining to patients with (n=523; 13.3%) and without (n=3408; 86.7%) a history of PPA use are presented in Table: Outcomes in Patients With and Without a History of PPA Use.

The lack of information on whether PAH was incident or prevalent, the status of existing comorbidities, whether patients were on concomitant mediations, and if the medication was taken as prescribed was a set of limitations of this study. Additionally, the inability to identify if patients started the maintenance phase with a titration package and the context of treatment discontinuation were also noted as the study limitations.

Kung et al (2018)⁸ conducted a retrospective study using dosing and shipment records from specialty pharmacies to examine the real-world dosing patterns of UPTRAVI. Patients with ≥6 months of exposure to UPTRAVI and 6 shipments were included.

At the time of analysis, 2490 patients were exposed to UPTRAVI for ≥6 months and had corresponding shipment data. The overall median time to reach the maintenance dose was 83 days, suggesting 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 28 October 2025.