UPTRAVI - PAH Associated With Connective Tissue Disease

SUMMARY

• The phase 3 GRIPHON trial was conducted to evaluate the long-term safety and efficacy of UPTRAVI in patients with symptomatic pulmonary arterial hypertension (PAH). In this event-driven study, UPTRAVI significantly reduced the risk of a morbidity/mortality event by 40% compared with placebo. The most common adverse events (AEs) in GRIPHON that occurred with higher frequency on UPTRAVI compared with placebo were headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing.¹
• At baseline, 334 patients (29%) were classified as PAH associated with connective tissue disease (PAH-CTD) in GRIPHON. A subgroup analysis showed that the treatment effect of UPTRAVI was consistent with the overall PAH study population among patients with PAH-CTD. The treatment effect in patients with different forms of connective tissue disease (CTD), including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and mixed CTD (MCTD), was also consistent across the subtypes.²
• Overall, in the PAH-CTD subgroup, 15 (9.1%) placebo-treated patients and 32 (19.2%) UPTRAVI-treated patients discontinued their study regimen prematurely because of an AE. The frequencies of AEs and serious AEs (SAEs) reported in the treatment groups were similar for the PAH-CTD subgroup and for the CTD subtypes.²
• SPHERE (NCT03278002), a United States (US)-based multicenter, prospective, observational, real-world registry study (November 2016 to March 2020), assessed the real-world outcomes of UPTRAVI in routine clinical practice and provided information on patient demographics and disease characteristics in the enrolled population. Of 759 patients with PAH, 205 (27%) had PAH-CTD overall, including 106 (27.4%) in the newly initiated group and 99 (26.6%) in the previously initiated group.³
  • In the interim analysis of the SPHERE study (data cutoff date, December 20, 2019; N=500), 132 (26.4%) patients had PAH-CTD, 246 (49.2%) had idiopathic PAH (IPAH), and 122 (24.4%) had other diagnoses.⁴ The median individualized maintenance dose of UPTRAVI in the PAH-CTD and IPAH subgroups was 1200 mcg twice daily (BID). More patients in the PAH-CTD subgroup (15.2%) vs the IPAH subgroup (11%) discontinued treatment due to AEs related to PAH disease progression.⁵
• A search of the scientific literature retrieved 3 additional real-world studies that described the use of UPTRAVI in patients with PAH-CTD; relevant information from these studies is summarized in this letter.^6-8
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^9-14

CLINICAL DATA

Phase 3 Study: GRIPHON

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 WHO group 1 PAH.

Efficacy: Primary Endpoint

UPTRAVI decreased the risk of a morbidity/mortality event vs placebo (risk reduction) by 40% (hazard ratio [HR], 0.60; 99% confidence interval [CI], 0.46-0.78; P<0.001).¹ The beneficial effect of UPTRAVI was primarily attributable to a reduction in hospitalization for worsening of PAH and a reduction in disease progression events.

Safety and Tolerability

The most common AEs in GRIPHON that occurred with higher frequency (≥5%) on UPTRAVI compared to placebo were headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing. The proportion of patients discontinuing treatment due to an AE was 14.3% on UPTRAVI and 7.1% on placebo.

Please refer to US-SR-8116 for full details on GRIPHON.

Subgroup Analyses of PAH-CTD Patients From the GRIPHON Study

The PAH-CTD population was a prespecified subgroup for evaluation of the primary endpoint, however, the more detailed analyses described were post hoc and exploratory in nature. Therefore, sample size should be considered, and results should be interpreted with caution.²

Patients and Treatment Exposure

Of the 1156 patients enrolled in GRIPHON, 334 were diagnosed with PAH-CTD. This comprised 170 with PAH associated with SSc (PAH-SSc), 82 with PAH associated with SLE (PAH-SLE), 37 with PAH associated with MCTD (PAH-MCTD), and 45 in whom the underlying CTD was not further defined (PAH-CTD-other). Due to smaller patient numbers, and corresponding number of primary endpoint events, the PAH-MCTD and PAH-CTD-other groups are presented as a single group (PAH-MCTD/CTD-other). Baseline characteristics of the PAH-CTD subgroup and the 3 CTD subtypes are shown in the Table: Patient Characteristics at Baseline.

UPTRAVI Dose

In the PAH-CTD subgroup, 40 patients (24%) had their individualized maintenance dose in the low-dose group (200 or 400 mcg BID), 45 (26.9%) in the medium-dose group (600, 800, or 1000 mcg BID) and 75 (44.9%) in the high-dose group (1200, 1400, or 1600 mcg BID). These proportions were similar to those observed in the overall GRIPHON population and there were no notable differences between CTD subtypes and the overall PAH-CTD subgroup.

Response to UPTRAVI Treatment

Among patients with PAH-CTD, UPTRAVI reduced the risk of a morbidity/mortality event by 41% vs placebo (HR, 0.59; 95% CI, 0.41-0.85). This response was consistent with that observed in the overall GRIPHON population. The treatment effect was consistent in patients with PAH-CTD irrespective of PAH therapy at baseline (interaction P=0.87) and across the CTD subtypes (interaction P=0.89) (Figure: Effect of UPTRAVI on the Primary Composite Endpoint of Morbidity/Mortality by PAH Therapy at Baseline and CTD Subtype).

In the PAH-CTD subgroup, the 6-minute walk distance (6MWD) decreased by a median of 10 m from baseline in the placebo group and 2 m from baseline in the UPTRAVI group (treatment effect, 12 m [95% CI, -4 to 27]). With respect to N-terminal pro-B-type natriuretic peptide (NT-proBNP), a median (quartile [Q]1-Q3) decrease from baseline to week 26 of -55.5 ng/L (-282.5 to 48) was observed with UPTRAVI, compared with a median increase of 13 ng/L (-99 to 404) with placebo (treatment effect, -140 [95% CI, -265 to -51]).

The frequencies of AEs and SAEs reported in the treatment groups were similar for the PAH-CTD subgroup and for the CTD subtypes. The most frequent AEs are listed in the Table: Most Frequent AEs Among Patients With PAH-CTD. AEs associated with therapies that target the prostacyclin (PGI2) pathway, occurring during the titration and maintenance periods, were reported (please refer to the full publication for the breakdown of AEs). Irrespective of the underlying CTD, these AEs were generally reported more frequently during the 12-week titration period.

Real-world Evidence

SPHERE Registry

SPHERE (SelexiPag: tHe usErs dRug rEgistry; NCT03278002) was a US-based, multicenter, prospective, observational, real-world registry study (November 2016 to March 2020) that assessed the real-world outcomes of UPTRAVI in routine clinical practice. The study also provides information regarding patient demographics and disease characteristics in the enrolled population.³

Of the total 829 adult (≥18 years of age) patients with pulmonary hypertension (WHO group 1-5) enrolled in SPHERE, 759 had PAH (WHO group 1), 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.³

Of the 759 patients with PAH, 205 (27%), 106 (27.4%), and 99 (26.6%) were with PAH-CTD in the overall, newly initiated, and previously initiated groups, respectively. However, treatment outcomes specific to the PAH-CTD population among the overall PAH population enrolled in SPHERE (n=759) are not available.³

SPHERE Registry Interim Data

Of the first 500 patients enrolled, 132 (26.4%) had PAH-CTD, 246 (49.2%) had IPAH, and 122 (24.4%) had other diagnoses.^4,5 Selected baseline characteristics are presented in the Table: Patient Demographics and Disease Characteristics at UPTRAVI Initiation.

UPTRAVI Dosing and Titration

Dose titration pattern and time to maintenance dose of UPTRAVI were similar in the PAH-CTD and IPAH subgroups. The median individualized maintenance dose in both subgroups was 1200 mcg BID.⁵

Safety

More patients in the PAH-CTD subgroup (15.2%) vs the IPAH subgroup (11.0%) discontinued treatment due to AEs related to PAH disease progression (See Table: AEs Leading to Treatment Discontinuation in >2% of Patients in Any Group).⁵

Giuliani et al (2025)⁶ conducted a post hoc analysis of the INSPECTIO study evaluating the clinical and hemodynamic characteristics of patients with PAH-CTD at baseline. They assessed the longitudinal evolution of noninvasive low-risk criteria over 12 months and examined the response to PAH-specific therapy. Additionally, a comparison between PAH-CTD and non-PAH-CTD groups was performed to determine differences between these subpopulations and to present current evidence on treatment patterns and risk-based management approaches in PAH-CTD.

Of the overall study population of 176 evaluable patients, 64 were classified into the PAH-CTD group and 112 were classified into the non-PAH-CTD group. Patients included in the study had a confirmed diagnosis of PAH via right heart catheterization (RHC), with a median time from diagnosis to study enrollment of 18.3 months.

PAH-CTD vs non-PAH-CTD patients were significantly older (mean age: 66.4 vs 59.6 years; P=0.0005) and more frequently female (93.8% vs 64.3%; P<0.0001), with a significantly shorter mean (standard deviation) time from RHC diagnosis to enrollment (28.4 [36.97] vs 57.3 [81.61]; P=0.0456). No statistically significant differences were observed in height, weight, or body mass index.

SSc/scleroderma was the most prevalent underlying CTD (78.2%; 50/64), followed by primary Sjögren’s syndrome (7.8%) and antisynthetase syndrome (4.7%). The most frequently reported comorbidities at enrollment were metabolic disorders (51.6%), vascular disorders (48.4%), and gastrointestinal conditions (42.2%).

At baseline, all patients in both the PAH-CTD and non-PAH-CTD groups were receiving PAH-specific therapy. Treatment distribution strategies differed between the groups, with a higher proportion of patients in the PAH-CTD group vs the non-PAH-CTD group receiving double combination therapy (56.3% vs 38.4%); triple therapy was more frequently administered in the non-PAH-CTD group vs the PAH-CTD group (32.1% vs 18.8%). Monotherapy was reported in 25.0% of PAH-CTD group and 29.5% of non-PAH-CTD group. These differences in treatment patterns were not statistically significant (P=0.0533).

In the PAH-CTD group, 17 patients (26.6%) showed improvement in at least 1 of 3 noninvasive low-risk criteria from baseline to month 12, whereas 7 patients (10.9%) met all 3 noninvasive low-risk criteria at month 12. See Table: Change in the Number of Noninvasive Low-Risk Criteria.

The PAH-CTD group showed a consistently higher proportion of patients in the intermediate-risk category compared with the non-PAH-CTD group; however, this difference was not statistically significant.

In the PAH-CTD group, the mean 6MWD distance increased from 336.5 m at baseline to 369.2 m at month 12 (Δ=+12.1 m; calculated based on 41 patients with measurements at baseline and 12 months), with no statistically significant change (P=0.4091). In the non-PAH-CTD group, the mean 6MWD decreased from 407.7 m at baseline to 400.2 m at month 12 (Δ=-5.7 m; based on 69 patients with measurements at baseline and month 12), with no statistically significant change (P=0.6118). Between-group comparisons showed no statistically significant difference over time (P=0.3357).

In the PAH-CTD group, the brain-type natriuretic peptide (BNP) level did not show a statistically significant change from baseline to month 12 (P=0.6022), based on a small sample size (n=18). The NT-proBNP level decreased within the CTD group (n=32), but this change was not statistically significant (P=0.5384). A significant reduction in NT-proBNP was observed in the non-PAH-CTD group vs the PAH-CTD group (94 vs -498 ng/L; P=0.0129). No significant between-group differences were reported for the BNP level.

Over the 12-month observation period, echocardiographic and hemodynamic parameters in the PAH-CTD group remained stable overall. Hemodynamic changes were broadly consistent with the echocardiographic profile. Vital signs, apart from the heart rate, did not show statistically significant changes.

Limitations of the study:⁶

• This post hoc analysis is subject to limitations related to the original study’s design and data collection, which may introduce biases not addressed in a prespecified analysis.
• In addition, the small sample size (n=64) may limit the generalizability of the findings and the power to detect statistically significant changes in certain secondary endpoints.

Gaine et al (2024)⁷ described the characteristics, treatment patterns, tolerability, and outcomes from the ongoing observational, multicenter, prospective EXPOSURE (EXPloratory Observational Study of Uptravi in Real-lifE) study in patients with PAH-CTD treated with UPTRAVI in clinical practice.

The analysis included PAH-CTD (n=178) patients newly initiated on UPTRAVI with follow-up information reported from September 2017 to November 2022. Of the PAH-CTD patients, 71% had SSc, 8% had MCTD, 7% had SLE, 6% had rheumatoid arthritis, 4% had Sjögren’s syndrome, and 3% had undifferentiated CTD. The median age of the PAH-CTD population was 68 years and 88% were females, with a median time since diagnosis of 1.7 years. At baseline, 1%, 33%, 63%, and 3% had WHO FC I, II, III, and IV, respectively.

The median titration duration for PAH-CTD patients was 1.5 months. Of the 151 PAH-CTD patients who completed titration, the median UPTRAVI individualized dose was 600 mcg BID. By distribution, the dose group comprised of 30% as low (200 or 400 mcg BID), 41% as medium (600, 800, or 1000 mcg BID), and 23% as high (1200, 1400, or 1600 mcg BID) in comparison to the low (24%), medium (27%), and high (45%) dose groups of PAH-CTD patients in the GRIPHON study. Eleven patients did not receive a dose consistent with the dosing groups.

UPTRAVI was initiated as a triple oral therapy in 142 (80%) PAH-CTD patients, with 131 (92%) taking UPTRAVI in combination with both an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 inhibitor (PDE-5i) and 11 (8%) taking UPTRAVI in combination with an ERA and sCG stimulator. Among the 13% of PAH-CTD patients initiating double therapy, UPTRAVI was initiated as combination therapy with ERA in 13 (57%) patients and with PDE-5i in 10 (43%) patients. The majority of the PAH-CTD patients (56%) initiating triple oral combination therapy escalated from double oral combination therapy. Most PAH-CTD patients were on double therapy for ≥1 year before treatment escalation with UPTRAVI. Of the 91 (61%) PAH-CTD patients on triple therapy at 6 months postbaseline, 89 patients remained on triple therapy from baseline, and 2 patients escalated from double therapy at baseline. At 6 months postbaseline, 21/143 (15%) patients de-escalated from triple to double combination therapy, whereas 89/143 (62%) remained on triple therapy. At 12 months postbaseline, majority of the PAH-CTD patients (n=122) maintained the treatment regimen with fewer follow-up observations (15% patients on double therapy; 56% patients on triple therapy).

One-year Kaplan-Meier (KM) estimates for PAH-CTD patients free from hospitalization were 63% (95% CI, 46-76). The 1-year and 2-year KM estimates for IPAH patients free from hospitalization were 76% (95% CI, 66-83) and 66% (95% CI, 54-76), respectively. The 1-year and 2-year KM survival estimates for PAH-CTD patients were 85% (95% CI, 69-93) and 71% (95% CI, 49-84), respectively. The 1-year, 2-year, and 3-year KM survival estimates for IPAH patients were 93% (95% CI, 85-97), 87% (95% CI, 75-93), and 82% (95% CI, 67-90), respectively. The incidence rates, mortality rates, and hospitalizations are reported in Table: Hospitalizations and Mortality During the UPTRAVI Exposure Period.

UPTRAVI discontinuation occurred in 79 (44%) PAH-CTD patients, with a median time to discontinuation of 4.3 months. The reasons for discontinuation were due to tolerability/AEs (20%), death (16%), PAH disease progression (4%), administrative reasons (2%), treatment non-compliance (<1%), and unknown reasons (<1%). There were 70 (39%) patients who experienced an AE while on UPTRAVI. The most frequent AEs occurring in ≥5% of patients were diarrhea (11%), headache (7%), and dyspnea (5%).

Limitation of the study:⁷

• There was a lack of diversity of CTD subtypes within the EXPOSURE study as the underlying disease was mainly SSc (71%).

Tsang et al (2023)⁸ presented results from a retrospective cohort study using the US-based Optum’s de-identified Clinformatics^® Data Mart database that evaluated the effect of oral UPTRAVI on clinical outcomes in patients with PAH (N=317) with (15.2% [n=80]) and without (74.8% [n=237]) CTD comorbidities. At baseline, patients in the PAH-CTD vs PAH non-CTD group were younger (62.7 vs 64.8 years; P=0.221), consisted of proportionately more female (82.5% vs 72.0%; P=0.065), and had a lower mean Charlson Comorbidity Index score (2.3 vs 3.1; P=0.013). The most common comorbidities in PAH-CTD cohort were hypertension (91.3%), coronary artery disease (42.5%), and interstitial lung disease (40%). The most common comorbidities in PAH without CTD cohort were hypertension (84.4%), chronic obstructive pulmonary disease (55.7%) and apnea (48.5%). After adjusting for the baseline demographics and clinical characteristics, among patients with PAH-CTD and PAH non-CTD, no statistically significant difference was reported in time to PAH-related hospitalization, time to all cause hospitalization, and time to disease progression (Table: Adjusted Outcomes for Patients With PAH-CTD Compared to PAH Non-CTD Patients Prescribed UPTRAVI).

Limitations of the study:⁸

• There was lack of specificity of ICD codes in the WHO PAH clinical classification and PAH etiology, and no specific ICD codes for PAH.
• The diagnosis code on a medical claim does not indicate the positive presence of a disease and a claim for filled prescription does not imply that the medication was consumed or taken as prescribed.
• The varying definition of PAH disease progression across different studies may result in conflicting information on PAH disease progression.
• Undifferentiated CTD was not considered in the study, which could have introduced misclassification of PAH patients in some cases.
  • Due to the small sample size of PAH-CTD cohort, the study did not examine CTD subtype and CTD medications used.
• The analysis may be underpowered to detect small differences between PAH with and without CTD, due to the small sample size.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 27 May 2026.