UPTRAVI - Treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

SUMMARY

• UPTRAVI is not approved by the regulatory agencies for use in chronic thromboembolic pulmonary hypertension (CTEPH). Johnson & Johnson does not recommend the use of UPTRAVI in a manner that is inconsistent with the approved labeling.
• SELECT, a phase 3 study, was designed to assess the efficacy and safety of UPTRAVI as an add-on to standard of care (SOC) therapy in adults with inoperable or persistent/recurrent CTEPH, after pulmonary endarterectomy (PEA) and/or balloon pulmonary angioplasty (BPA). The primary endpoint, pulmonary vascular resistance (PVR), showed no statistically significant difference which led to the discontinuation of the study for futility, as per the pre-defined interim analysis.¹
• Another phase 3 study in Japanese patients assessed the efficacy and safety of UPTRAVI in the treatment of patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension (PH) after PEA and/or BPA. In the full analysis set (FAS), the mean difference in PVR between the UPTRAVI group and placebo group after 20 weeks of treatment was -93.5 (95% confidence interval [CI], -156.8 to -30.3) dyn·sec/cm⁵, indicating a significant decrease in PVR in the UPTRAVI group compared with the placebo group (P=0.006). The adverse drug reactions (ADRs) that occurred at a rate of ≥10% in the UPTRAVI group were headache, diarrhea, nausea, malaise, pain in the jaw, decreased appetite, myalgia, vomiting, and arthralgia.²
• A phase 2 study in Japanese patients assessed the efficacy and safety of UPTRAVI in the treatment of CTEPH. In the per-protocol analysis set, the change (mean±standard deviation [SD]) from baseline to week 17 in PVR was -104±191 dyn·sec/cm⁵ in the UPTRAVI group and 26±180 dyn·sec/cm⁵ in the placebo group. The most frequently reported adverse events (AEs) in the UPTRAVI group (experienced at a rate ≥10%) were headache, diarrhea, pain in jaw, myalgia, hot flush, malaise, flushing, nausea, and arthralgia.³
• A single-center, retrospective, observational study evaluated UPTRAVI monotherapy vs riociguat monotherapy before BPA in newly diagnosed, treatment-naïve patients with inoperable CTEPH. Improvements in mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were reported after treatment with UPTRAVI and riociguat. Adjusted analyses showed no significant between-group differences in mPAP or PVR improvement; however, riociguat was associated with significantly greater improvements in cardiac output (CO), cardiac index, and stroke volume compared with UPTRAVI.⁴
• A prospective, randomized investigational study evaluated the difference of efficacy and safety of UPTRAVI and riociguat in treatment-naïve patients with inoperable CTEPH. In the UPTRAVI group, the median PVR decreased from 10.35 Wood units (WU) (interquartile range [IQR], 7.45-15.8) at baseline to 7.85 WU (IQR, 6.05-11.3) at follow-up (P=0.006). Median cardiac index increased from baseline to follow-up (P=0.037), and median arterial oxygen saturation (SaO₂) decreased over the same period (P=0.02). In the riociguat group, the median PVR decreased from 7.09 WU (IQR, 6.03-10.25) at baseline to 5.39 WU (IQR, 3.23-6.24) at follow-up (P=0.002). A decrease in median (IQR) mPAP was observed from baseline to follow-up (P=0.025), and median (IQR) mean arterial blood pressure also decreased significantly (P=0.025).⁵
• Two retrospective analyses^6,7 of mixed cohorts, including a small number of patients with CTEPH, and 5 publications^8-12 describing single cases of patients with CTEPH, who were treated with UPTRAVI are included as additional citations.
• Please note that this document does not contain any reference to the local prescribing information. For complete prescribing recommendations about UPTRAVI in your country, please refer to your local product information.

CLINICAL DATA

Information From Phase 3 Study - SELECT

Kim et al (2024)¹ reported data of a multicenter, randomized, double-blind, placebo-controlled, parallel-group, group-sequential, phase 3, SELECT study designed to investigate the efficacy and safety of UPTRAVI as an add-on to SOC therapy in adult patients with inoperable or persistent/recurrent CTEPH, after PEA and/or BPA. Patients were randomized 1:1 to receive UPTRAVI or placebo. Treatment with UPTRAVI was initiated at 200 mcg twice daily (BID) and titrated in weekly increments of 200 mcg up to 1600 mcg BID until the individual maximum tolerated dose was reached.

Inclusion Criteria

Adult patients (18-85 years) with inoperable (with or without BPA) or persistent/recurrent CTEPH after PEA and/or BPA; World Health Organization [WHO] functional class [FC], I-IV) with a 6-minute walk distance [6MWD] of 100-450 m; receiving full anticoagulation therapy for ≥90 days.

• Patients were recruited in 2 sequential cohorts.
  • The hemodynamic set consisted of the first 91 randomized patients who were to undergo a right-heart catheterization (RHC); and left-heart catheterization (LHC), if needed, at week 20, along with overall study assessments.
  • The nonhemodynamic cohort consisted of the remaining patients who did not undergo a post-baseline hemodynamic assessment.

The mPAP in all patients was ≥25 mmHg and PVR for hemodynamic and nonhemodynamic sets were ≥5 and ≥3.75 WU, respectively, collected ≥90 days after last PEA or BPA, as applicable.

Endpoints

The primary endpoint was PVR (at rest within 2-5 hours post-dose) at week 20, expressed as percent of baseline PVR in the hemodynamic set.

The secondary endpoints were change from baseline to week 26 in 6MWD, time to clinical worsening (TTCW; defined as any of the following: all-cause death, non-planned PH-related hospitalization, or PH-related deterioration), and change from baseline to week 26 in PAH-Symptoms and Impact questionnaire (SYMPACT^®) cardiopulmonary symptoms and cardiovascular symptoms domains, Borg Dyspnea Index/Borg category ratio 10 Scale (BDI/Borg CR10^®), N-terminal pro-B-type natriuretic peptide (NT‑proBNP).

Study Results

A total of 128 patients were randomized (FAS, included patients assigned to a study treatment, UPTRAVI, n=64; placebo, n=64) and received study treatment (safety analysis set [SAF, assessed patients who received 1 or more doses of the study treatment], UPTRAVI, n=64; placebo, n=64). In the FAS, most of the patients in the UPTRAVI group (12 [18.8%]) were on combination therapy with endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitor (PDE-5i) compared with the placebo group (4 [6.3%]), and majority of the patients in placebo group (13 [20.3%]) were on ERAs and soluble guanylate cyclase combination therapy compared with the UPTRAVI group (6 [9.4%]). Selected baseline characteristics are presented in the Table: Selected Baseline Characteristics. Please refer to the full text of the publication for complete details on the baseline characteristics.

Efficacy

The primary endpoint, PVR, showed no statistically significant difference which led to the discontinuation of the study for futility, as per the pre-defined interim analysis. The between-treatment geometric least squares (LS) mean ratio of PVR (week 20/baseline) was 0.95 (95% CI, 0.84-1.07; P=0.412) in the hemodynamic set. In the hemodynamic set, the mean (SD) change in PVR from baseline to week 20 for UPTRAVI and placebo were -92.4 (163.4) and -82.8 (179) dyn·sec/cm⁵, respectively. There were no treatment differences for any secondary endpoints.

Safety

Safety was assessed in the SAF. The mean (SD) treatment duration of UPTRAVI and placebo were 11.8 (8) months and 11.4 (7.7) months, respectively. The individual maximum tolerated dose for UPTRAVI, and placebo were 1001.6 (534.7) mcg and 1271.9 (524.2) mcg BID. In both the UPTRAVI (45.3%, n=29) and placebo (71.9%, n=46) groups, the commonly reached individual maximum tolerated dose was high dose (1200, 1400, or 1600 mcg BID). Higher rates of AEs (≥1) were reported in the UPTRAVI group (n=63, 98.4%) compared with the placebo group (n=53, 82.8%).

During the double-blind period, 2 deaths were reported from each group, all of which were treatment-emergent (occurring within 3 days after the last dose of study treatment). The causes of death were right ventricular (RV) failure and pneumonia in the UPTRAVI group and acute respiratory failure and death in the placebo group. In the UPTRAVI group, another death was reported due to multiple organ dysfunction syndrome 11 days after the last dose of UPTRAVI in the double-blind period. A summary of safety results during the double-blind treatment period (SAF) is presented in the Table: Safety Results (SAF).

Information From a Phase 3 Study

Ogo et al (2021)² reported data of a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group, comparison study designed to investigate the efficacy and safety of UPTRAVI in Japanese patients with inoperable CTEPH or persistent/recurrent PH after PEA and/or BPA. A total of 78 patients were randomized 1:1 to receive oral UPTRAVI (200-1600 mcg BID; n=39) or placebo (n=39) for 20 weeks. Treatment with UPTRAVI was initiated at 200 mcg BID and titrated in increments of 200 mcg with a minimum interval of 3 days, up to 1600 mcg BID. The maximum tolerated dose was determined for each subject over 12 weeks and was subsequently maintained for 8 weeks. The distribution of the maintenance doses is presented in the Table: Dose Distribution (FAS).

Inclusion and Exclusion Criteria

In addition to patients with inoperable CTEPH or persistent/recurrent PH after PEA and/or BPA, the inclusion criteria consisted of patients 20-85 years old with CTEPH (as confirmed by 2 or more of the following to reveal deficient pulmonary blood flow: pulmonary ventilation/perfusion scan, pulmonary angiography, and a chest computed tomography scan) and who could not undergo PEA due to the presence of organized peripheral thrombus, high-risk status (eg, comorbidities or old age), or other reasons (eg, refusal to undergo surgery). The pulmonary hemodynamic variables at rest and set at baseline as determined by RHC included mPAP ≥25 mmHg, pulmonary artery wedge pressure (PAWP) ≤15 mmHg, and PVR >360 dyn·sec/cm⁵. PEA or BPA during the study were not allowed.

Study Results

The baseline characteristics are presented in the Table: Baseline Characteristics (FAS). Of the 39 patients in the UPTRAVI group, 5 discontinued the study (3 developed AEs, and 2 withdrew their consent), while of the 39 patients in the placebo group, 4 discontinued the study (because of AEs).

Primary Endpoint

The primary endpoint was the change in resting PVR from baseline to week 20. The change in PVR from baseline to week 20 in the UPTRAVI group was -98.2±111.3 dyn·sec/cm⁵, whereas that in the placebo group was -4.6±163.6 dyn·sec/cm⁵. The mean difference in PVR between the UPTRAVI and placebo groups after 20 weeks of treatment was -93.5 dyn·sec/cm⁵ (95% CI, -156.8 to -30.3), indicating a significant decrease in PVR in the UPTRAVI group compared with the placebo group (P=0.006). Results were consistent among all subgroup analyses of PVR by sex, age, disease classification, presence/absence of prior PEA/BPA, presence/absence of concomitant riociguat or ERA, and baseline PVR.

Secondary Endpoints

The results for secondary endpoints are presented in the Table: Changes in Pulmonary Hemodynamic Variables, 6MWD, Borg Dyspnea Scale score, NT-proBNP, EQ-5D-5L and WHO FC (FAS).

Safety Endpoints

The safety endpoints were ADRs, laboratory test values, vital signs, and electrocardiogram at each visit. Most ADRs occurred in the early phase of treatment and at low doses. Most patients improved or recovered with symptomatic treatment without discontinuation of the study drug.

ADRs occurred in 35 of 39 patients (89.7%) in the UPTRAVI group. The AEs associated with UPTRAVI are presented in the Table: AEs Related to UPTRAVI Usage (FAS).

Of the 39 patients in the UPTRAVI group, 3 discontinued the study due to AEs (diarrhea, nausea, and vertigo in 1 patient and nausea and headache in 1 patient each), while of the 39 patients in the placebo group, 4 discontinued the study due to AEs (abdominal discomfort, decreased white blood cell count, headache, and cardiorespiratory arrest in 1 patient each).

Serious AEs in the study included atrial tachycardia and RV failure in 1 patient (2.6%), each, in the UPTRAVI group, and cardiorespiratory arrest, colon cancer, and hemoptysis in 1 patient (2.6%), each, in the placebo group. The atrial tachycardia that occurred in the UPTRAVI group, for which a causal relationship could not be ruled out, was moderate. No abnormal laboratory test values or electrocardiography results that could be considered a clinical problem occurred throughout the study period.

Information From a Phase 2 Study

Tanabe et al (2020)³ reported data of a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group, comparison study, designed to investigate the efficacy and safety of UPTRAVI in Japanese patients with non-operated or persistent/recurrent CTEPH. A total of 34 patients were randomized 3:1 to receive oral UPTRAVI (100-800 mcg BID; n=25) or placebo (n=9) for 17 weeks. At baseline, in the UPTRAVI treatment group, a total of 13 patients were in WHO FC II, 11 patients in FC III and 1 patient in FC IV, compared with 5 patients in WHO FC II, 3 patients in FC III, and 1 patient in FC IV in the placebo group. Efficacy data are presented below for the per-protocol analysis set (N=28), and safety data are presented for the safety analysis set (N=34).

Primary Endpoint

The primary endpoint was the change from baseline to week 17 in PVR at rest. In the UPTRAVI group, PVR (mean±SD) decreased from 700±302 dyn·sec/cm⁵ to 596±266 dyn·sec/cm⁵ after 17 weeks and the change from baseline to week 17 in PVR was -104±191 dyn·sec/cm⁵ (N=21, P=0.0266, Wilcoxon signed rank test). In the placebo group, PVR increased from 756±303 dyn·sec/cm⁵ to 782±391 dyn·sec/cm⁵ and the change from baseline to week 17 in PVR was 26±180 dyn·sec/cm⁵ in the placebo group (N=7, P=0.8125, Wilcoxon signed rank test).

Based on these values, treatment effect was -130±189 dyn·sec/cm⁵ (95% CI, -299 to 39 dyn·sec/cm⁵; P=0.1553, Wilcoxon rank sum test) after 17 weeks of UPTRAVI treatment.

Secondary Endpoints

Secondary endpoints included the change from baseline to week 17 in additional hemodynamic parameters, 6MWD, NT-proBNP concentration and WHO FC, the results of which are presented in the Table: Changes From Baseline to Week 17 in Pulmonary Hemodynamic Variables, 6MWD, NT-proBNP, and NYHA/WHO FC (Per-Protocol Set).

Safety

Serious AEs occurred in 2 patients (8%) in the UPTRAVI group. After 117 days, disseminated intravascular coagulation occurred in 1 patient, followed by congestive heart failure and stress-induced cardiomyopathy, leading to the patient’s death after 14 days. Congestive heart failure and stress-induced cardiomyopathy occurred due to CTEPH deterioration according to the investigator, but there was no causal relationship with the investigational drug. Right ventricular failure occurred in another patient after 71 days of treatment, leading to a decrease in the UPTRAVI dose administered. Following the dose titration of UPTRAVI, the symptoms occurred. The patient recovered 8 days after the drug dose reduction, hence, a correlation with the investigational drug could not be ruled out.

AEs (excluding those without a causal relationship) occurred in 22 of 25 patients (88%) in the UPTRAVI group and 6 of 9 patients (66.7%) in the placebo group.

The most frequently reported AEs in the UPTRAVI group (experienced at a rate ≥10%) were headache (56%), diarrhea (56%), pain in jaw (36%), myalgia (28%), hot flush (20%), malaise, flushing (16.0%), nausea, and arthralgia (12.0%).

In the placebo group, headache (33.3%), diarrhea (22.2%), flushing, and arthralgia (11.1%) were observed.

Information From Additional Relevant Literature

Komura et al (2026)⁴ reported data from a single-center, retrospective, observational study conducted at the Yokohama City University Hospital that evaluated the hemodynamic effects of UPTRAVI monotherapy in newly diagnosed, treatment-naïve patients with inoperable CTEPH before BPA and compared these outcomes with those observed in patients treated with riociguat.

Inclusion and Exclusion Criteria

A total of 40 consecutive patients with newly diagnosed, treatment-naïve, inoperable CTEPH scheduled for their first BPA session between August 2021 and February 2024 were screened. Of these, 15 patients received UPTRAVI pretreatment and 18 patients received riociguat pretreatment. Seven patients who proceeded directly to BPA without pulmonary hypertension-targeted pretreatment were excluded. In the riociguat group, 3 patients who required urgent BPA because of clinical deterioration were excluded due to insufficient dose titration.

Study Results

The final cohort included 30 patients treated with either UPTRAVI monotherapy (n=15) or riociguat monotherapy (n=15) before the first BPA session. Baseline demographics and clinical characteristics are presented in Table: Baseline Demographics and Clinical Characteristics. In the UPTRAVI group, the most commonly administered dose was 3.2 mg/day (n=7), and 46.7% of patients reached the maximum recommended dose; the mean daily dose was 2.17 mg/day. In the riociguat group, the most commonly administered dose was 7.5 mg/day (n=8), and 53.3% of patients reached the maximum recommended dose; the mean daily dose was 5.7 mg/day.

Efficacy

Changes in hemodynamic parameters before and after UPTRAVI vs riociguat treatment are presented in Table: Hemodynamic Parameters Before and After UPTRAVI vs Riociguat Treatment.

Adjusted analyses, performed using analysis of covariance (ANCOVA) models and adjusted for the baseline values of each hemodynamic parameter and key clinical covariates, confirmed the absence of significant differences in mPAP or PVR improvement. However, riociguat was associated with significantly greater improvements in CO, cardiac index, and stroke volume. No significant between-group differences were observed in the right atrial pressure, PAWP, mixed venous oxygen saturation, or SaO₂.

Safety

Both treatments were generally well tolerated, with no treatment discontinuations or serious AEs reported. In the UPTRAVI group, adverse effects occurred in 9 patients (60%) and were most commonly gastrointestinal symptoms, including diarrhea (n=6; 40%), followed by headache (n=2; 13%) and hypotension (n=1; 7%). Dose reduction was required in 2 patients (13%). In the riociguat group, AEs were reported in 7 patients (47%) and included hypotension (n=3; 20%), headache (n=2; 13%), dizziness (n=1; 7%), and peripheral edema (n=1; 7%); dose reduction was required in 1 patient (7%).

Nakano et al (2025)⁵ reported a prospective, investigational randomized controlled trial that evaluated the difference of efficacy and safety of UPTRAVI and riociguat in patients with inoperable CTEPH. A total of 24 patients were randomized to receive either UPTRAVI or riociguat, with PVR as an allocation factor. Study treatment was titrated to the maximum tolerated dose within 16 weeks, and follow-up assessments were conducted at week 20.

Study Results

Among the 24 enrolled patients, 21 completed the follow-up and were included in the analysis (UPTRAVI, n=10; riociguat, n=11). The median age was 75 years (IQR, 69-80), all were treatment-naïve and 24% of patients were male; the median baseline PVR was 8.9 WU (IQR, 6.0-12.2). Baseline characteristics, including PVR, were comparable between the treatment groups.

Efficacy

Efficacy outcomes have been presented in Table: Efficacy Outcomes. The median change in PVR did not differ significantly between the UPTRAVI and riociguat groups (-2.605 WU and -2.85 WU, respectively; P=0.916). Exercise tolerance and B-type natriuretic peptide (BNP) were reported to be comparable in both groups at baseline and after treatment.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 03 July 2026.