SUMMARY

• The PORtopulmonary Hypertension Treatment wIth maCitentan - a randOmized Clinical Trial (PORTICO) was a randomized, double-blind, placebo-controlled, prospective, multicenter phase 4 study looking to assess the efficacy and safety of OPSUMIT in patients with portopulmonary hypertension (PoPH). At week 12, treatment with OPSUMIT resulted in a 35% reduction in pulmonary vascular resistance (PVR) versus placebo.¹
• During the 12-week double-blind period, the most common adverse events (AEs) reported were peripheral edema, headache, and bronchitis.¹
• A pharmacokinetic (PK) sub-study was done in 10 patients treated with open-label macitentan for at least 4 weeks.¹
• In a post hoc analysis of improvement in risk category for liver transplant (LT) patients, 20 (47%) OPSUMIT-treated and 6 (14%) placebo-treated patients had improved their risk category for LT perioperative mortality after 12 weeks. Additionally, 18 (42%) OPSUMIT-treated and 3 (7%) placebo-treated patients who were in the high-risk waitlist mortality group at baseline transitioned to the low-risk category on the basis of lower PVR (≤450 dyn∙sec∙cm^–5).²
• The OPsumit^® USers Registry (OPUS) and OPsumit^® Historial USers cohort study (OrPHeUS) combined data sets included PoPH patients, and was used to describe the patient characteristics, treatment patterns, outcomes, and safety in patients with PoPH newly treated with OPSUMIT. Kaplan-Meier (KM; 95% confidence limit [CL]) estimates indicated that 48.6% (40.7-56.0) and 28.6% (20.9-36.7) of patients with PoPH were hospitalization free at 1 and 2 years, respectively. The 1- and 2-year KM survival estimates (95% CL) were 82.2% (75.1-87.4) and 71.7% (62.9-78.7), respectively. A total of 46 (22.3%) deaths were reported during the OPSUMIT exposure period.³

CLINICAL DATA

PORTICO

PORTICO was a randomized, double-blind, placebo-controlled, prospective, multicenter phase 4 study to assess the safety and efficacy of OPSUMIT 10 mg in patients with PoPH. The study design is presented in the Figure: PORTICO Study Design.¹

Results

Baseline Characteristics

Overall, 119 patients were screened, and 85 patients were randomized (placebo, n=42; OPSUMIT, n=43). Baseline characteristics were generally similar between the treatment groups and are summarized in Table: Baseline Characteristics.

Primary Endpoint

After 12 weeks of treatment, the model-adjusted ratio of geometric means for OPSUMIT:placebo was 0.65 (95% CL, 0.59-0.72; P<0.0001), representing a 35% reduction in PVR in the OPSUMIT treatment group compared to placebo (Figure: Primary Endpoint -  PVR at Week 12 Expressed as Ratio of Baseline). The treatment effect with OPSUMIT was also consistent across prespecified subgroups.¹

Secondary Endpoints

At week 12, there were significant improvements in mean pulmonary arterial pressure (mPAP), cardiac index, and total pulmonary resistance (TPR) in the OPSUMIT group compared with the placebo group while there was no significant difference in mean right atrial pressure (mRAP), mixed venous oxygen saturation (SvO₂), and N-terminal pro-brain natriuretic peptide (NT-proBNP) (Table: Change in Other Hemodynamic Parameters at Week 12). Additionally, there were no significant differences between the groups in 6-minute walk distance (6MWD) or World Health Organization (WHO) functional class (FC).¹

Safety

During the double-blind period, the most frequent AEs in the OPSUMIT group were peripheral edema (26%), headache (16%), and bronchitis (9%) (Table: AEs Reported During the Double-blind and OPSUMIT Treatment Periods). Nine (21%) patients on OPSUMIT experienced a serious adverse event (SAE) compared to 6 (14%) patients on placebo. There were 4 (9%) patients in the OPSUMIT group with an AE leading to treatment discontinuation compared to no patients in the placebo group. No patients in either treatment group experienced hemoglobin levels ≤8 g/dL. Fourteen patients experienced a hemoglobin decrease from baseline of ≥2 g/dL (12 [28%] in the OPSUMIT group and 2 [5%] in the placebo group). One patient in the OPSUMIT group experienced an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≥3 × upper limit of normal (ULN) associated with total bilirubin ≥2 × ULN. OPSUMIT did not affect mean hepatic venous pressure gradient or mean systolic pressure. There were no deaths during the double-blind period.¹

PK in Patients With PoPH: Findings From the PORTICO Sub-study

A PK sub-study was done in 10 patients treated with open-label macitentan for at least 4 weeks. Most were male (n=7), with a mean age of 54.9 years. The overall geometric mean maximum plasma concentration (C_max) was 368.6 ng/mL (coefficient of variation 26.0) for macitentan with a median time to C_max (t_max) of 6.5 hours, and overall geometric mean area under the plasma concentration-time curve at steady state (AUC_tau,ss) of 6655.4 h∙ng/mL (32.2%). The geometric mean of the trough concentration was 200.2 ng/mL (38.0%) for macitentan and 711.5 ng/mL (30.8%) for its active metabolite, ACT-132577.¹

Post Hoc Analysis: Improvement in Risk Categorization for LT Mortality

This post-hoc analysis of PORTICO aimed to evaluate the implications of the hemodynamic changes obtained during OPSUMIT treatment with respect to patients’ risk of LT perioperative and waitlist mortality.²

Results

After 12 weeks, 20 (47%) OPSUMIT-treated and 6 (14%) placebo-treated patients had improved their risk category for LT perioperative mortality (Table: Change from Baseline to Week 12 in LT Perioperative Waitlist Mortality Risk Category). The LT perioperative mortality risk categories were defined as low (mPAP <35 mmHg or 35 mmHg≤mPAP<45 mmHg and PVR <240 dyn∙sec∙cm^–5), intermediate (35 mmHg≤mPAP<45 mmHg and PVR ≥240 dyn∙sec∙cm^–5), and high (mPAP ≥45 mmHg). The odds ratio for improvement in risk category (in favor of OPSUMIT-treated patients) was 4.9 (95% CI: 1.6 to 17.7, P=0.004).²

After 12 weeks, 18 (42%) OPSUMIT-treated and 3 (7%) placebo-treated patients who were in the high-risk waitlist mortality group at baseline transitioned to the low-risk category on the basis of lower PVR (≤450 dyn∙sec∙cm^–5) (Table: Change from Baseline to Week 12 in LT Waitlist Mortality Risk Category). Low risk was defined as PVR ≤450 dyn∙sec∙cm^–5 and high risk was defined as PVR >450 dyn∙sec∙cm^–5. The odds ratio for changing to the low-risk group was 10.5 times higher for the OPSUMIT patients compared to the placebo patients (95% CI: 2.4 to 66.8, P=0.001).²

Based on mPAP and PVR, patients who were not eligible for the LT model for end-stage liver disease (MELD) exception at baseline and achieved eligibility criteria at week 12, included 6 (14%) OPSUMIT-treated and 2 (5%) placebo-treated patients.²

OPUS and OrPHeUS

OPUS was a prospective, multicenter, long-term, observational drug registry in the United States (US; NCT02126943); conducted between April 2014 and finished in June 2020.^3,4 Patients were excluded if they were enrolled in an ongoing clinical trial.⁴ OrPHeUS was a retrospective, multicenter, US medical center chart review (NCT03197688).^3,4 OrPHeUS included patients who newly initiated OPSUMIT between October 2013 and December 2016 (inclusive) with individual patient data recorded up to March 2017.⁵ Patients who were enrolled in a clinical trial involving OPSUMIT, and those who were enrolled in OPUS were not allowed to participate in OrPHeUS.⁴ The data from OPUS and OrPHeUS were combined to describe the patient characteristics, treatment patterns, outcomes, and safety in patients with PoPH newly treated with OPSUMIT.³

Baseline Demographics

OPUS and OrPHeUS included a total of 206 patients with PoPH, of which 108 (52.4%) patients were female. The median age (interquartile range [IQR; Q1-Q3]) of patients in the PoPH population was 58 (51-64) years and 165 (80.1%) were white. The median (Q1-Q3) time from PAH diagnosis to OPSUMIT treatment in PoPH population was 7.2 (1.1-35.4) months and the median (Q1-Q3) 6MWD distance was 317 (240-400) meters. Patients were primarily WHO FC II or III status (37.3% and 52.0%, respectively). Hepatic comorbidities were reported for 100% of patients with PoPH, 72.8% patients had cirrhosis and liver test abnormalities were reported in 31.6% of patients.³

Clinical Characteristics

Treatment Patterns

At OPSUMIT initiation (n=206), 25.2% patients were on OPSUMIT monotherapy, 66.0% patients were on double combination therapy, and 8.7% patients were on triple combination therapy. Among the patients receiving double combination therapy, 57.3% received OPSUMIT with a phosphodiesterase type 5 inhibitor (PDE-5i). Among the patients on triple combination therapy, 8.7% received OPSUMIT with both a PDE-5i and a prostanoid. At 24 months (n=55), 21.8% were on monotherapy. The proportion of patients on double therapy decreased to 54.5%, while the proportion of patients on triple therapy increased to 23.6%.

Hospitalization and Survival

The median OPSUMIT exposure time IQR (Q1-Q3) for patients with PoPH was 11.9 (3.1-26.0) months. A total of 119 (57.8%) patients experienced at least 1 hospitalization during the OPSUMIT exposure period. KM estimates (95% CL) showed that 48.6% (40.7-56.0) and 28.6% (20.9-36.7) of patients were hospitalization free at 1 and 2 years, respectively. A total of 46 (22.3%) deaths were reported during the OPSUMIT exposure period. The 1- and 2-year KM survival estimates (95% CL) were 82.2% (75.1-87.4) and 71.7% (62.9-78.7), respectively. LT status was assessed for 96 patients in OPUS during observation period, of whom 28 (29.2%) were in medical need of LT.³

Safety

Treatment with OPSUMIT was discontinued in 112 (54.4.%) patients (Table: OPSUMIT Exposure and Discontinuation).

Dyspnea (17.7%), increased bilirubin (14.6%), anemia, hepatic encephalopathy, and mental status changes (all 10.4%) were the most common SAEs in the PoPH population. One patient had hemorrhage of esophageal varices. A total of 101 (49.0%) patients experienced at least 1 hepatic AE.³ The hepatic AEs, elevated liver enzymes and other AEs are presented in the Table: Hepatic Adverse Events, Liver Enzyme Elevations, and Adverse Events.

Limitations

• Due to potential bias in patient selection, the results may not be directly comparable to those of the disease registries, which are more representative of the full PoPH population.
• Several parameters, including PAH diagnosis and death, that were reported in the analysis were assessed by the investigators and were not adjudicated.
• The reasons for hospitalization were not collected; hence, the contribution of PAH and underlying liver disease to the rate of hospitalization was unknown.
• Due to the observational nature of the study, clinical assessments may not be performed in real-world settings, resulting in significant missing of data such as WHO FC, 6MWD, as well as severity and outcomes of liver disease for the PoPH population.³

Analysis by LT Candidacy in OPUS

An analysis of OPUS looked at the treatment patterns and safety by LT candidacy. This analysis had a data cut-off of January 2020. Data was presented in the following analysis sets: all PoPH patients, PoPH patients not requiring LT, PoPH patients requiring LT, PoPH patients who require LT but not registered on waiting list, PoPH patients on LT waiting list, and PoPH LT patients. Information regarding patients’ need for LT was collected retrospectively and was independent of OPSUMIT treatment. Patient characteristics at baseline, treatment patterns during the clinical course of PoPH, and safety and survival were described in the data. See poster for additional information.⁶

Information from a Literature Search

Li et al (2023)⁷ reported a case study of a 48-year-old man with severe PoPH, chronic liver failure, and moderate hepatopulmonary syndrome who was started on OPSUMIT 10 mg once daily along with other medications. After 7 weeks, the patient’s activity tolerance improved, echocardiography showed a decreasing pulmonary artery systolic pressure, and arterial partial pressure of oxygen, cardiac troponin I, and NT-proBNP levels returned to normal.

Hernandez et al (2023)⁸ reported a case study of a 57-year-old man diagnosed with PoPH who was managed with tadalafil 40 mg plus OPSUMIT 10 mg as maintenance therapy. After 4 months of treatment adjustment, the patient improved to WHO FC I, with decreased NT-proBNP levels and improved 6MWD.

Mazzola et al (2022)⁹ reported a case study of a 67-year-old woman with PoPH who was started on OPSUMIT 10 mg once daily. At 3- and 6-month follow-up, the treatment showed improvements in functional and risk classes and echocardiographic parameters.

Ishikawa et al (2021)¹⁰ reported a case study of a 65-year-old man with hepatocellular carcinoma (HCC) who was managed with lenvatinib and OPSUMIT dual therapy for PoPH that was exacerbated following administration of lenvatinib for HCC.

Vionnet et al (2018)¹¹ reported a case study of a 37-year-old woman with severe PoPH, who was managed with dual oral therapy (sildenafil and OPSUMIT) before LT.

Safdar et al (2017)¹² identified 24 patients with PAH (including 2 with PoPH) in a retrospective study and reported data regarding the tolerability in patients who were switched from bosentan to OPSUMIT.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 02 July 2024.