SUMMARY

• The phase 3 SERAPHIN trial was conducted to assess the long-term safety and efficacy of OPSUMIT in patients with symptomatic pulmonary arterial hypertension (PAH).¹
• Quality of life was assessed in SERAPHIN as an exploratory analysis using the 36-Item Short Form Survey (SF-36) questionnaire.²
• At month 6, OPSUMIT significantly improved 7 of 8 SF-36 domains, and the physical component summary (PCS) and mental component summary (MCS) scores, vs placebo. OPSUMIT significantly reduced the risk of a ≥3-point deterioration in PCS (hazard ratio [HR], 0.60; 95% confidence limit [CL], 0.47-0.76; P<0.0001) and MCS scores (HR, 0.76; 95% CL, 0.61-0.95; P=0.0173) up to end of treatment (EOT) vs placebo.²
• Patients with a baseline PCS score above the median baseline value had a significantly reduced risk of morbidity/mortality compared with patients with a PCS score below the median; a similar result was observed for the MCS score.²

CLINICAL DATA

Phase 3 Clinical Experience in PAH

Comparison of OPSUMIT, Macitentan 3 mg and Placebo Treatment in the Study Population

The Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome (SERAPHIN) trial was a multicenter, double-blind, randomized, placebo-controlled, event-driven phase 3 study to assess the long-term safety and efficacy of OPSUMIT in patients with symptomatic PAH.¹ Patients ≥12 years of age (N=742) were randomized 1:1:1 to receive OPSUMIT, macitentan 3 mg, or placebo once daily. Patients were allowed to receive background therapy for PAH with either phosphodiesterase-5 inhibitors (PDE-5i), oral or inhaled prostanoids, calcium channel blockers, or L-arginine, provided the patient had been on a stable dose for ≥3 months prior to randomization. The primary endpoint was the time from treatment initiation to first morbidity or mortality event in all randomized patients up to EOT. This composite endpoint was defined as death, atrial septostomy, lung transplantation, initiation of intravenous (IV) or subcutaneous (SC) prostanoids or worsening of PAH. Quality of life was assessed as an exploratory endpoint.

Exploratory Analysis of Health-Related Quality of Life in SERAPHIN

Health-Related Quality of Life Outcome Measure

The SF-36 (Version 2) questionnaire comprises 36 questions, which are summarized in 8 health domain scores: physical functioning (PF), role limitations due to physical health (RP), role limitations due to emotional problems (RE), mental health (MH), bodily pain (BP), general health perceptions (GH), vitality (VT), and social functioning (SF). The domain scores are combined into PCS and MCS scores. Domain and component summary scores are converted to norm-based scores based on the 1998 United States (US) general population (mean, 50; standard deviation [SD], 10). A higher SF-36 score denotes better healthrelated quality of life (HRQoL, scale 0-100).²

Patients aged ≥14 years completed the SF-36 questionnaire at baseline, month 6, month 12, and EOT. The short-term impact of OPSUMIT on HRQoL was evaluated by assessing the change from baseline to month 6 in SF-36 individual domain and component summary scores. The long-term impact of OPSUMIT was evaluated by assessing the time to a clinically meaningful deterioration (≥3-points) in SF-36 component summary scores up to EOT. Additionally, the prognostic significance of HRQoL was assessed by evaluating the time to morbidity/mortality event according to the baseline SF-36 component summary scores.²

Patient Characteristics

Of the 742 patients randomized in SERAPHIN, 710 were included in this exploratory analysis (placebo, n=239; macitentan 3 mg, n=237; OPSUMIT, n=234). Thirty-two patients (placebo group, n=11; macitentan 3 mg, n=13; OPSUMIT, n=8) were not included as they did not have complete baseline HRQoL data. Demographics and baseline clinical characteristics, including SF-36 scores, were similar across the treatment groups and are summarized in Table: Demographics and Baseline Clinical Characteristics.²

Change in HRQoL

In the placebo group, individual SF-36 domain scores (PF, BP, GH, VT, SF, RE and MH) as well as PCS and MCS scores deteriorated from baseline to month 6. Treatment with OPSUMIT significantly improved 7 of the 8 SF-36 domains (all domains except GH) compared with placebo. Improvements in the PCS and MCS scores from baseline to month 6 after treatment with OPSUMIT compared with placebo were also significant (Figure: Change From Baseline to Month 6 in Individual SF-36 Domains as well as Physical and Mental Component Summary Scores). Significant improvements in 7 out of 8 SF-36 individual domain scores and PCS and MCS scores were also shown after treatment with macitentan 3 mg compared with placebo.²

The placebo-corrected treatment effect of OPSUMIT on PCS scores was consistent across all pre-specified subgroups, including PAH background therapy. For MCS scores, the treatment effect of OPSUMIT was consistent across most of the subgroups except for sex (interaction P=0.0289). With respect to the SF-36 domain scores, the treatment effect of OPSUMIT compared with placebo at month 6 was consistent across all the subgroups except 6-minute walk distance (6MWD; RE and GH domains), sex (BP and VT domains) and PAH etiology (BP domain). The treatment effect of macitentan 3 mg on the PCS and MCS scores at month 6 was consistent across the subgroups.²

Time to Deterioration in HRQoL

Treatment with OPSUMIT significantly reduced the risk of a ≥3-point deterioration in PCS scores (HR, 0.60; 95% CL, 0.47-0.76, P<0.0001; Figure: Kaplan-Meier Analyses of Time to ≥3-Point Deterioration in (A) Physical and (B) Mental Component Summary Scores for OPSUMIT or Macitentan 3 mg vs Placebo Panel A) and MCS scores (HR, 0.76; 95% CL, 0.61-0.95; P=0.0173; Figure: Kaplan-Meier Analyses of Time to ≥3-Point Deterioration in (A) Physical and (B) Mental Component Summary Scores for OPSUMIT or Macitentan 3 mg vs Placebo Panel B) up to EOT vs placebo. Significant reductions in the risk of a ≥3-point deterioration in PCS (HR, 0.71; 95% CL, 0.56-0.89; P=0.0026) and MCS (HR, 0.79; 95% CL, 0.64-0.99; P=0.0395) scores were also observed with macitentan 3 mg vs placebo.²

Association Between HRQoL and Long-term Outcome

When analyzed as continuous variables, the PCS and MCS scores at baseline were associated with the risk of a primary endpoint event. Every 5-unit increase in PCS and MCS scores at baseline was associated, respectively, with a 17% (HR, 0.83; 95% CL, 0.77-0.89) and a 6% (HR, 0.94; 95% CL, 0.89-0.99) lower risk of experiencing a morbidity/mortality event. To illustrate this result, the association between time to first morbidity/mortality event and baseline values above/below the median SF-36 PCS and MCS scores was also analyzed (Figure: Kaplan-Meier Analyses of Time to First Confirmed Morbidity/Mortality Event According to Median Baseline (A) Physical and (B) Mental Component Summary Scores). For patients with a PCS score above the median baseline value (35.5), the risk of a morbidity/mortality event was significantly reduced by 39% compared with patients who had a PCS score below the median baseline value (Figure: Kaplan-Meier Analyses of Time to First Confirmed Morbidity/Mortality Event According to Median Baseline (A) Physical and (B) Mental Component Summary Scores Panel A). For patients with an MCS score above the median baseline value (42.7), the risk of a morbidity/mortality event was significantly reduced by 22% compared with patients who had an MCS score below the median baseline value (Figure: Kaplan-Meier Analyses of Time to First Confirmed Morbidity/Mortality Event According to Median Baseline (A) Physical and (B) Mental Component Summary Scores Panel B). However, an exploratory analysis found no significant association between change from baseline to month 6 in PCS and MCS and subsequent morbidity/mortality event.²

Limitations of Analyses

The SF-36 is a generic measure of HRQoL and is not tailored to specifically assess the impact of PAH-specific symptoms. However, SF-36 has been frequently used to evaluate HRQoL in PAH studies and findings from a cross sectional study of 93 PAH patients who completed the SF-36 suggest that this instrument is sensitive to PAH-related symptoms. Secondly, the extent of missing data at month 12 precluded meaningful analysis of the SF36 change from baseline to month 12. Nevertheless, the analysis of the time to a deterioration in HRQoL over the course of the entire study gives insight into the long-term impact of OPSUMIT on HRQoL; the observed benefit of OPSUMIT over placebo is maintained throughout the study. Thirdly, other than the pre-specified analysis of change from baseline to month 6 in SF-36, all other exploratory analyses were post hoc and not adjusted for multiple comparisons.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 26 August 2024.