Macitentan (1) – Opsumit®

• Clinical trials
  • The assessment of the extent of the additional benefit of macitentan is based on the SERAPHIN trial.
  • This study is a multicentre, double-blind, randomised, event-driven Phase III trial.
  • Patients with pulmonary arterial hypertension (PAH) were randomised in a 1:1:1 ratio to two intervention groups (macitentan 3 mg and macitentan 10 mg) and a placebo control group.

Treatment of pulmonary arterial hypertension (PAH) in adult patients

• mortality
  • Analysis of the endpoints ‘all-cause mortality to end of treatment (EOT)’, ‘all-cause mortality to end of study (EOS)’ and ‘death due to PAH to EOS’ showed no statistically significant difference between the macitentan treatment group and the placebo group.
• Morbidity – occurrence of the first morbidity or mortality event
  • During the observation period (EOT plus 7 days), a morbidity or mortality event occurred in 76 patients (31.4 %) in the macitentan arm and in 116 patients (46.4 %) in the placebo arm.
  • Macitentan resulted in a statistically significant reduction in the occurrence of the first mortality/morbidity endpoint (HR: 0.55; 97.5% CI: [0.39; 0.76]; p < 0.0001) compared with placebo.
  • The post-hoc analysis of the number of events during the study period also showed statistical significance (RR: 0.68; 95% CI: [0.53; 0.86]; p = 0.0009).
  • The endpoint ‘first morbidity or mortality event’ is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The ‘mortality’ component of the endpoint is already assessed as separate endpoints via the secondary endpoints ‘death from any cause up to the end of treatment (EOT)’, ‘death from any cause up to the end of the study (EOS)’ and ‘death due to PAH up to the end of the study (EOS)’.
  • At the time of the assessment, no validation studies were available for the composite endpoint.
  • Patient relevance cannot be clearly determined due to the composition of different endpoint categories with varying degrees of severity.
  • The most frequently occurring event within the combined primary endpoint was ‘other worsening of PAH’, which occurred in 59 patients in the macitentan arm (24.4 %) and 93 patients in the placebo arm (37.2 %).
  • This difference is statistically significant (RR: 0.66; 95% CI: [0.49; 0.87]; p = 0.0025) and corresponds to an absolute reduction in ‘other worsening of PAH’ of approximately 13%.
  • The clinical relevance of the endpoint ‘other worsening of PAH’ is not proven, as it consists of subjective components or components whose clinical relevance has not been established and which are not verifiable (e.g. worsening of PAH symptoms, the need for a new PAH medication).
  • In terms of severity and significance, the endpoint ‘Other worsening of PAH’ differs majorly for the patient from the other components of the composite endpoint.
  • For this composite endpoint, the pharmaceutical manufacturer has not provided a separate analysis of the individual components.
  • Taken together, the results for the primary endpoint do not allow for a conclusion to be drawn regarding the extent of the additional benefit.
• Health-related quality of life – SF-36
  • The change in quality of life from baseline to month 6 was measured using the non-disease-specific Medical Outcomes Study 36-Item Short Form Health Survey Version 2 (SF-36).
  • The treatment effect is statistically significant across all dimensions with the exception of the ‘General Health’ dimension.
  • The improvement in the mental and physical summary scales compared with placebo is 3.4 (MCS) and 3.0 (PCS) respectively, and is also statistically significant in each case.
  • Given the size of the effect, a clinically relevant difference cannot be assumed.
  • The 95% confidence interval for these scales does not lie entirely above the irrelevance threshold of 0.2 (Hedges’ g).
  • No individual responder analysis is available.
  • Taken together, the results on quality of life do not allow a conclusion to be drawn regarding the extent of the additional benefit.
• Side effects
  • In the SERAPHIN trial, adverse events (AEs) were recorded up to EOT + 28 days.
  • The proportion of patients with at least one AE was 94.6% in the macitentan arm and 96.4% in the placebo arm.
  • Serious adverse events (SAEs) occurred in 45% of patients in the macitentan arm compared with 55% in the placebo arm.
  • This difference is statistically significant (RR: 0.82; 95% CI: [0.68; 0.99]; p = 0.0303) and corresponds to an absolute reduction in SAEs of approximately 10% in the macitentan arm.
  • Severe AEs occurred in 34.7% of patients in the macitentan arm compared with 45% in the placebo arm.
  • This finding is also statistically significant (RR: 0.77; 95% CI: [0.61; 0.99]; p = 0.0215) and corresponds to an absolute reduction in severe AEs of approximately 10% in the macitentan arm.
  • Worsening of PAH and right heart failure were the most common serious and severe AEs and occurred less frequently in patients in the macitentan arm.
  • However, worsening of PAH and right heart failure are already factored in as components of the primary endpoint’s morbidity.
  • Therapy discontinuations due to AEs occurring in the study were similarly frequent in the treatment arms – macitentan: 10.7 per cent, placebo: 12.4 per cent – with no statistically significant difference.
  • The main reason for early discontinuation was AEs related to the underlying condition, predominantly worsening of PAH or right heart failure.
  • With regard to the adverse events (AEs) under consideration, a statistically significant difference was observed for the AE ‘decrease in haemoglobin’ to the detriment of macitentan, 15.7% vs. 4.8% (RR: 3.26; 95% CI: [1.74; 7.62]; p ˂ 0.0001).
  • During treatment with macitentan, 8.7% of patients experienced at least one AE related to liver disorders or abnormal liver function, compared with 14.5% in the placebo arm.
  • This difference is statistically significant and indicates an advantage of treatment with macitentan (RR: 0.60; 95% CI: [0.32; 1.00]; p = 0.0493).
  • The interpretability of the available results regarding side effects is limited, particularly due to the double counting of events in both morbidity and safety endpoints; however, overall, they support the classification of the extent of the additional benefit as minor.

Courtesy translation only, please refer to the German original.