Sotatercept (2) – Winrevair®

• Clinical trials
  • To assess the additional benefit of sotatercept, the pharmaceutical manufacturer has submitted the results of the randomised, double-blind, placebo-controlled Phase III ZENITH trial.

Adults with pulmonary arterial hypertension (PAH) in WHO functional class (WHO-FC) IV

• Hint for a non-quantifiable additional benefit.
• Overall, primarily due to the demonstrated clear advantage in the endpoint of disease progression, there is an additional benefit, the extent of which cannot be quantified due to uncertainties regarding the implementation of the appropriate comparator therapy.
• In summary, there is a hint of a non-quantifiable additional benefit of sotatercept compared with the appropriate comparator therapy.
• mortality
  • Two analyses of overall survival are presented:
  • The main analysis takes into account death from any cause, with the exception of events occurring after lung transplantation or entry into the SOTERIA extension study.
  • The sensitivity analysis takes into account death from any cause, including events occurring after lung transplantation or entry into the SOTERIA extension study; however, patients in the control arm of the ZENITH study who received sotatercept in the SOTERIA extension study are still treated as patients in the placebo arm.
  • For the overall survival endpoint, there is no statistically significant difference between the treatment groups in either the primary analysis or the sensitivity analysis.
  • For the endpoint of all-cause mortality, there was no statistically significant difference between the treatment groups.
• Morbidity – disease worsening
  • The disease progression endpoint is a composite endpoint defined as all-cause death, lung transplantation or hospitalisation for ≥ 24 hours due to PAH progression (adjudicated by a blinded committee).
  • For the endpoint ‘disease worsening’, defined as death from any cause, lung transplantation or hospitalisation for ≥ 24 hours due to worsening PAH, a statistically significant advantage was observed in favour of sotatercept compared with the control arm.
  • In the morbidity endpoint category, the ‘disease worsening’ endpoint showed a clear advantage of sotatercept compared with the comparator arm.
• Morbidity – Walking ability (6MWT)
  • Walking capacity and physical endurance were assessed using the 6-minute walk test.
  • For the 6-minute walk test (6MWT) endpoint, the pre-specified analysis of the median difference between the treatment arms at week 24 is presented. No statistically significant difference was observed between the treatment groups.
  • No statistically significant difference was observed between the treatment groups for either the walking ability or health status endpoints.
• Morbidity – Dyspnoea
  • For the endpoint of dyspnoea, assessed using the Borg CR10 scale, there was no statistically significant difference between the treatment groups.
  • However, there is an effect modification by the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 risk score: For patients with a REVEAL Lite 2.0 risk score of ≥ 11 at the start of the study, there was a statistically significant advantage of sotatercept compared with the control arm (HR 6.69 [1.38; 32.38]; p-value 0.018). By contrast, no statistically significant difference was observed for patients with a REVEAL Lite 2.0 risk score of 9 to 10 at the start of the study.
  • For the endpoint of dyspnoea, no statistically significant difference was observed between the treatment groups in the overall population. However, based on an analysis of effect modification, an advantage of sotatercept over the comparator arm was observed in individuals with a REVEAL Lite 2.0 risk score of ≥ 11 at the start of the study.
• Morbidity – Health Status (EQ-5D VAS)
  • Health status was assessed using the EQ-5D visual analogue scale (VAS). At the final data cut-off, there was no statistically significant difference between the treatment groups.
  • No statistically significant difference was observed between the treatment groups for either the walking ability or health status endpoints.
• quality of life
  • No data on health-related quality of life were collected in the ZENITH study.
  • No data were collected for the health-related quality of life endpoint category.
• Side effects
  • For the endpoints of SUEs and discontinuation due to AEs, there was no statistically significant difference between the treatment groups in either case.
  • In the endpoint category of side effects, there was no statistically significant difference between the treatment groups.
• Overall assessment
  • For the assessment of the additional benefit of sotatercept in combination with other PAH therapies for the treatment of adults with WHO Class IV PAH, results are available from the ZENITH study for the endpoint categories of mortality, morbidity and side effects.
  • Overall, there are uncertainties regarding the implementation of the appropriate comparator therapy, as it is unclear for what proportion of the study participants a therapy escalation in line with the defined appropriate comparator therapy was, in fact, no longer possible.
  • Overall, for sotatercept in combination with other PAH therapies in adults with WHOclassification IV, primarily due to the demonstrated significant advantage in the endpoint of disease worsening; however, the extent of this additional benefit cannot be quantified due to the uncertainties regarding the implementation of the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.