WINREVAIR (sotatercept) - Pulmonary arterial hypertension (PAH)

The clinical benefit of WINREVAIR (sotatercept) is substantial in the MA indication.

Considering:

• evidence of the efficacy of WINREVAIR (sotatercept) versus placebo in a randomised, double-blind study in patients with PAH and WHO Functional Class II or III, as an adjunct to standard therapy (monotherapy, double therapy or triple therapy):
• on a clinically relevant outcome measure, the 6-minute walk distance, which was the primary endpoint;
• an efficacy on this endpoint of +40.8 metres, 95% CI [27.5; 54.1], p<0.001) between the 2 groups;
• an improvement observed for the ranked secondary endpoints, in particular:
  • in functional capacity assessed at week 24 based on change of WHO functional class (29.4% of patients in the sotatercept group versus 13.8% in the placebo group, p<0.001);
  • in the risk of morbidity and mortality assessed at week 24, based on a composite endpoint of disease improvement (38.9% of patients in the sotatercept group versus 10.1% in the placebo group, p<0.001), and on the time to death or first occurrence of a clinical worsening event (HR: 0.163, 95% CI [0.076; 0.347], p<0.001) and on attainment or maintenance of a low risk score on the French risk score (39.5% of patients in the sotatercept group versus 18.2% in the placebo group, p<0.001);

but with the following limitations:

• the lack of robust evidence for the mortality endpoint alone;
• a modest impact on quality of life;
• a safety profile with a 20% risk of treatment-related effects, in particular dizziness, epistaxis and telangiectasia, and 3% adverse events leading to treatment discontinuation;
• patients having been placed in the wrong strata during randomisation;
• missing data in 19 patients (13 in the placebo group and 6 in the sotatercept group), leading to possible over-estimation of the differences observed;
• the limited experience concerning both efficacy and safety (follow-up median of 8 months for the primary analysis);
• missing data assumed to be correlated with the observed data, without it being possible to verify this;
• numerous major protocol deviations, related to the treatment or missing visits (in particular, endpoint measurement in 14% of subjects included): 73 (44.8%) patients in the sotatercept group and 66 (41.3%) patients in the placebo group;
• calculation of the study population based on an expected difference of 25 m between the groups, whereas the minimum clinically relevant difference is 33 m (this value was determined in 2023, i.e. after the start of the clinical study);
• the 4th-ranked position of the secondary endpoint concerning improvement of WHO functional class, whereas this was the only secondary endpoint taken into account for control of type II error risks;

the Committee deems that WINREVAIR (sotatercept) provides a moderate clinical added value (CAV III) in the current care pathway, which includes the relevant comparators.