Mepolizumab (3) – Nucala®

• Clinical trials
  • The SYNAPSE trial is a randomised, double-blind Phase III trial comparing mepolizumab with placebo, in an add-on design to maintenance therapy with intranasal mometasone furoate.

Adults with severe chronic rhinosinusitis with nasal polyps (CRSwNP) that cannot be adequately controlled with systemic corticosteroids and/or surgery

• For adults with severe chronic rhinosinusitis with nasal polyps (CRSwNP) that cannot be adequately controlled with systemic corticosteroids and/or surgery, the additional benefit of mepolizumab as an add-on therapy compared with the appropriate comparator therapy is not proven.
• To demonstrate the additional benefit of mepolizumab, the pharmaceutical manufacturer has submitted the results of the double-blind, randomised SYNAPSE study, including analyses at week 52.
• As the SYNAPSE study does not provide data in comparison with the currently defined appropriate comparator therapy, the study cannot therefore be used to establish the additional benefit of mepolizumab.
• mortality
  • No deaths occurred in the SYNAPSE study up to week 52.
• morbidity
  • For the symptomatic endpoints (nasal obstruction, nasal discharge and loss of the sense of smell, each assessed using a visual analogue scale (VAS)), the proportion of patients showing an improvement of ≥ 1.5 points at week 52 showed a statistically significant advantage in favour of mepolizumab + mometasone furoate compared with placebo + mometasone furoate (nasal obstruction VAS: RR 0.87 [95% CI 0.75; 0.98] p-value = 0.022; nasal discharge VAS: RR 0.87 [95% CI 0.75; 0.98] p-value = 0.022; loss of sense of smell VAS: RR 0.73 [95% CI 0.57; 0.95] p-value = 0.007).
  • With regard to the impact of the disease on daily activities, the SYNAPSE study shows a statistically significant advantage in favour of mepolizumab + mometasone furoate compared with placebo + mometasone furoate. However, the 95% confidence interval for the standardised mean difference (Hedges’ g) does not lie entirely outside the irrelevance range of −0.2 to 0.2. It cannot therefore be concluded that the observed effect is clinically relevant.
  • Avoiding, in particular, repeat surgery for nasal polyps following an initial operation is a key therapeutic objective, partly due to procedure-specific complications. In the present indication, the endpoint of nasal polyp surgery (NP surgery) is, in principle, a patient-relevant endpoint. There are differing views on the suitability of the operationalisation of the endpoint used in the present study.
• Health-related quality of life
  • Health-related quality of life was assessed in this study using the SF-36. For the SF-36, the physical composite score (PCS) and the mental composite score (MCS) are considered separately. For the SF-36, a statistically significant difference in favour of mepolizumab + mometasone furoate compared with placebo + mometasone furoate was observed (15% of the scale range) by week 52, a statistically significant advantage in favour of mepolizumab + mometasone furoate compared with placebo + mometasone furoate (PCS: RR 0.55 [95% CI 0.39; 0.76] p-value < 0.001; MCS: RR 0.68 [95% CI 0.47; 0.99] p-value = 0.03).
• Side effects
  • No statistically significant difference was observed between the treatment arms for the endpoints of adverse events (AEs), serious adverse events (SAEs) and discontinuation due to AEs.
• Overall assessment
  • Overall, therefore, the additional benefit is not proven and the resolution is limited to 1 December 2022.

Courtesy translation only, please refer to the German original.