Sarilumab (3) – Kevzara®

• Clinical trials
  • For the present benefit assessment, the pharmaceutical manufacturer has submitted the SAPHYR study. This is a randomised, double-blind, parallel-group, multicentre study comparing sarilumab plus prednisone with placebo plus prednisone.

Adults with polymyalgia rheumatica who have responded inadequately to glucocorticoids or who experience a relapse whilst tapering off glucocorticoids

• For adults with polymyalgia rheumatica who have responded inadequately to glucocorticoids or who have experienced a relapse whilst tapering off glucocorticoids, the additional benefit of sarilumab compared with the appropriate comparator therapy is not proven.
• mortality
  • The results on all-cause mortality are based on data on fatal adverse events. No deaths occurred. There is therefore no statistically significant difference between the treatment arms for the endpoint of all-cause mortality.
• Morbidity – Remission
  • Achieving and maintaining remission is a key therapeutic objective in this therapeutic indication.
  • Overall, the endpoint ‘sustained remission’ and its individual components are not taken into account in light of the aforementioned confounding factors, which may have a particularly disadvantageous effect on the comparator arm.
  • No operationalisations suitable for benefit assessment are available for the endpoint ‘sustained remission’.
• Morbidity – time to first PMR relapse following clinical remission
  • In the dossier, the pharmaceutical manufacturer has submitted an analysis of the time to first PMR relapse following clinical remission. Due to the high rate of censoring in the event-time analysis (52% versus 22%), and notwithstanding the criticisms raised in connection with the endpoint ‘sustained remission’, this endpoint is not taken into account for the present benefit assessment.
• Morbidity – change in the duration of morning stiffness
  • For the endpoint ‘change in the duration of morning stiffness’, an analysis of the mean differences over the course of the study reveals a statistically significant difference of 22.43 minutes between the treatment arms in favour of sarilumab.
  • However, the medians and means of the baseline values for the patient characteristic of morning stiffness, as well as the observed standard deviations of the two treatment arms, differ significantly. There is therefore uncertainty as to the extent to which the present effect estimate was influenced by this.
  • Overall, the uncertainties are so great that no additional benefit can be inferred from the available results for the endpoint ‘duration of morning stiffness’.
• Morbidity – Upper limb mobility
  • For the endpoint ‘mobility of the upper limbs’, assessed as part of the PMR-AS study, an analysis of the mean differences over the duration of the study reveals a statistically significant advantage for sarilumab compared to the other treatment arms.
  • Overall, however, it cannot be concluded that the effect is clinically relevant, as the 95% confidence interval for the standardised mean difference (SMD) does not lie entirely below the irrelevance threshold of −0.2.
• Morbidity – Physical functional status
  • The endpoint ‘physical functioning’ was assessed using the patient-reported HAQ-DI questionnaire. The pharmaceutical manufacturer provides responder analyses showing a clinically relevant improvement in the HAQ-DI of ≥ 0.45 points. No statistically significant difference was observed between the treatment arms.
• Morbidity – Patient-reported global assessment of disease activity
  • In the SAPHYR study, the endpoint ‘patient-reported global assessment of disease activity’ was assessed as a VAS within the HAQ-DI. The responder analyses used to assess a clinically relevant improvement in the HAQ-DI VAS of ≥ 15 points show no statistically significant difference between the treatment arms.
• Morbidity – Fatigue
  • The endpoint ‘fatigue’ was assessed in this study using the ‘Functional Assessment of Chronic Illness Therapy-Fatigue’ (FACIT-Fatigue) questionnaire. No statistically significant difference was observed between the treatment arms in the proportion of patients with a clinically relevant improvement in the FACIT-Fatigue score of ≥ 7.8 points.
• Morbidity – Health status
  • For the health status endpoint, assessed using the VAS of the European Quality of Life Questionnaire 5 Dimensions (EQ-5D), there was no statistically significant difference between the treatment arms in the proportion of patients showing a clinically relevant improvement of ≥ 15 points.
• Health-related quality of life
  • Health-related quality of life was assessed using the physical and mental health summary scores of the generic Short Form 36-Item Health Survey Version 2 questionnaire. The responder analyses for a clinically relevant improvement of ≥ 10 points showed no statistically significant differences between the treatment arms for either total score.
• Side effects
  • For the endpoints of serious adverse events and discontinuation due to adverse events (AEs), as well as for AEs in the system organ class of infections and serious infections, there was no statistically significant difference between the treatment groups in each case.
• Overall assessment
  • For the endpoint categories of mortality, health-related quality of life and side effects, there was neither an advantage nor a disadvantage for sarilumab + prednisone compared with placebo + prednisone.
  • For the endpoint category ‘morbidity’, a statistically significant difference in favour of sarilumab was observed for the endpoints ‘duration of morning stiffness’ and ‘upper limb mobility’. However, for the endpoint ‘upper limb mobility’, it cannot be concluded that the observed effect is clinically relevant.
  • For the endpoint ‘duration of morning stiffness’, no additional benefit can be inferred due to uncertainties regarding the specific operationalisation and differences in baseline values.
  • For the endpoints of pain, physical functional status, patient-reported global assessment of disease activity, fatigue and health status, there are neither advantages nor disadvantages of sarilumab compared with the appropriate comparator therapy.
  • For the endpoint ‘sustained remission’, there are no operationalisations suitable for benefit assessment.
  • Overall, therefore, for adults with polymyalgia rheumatica who have responded inadequately to glucocorticoids or who experience a relapse whilst tapering off glucocorticoids, an additional benefit of sarilumab over the appropriate comparator therapy is not proven.

Courtesy translation only, please refer to the German original.