Sarilumab (1) – Kevzara®

• Clinical trials
  • The MONARCH study is a randomised, multicentre, double-blind RCT with a parallel-group design designed to compare sarilumab with adalimumab (as monotherapy).

a) Patients who do not have any unfavourable prognostic factors and who have responded inadequately to, or have been unable to tolerate, previous treatment with a disease-modifying antirheumatic drug (conventional DMARDs, including methotrexate (MTX))

• For patients without adverse prognostic factors who have responded inadequately to or are intolerant of previous treatment with a disease-modifying antirheumatic drug (conventional DMARDs, including MTX) or who were unable to tolerate such treatment, the additional benefit of sarilumab (in combination with MTX or as monotherapy in cases of MTX intolerance or contraindication) compared with the appropriate comparator therapy is not proven.
• No study was submitted that would have been suitable for assessing the additional benefit of treatment with sarilumab (neither as monotherapy nor in combination with MTX) compared with the appropriate comparator therapy.

b1) bDMARD-naive patients for whom first-line therapy with bDMARDs is indicated – sarilumab as monotherapy (if MTX is not tolerated or treatment with MTX is unsuitable)

• For bDMARD-naïve patients for whom treatment with bDMARDs is indicated for the first time (including both patients with unfavourable prognostic factors who have responded inadequately to or are intolerant of previous treatment with a disease-modifying antirheumatic drug (conventional DMARDs, including MTX) or have been unable to tolerate it, as well as patients with or without unfavourable prognostic factors who have responded inadequately to, or have been unable to tolerate, previous treatment with multiple disease-modifying antirheumatic drugs (conventional DMARDs, including MTX) or were unable to tolerate it), there is a hint of considerable additional benefit for sarilumab as monotherapy (population b1) compared with the appropriate comparator therapy, adalimumab,
• The significant positive effects of sarilumab on several morbidity endpoints and on health-related quality of life, without any disadvantages in terms of side effects compared with the appropriate comparator therapy, are assessed as a significant improvement in treatment-related benefit that has not been achieved to date.
• Based on these considerations, based on the information in the dossier and the results of the benefit assessment, the extent of the additional benefit of sarilumab as monotherapy compared with the appropriate comparator therapy, adalimumab, for the treatment of patients with moderate to severe rheumatoid arthritis who are being considered for bDMARDtherapy, is classified as considerable.
• Taken as a whole, the uncertainties described justify a downgrading of the certainty of the evidence, such that there is a hint of additional benefit.
• mortality
  • In the MONARCH study, overall mortality was recorded as the number of deaths during the observation period as part of the adverse event monitoring.
  • In the relevant patient population, there were no deaths, or one death, in the sarilumab arm by week 24.
  • Overall mortality did not differ statistically significantly between the two treatment groups.
• morbidity
  • In this analysis, morbidity is defined in terms of remission (CDAI ≤ 2.8), low disease activity (DAS28-ESR < 3.2), disease-specific symptoms (number of tender joints, number of swollen joints, morning stiffness, pain, fatigue), disease activity and physical functional status (HAQ-DI).
• Morbidity – Remission (CDAI ≤ 2.8)
  • Remission – assessed using the Clinical Disease Activity Index (CDAI) – is considered to be clinically relevant.
  • At week 24, there was no statistically significant difference in the proportion of patients achieving remission between treatment with sarilumab and the comparator intervention with adalimumab.
  • The endpoint ‘remission’ was also assessed using the Simplified Disease Activity Index (SDAI) and the Boolean definition according to ACR-EULAR. Even with these operationalisations, no statistically significant difference was observed between the treatment arms.
  • Overall, Sarilumab showed neither a positive nor a negative effect compared with Adalimumab for the endpoint of remission.
• Health-related quality of life – Health Survey Short Form 36 (SF-36)
  • The Health Survey Short Form 36 (SF-36) is a generic instrument for measuring health-related quality of life, comprising 8 domains and a total of 36 questions.
  • The post-hoc responder analyses , presented by the pharmaceutical manufacturer in addition to the evaluation as the mean change in the total score and based on a relevance threshold of ≥ 5, could not be taken into account for the benefit assessment of sarilumab due to incompleteness; the corresponding responder analyses for a MID of 5 were submitted for only one of the two SF-36 total scores (SF-36 PCS).
• Side effects – SAE, discontinuation due to AEs
  • For the patient-relevant endpoints SAE and discontinuation due to AEs, there is no statistically significant difference between sarilumab and the comparator treatment with adalimumab.
  • Nor were there any relevant differences when comparing the System Organ Classes (SOC) and Preferred Terms (PTs).
• Overall assessment
  • For bDMARD-naïve patients who are eligible for a bDMARD for the first time and who have been unable to tolerate MTX or are unsuitable for it, the summary findings in the morbidity endpoint category show no significant difference between sarilumab and adalimumab for the endpoint of remission; however, based on the low disease activity, a statistically significant advantage for sarilumab over the appropriate comparator therapy, adalimumab, can be inferred.
  • Furthermore, further advantages of sarilumab over adalimumab can be inferred for the patient-relevant endpoints of pain, patient-reported disease activity and physical functioning.
  • In the quality of life category, there is a statistically significant, clinically relevant effect in favour of sarilumab for the physical total score of the SF-36v2, whereas, for the mental health summary score of the SF-36v2, neither advantages nor disadvantages of sarilumab compared with adalimumab can be identified.
  • In the category of side effects, Sarilumab overall exhibits a comparable side effect profile to that of Adalimumab.
  • Overall, in the population shown here comprising bDMARD-naïve patients for whom treatment with bDMARDs is indicated for the first time, the categories of morbidity and quality of life show better outcomes with Sarilumab compared to the appropriate comparator therapy, Adalimumab, in the 24-week study, with no adverse effects of sarilumab to counterbalance them.
  • Overall, the adverse reaction profile of sarilumab is considered comparable to that of adalimumab, although a definitive assessment of the adverse reaction profile is not currently possible, particularly due to the minor number of patients in the study.

b2) bDMARD-naive patients for whom first-line treatment with bDMARDs is indicated – sarilumab in combination therapy with MTX

• No data were submitted to assess the additional benefit of sarilumab as combination therapy with MTX compared with the appropriate comparator therapy; consequently, the additional benefit of sarilumab in combination with MTX is not proven.

c) Patients who have responded inadequately to or have been unable to tolerate previous treatment with one or more bDMARDs

• For patients who have responded inadequately to prior treatment with one or more bDMARDs, the additional benefit of sarilumab (in combination with MTX or as monotherapy in cases of MTX intolerance or contraindication) there is no proof that it is more effective than the appropriate comparator therapy.
• No study has been submitted that would have been suitable for assessing the additional benefit of treatment with sarilumab (neither as monotherapy nor in combination with MTX) compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.