Tofacitinib (1) – Xeljanz®

• Clinical trials
  • The ORAL STANDARD study is a randomised, multicentre, double-blind, 52-week RCT with a parallel-group design.
  • The ORAL STRATEGY trial is a randomised, multicentre, double-blind, parallel-group trial with a study duration of 12 months.

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 (classical DMARDs, including methotrexate (MTX))

• For patients who do not have any unfavourable prognostic factors and who have responded inadequately to, or are intolerant of, previous treatment with a disease-modifying antirheumatic drug (classical DMARDs, including MTX), the additional benefit of tofacitinib (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 tofacitinib (neither as monotherapy nor in combination with MTX) compared with the appropriate comparator therapy.

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

• No data were submitted to assess the additional benefit of tofacitinib as monotherapy (in cases of MTX intolerance or contraindication) compared with the appropriate comparator therapy; consequently, the additional benefit of tofacitinib in combination with MTX is not proven.

b2) bDMARD-naïve patients for whom first-line therapy with bDMARDs is indicated – tofacitinib in combination therapy with MTX

• 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 were unable to tolerate them, as well as patients with or without unfavourable prognostic factors who have responded inadequately to previous treatment with multiple disease-modifying antirheumatic drugs (conventional DMARDs, including MTX) or were unable to tolerate it), the additional benefit of tofacitinib (as monotherapy or in combination with MTX) compared with the appropriate comparator therapy is not proven.
• In light of these considerations, based on the information in the dossier, the results of the benefit assessment and the addendum, the G-BA considers that the additional benefit of tofacitinib plus MTX compared with the appropriate comparator therapy, adalimumab plus MTX, for the treatment of patients with moderate to severe rheumatoid arthritis who are eligible for bDMARD therapy for the first time, is not proven.
• mortality
  • No usable data on overall mortality are available for the relevant patient population.
  • In both studies, deaths were recorded as part of the adverse event monitoring. In the overall study population of the relevant study arms, one and two deaths, respectively, occurred in one of the two study arms during the observation period. Overall mortality did not differ statistically significantly between the two treatment groups.
• Morbidity – Remission (CDAI ≤ 2.8)
  • Remission – assessed using the Clinical Disease Activity Index (CDAI) – is considered to be of clinical relevance.
  • At week 52, in the patient population with an inadequate response to prior therapy with a cDMARD, approximately the same number of patients achieved remission whilst receiving tofacitinib+MTX or adalimumab+MTX, when the results of both individual studies and the meta-analysis were taken into account (overall RR: 0.98 [0.69; 1.40]; p-value = 0.919).
  • In the patient population with an inadequate response to prior therapy with multiple cDMARDs, the ORAL STRATEGY study showed a significant benefit of tofacitinib+MTX over adalimumab+MTX (RR: 1.81 [1.07; 3.07]; p-value = 0.028). However, neither the ORAL STANDARD study nor the meta-analysis of both studies reveals a statistically significant effect in favour of tofacitinib plus MTX compared with adalimumab plus MTX (overall RR: 1.46 [0.96; 2.21]; p-value = 0.076).
  • Furthermore, the endpoint ‘remission’ was assessed in both studies using the Simplified Disease Activity Index (SDAI), the DAS28-4 ESR or CRP, and the Boolean definition according to ACR-EULAR. The effects observed for the ‘remission’ endpoint when operationalised as CDAI ≤ 2.8 cannot be confirmed by any of the other operationalisations of remission presented. Overall, for the endpoint ‘remission’, tofacitinib plus MTX showed neither a positive nor a negative effect compared with adalimumab plus MTX.
• 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 responder analyses presented by the pharmaceutical manufacturer in addition to the evaluation as the mean change in the total score – based on a relevance threshold of ≥ 2.5 – are not taken into account for the benefit assessment, as in the present indication a MID ≥ 2.5 is not considered valid for the total scales of the SF-36 is not considered valid.
• Side effects – severe adverse events (SAEs)
  • For the SAE endpoint, depending on prior therapy, the ORAL STANDARD study showed a statistically significant disadvantage of tofacitinib+MTX compared with adalimumab+MTX in patients with an inadequate response to a cDMARD (15.7% vs. 5.1%; RR 3.05 [1.04; 8.97]; p=0.030). Neither the ORAL STRATEGY study nor the meta-analysis of both studies confirms the negative effects of tofacitinib plus MTX compared with adalimumab plus MTX for this patient population;
  • Furthermore, for the SAE endpoint in patients with an inadequate response to a cDMARD, the ORAL STANDARD study shows an effect modification by the characteristic of age. A statistically significant disadvantage was observed for patients under 65 years of age. However, this effect modification is not consistent between the two studies. The meta-analytic evaluation of the two studies also revealed no effect modification by the characteristic of age; consequently, this is classified as irrelevant in the overall assessment.
• Overall assessment
  • In summary, within the morbidity endpoint category, there are no statistically significant advantages or disadvantages for tofacitinib+MTX compared with the appropriate comparator therapy, adalimumab+MTX, either in terms of remission or low disease activity.
  • Nor can any differences be identified between the treatment groups, either for the patient-relevant symptoms of fatigue, pain, disease activity or swollen/tender joints, or for physical functional status.
  • In the quality of life category (assessed using the generic SF-36v2 acute instrument), there were likewise no statistically significant differences between tofacitinib+MTX and the comparator treatment with adalimumab+MTX.
  • In the category of side effects, there was again no overall higher incidence of side effects with tofacitinib+MTX compared with adalimumab+MTX.
  • Overall, in the population presented here, there are neither positive nor negative effects for tofacitinib+MTX compared with the appropriate comparator therapy, adalimumab+MTX, in the endpoint categories of mortality, morbidity and quality of life; for the endpoints considered here, there are no differences for bDMARD-naïve patients for whom bDMARD therapy is being considered for the first time.
  • The disadvantages of tofacitinib+MTX compared with adalimumab+MTX in terms of side effects from the ORAL STANDARD study are limited to the patient population with an inadequate response to a cDMARD (n=161) and are not confirmed in the ORAL STRATEGY (n=457) and in the meta-analysis, meaning that no additional benefit is derived for tofacitinib+MTX compared with the specific appropriate comparator therapy, adalimumab+MTX.

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

• For patients who have responded inadequately to prior treatment with one or more bDMARDs, the additional benefit of tofacitinib (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.
• The dossier did not provide any data for the relevant patient population c to assess the additional benefit of treatment with tofacitinib (in combination with MTX or as monotherapy in cases of MTX intolerance or contraindication) compared with the appropriate comparator therapy.
• The analyses for patient population c submitted with the statement are dated 11 January 2017. It is therefore not clear to what extent these complete analyses could not in fact have been submitted by the relevant date for the dossier submission (1 May 2017). This justifies the conclusion that the data could also have been submitted at an earlier date. Consequently, the data submitted subsequently with the response can be regarded as having been submitted after the deadline and were therefore no longer taken into account in the ongoing benefit assessment procedure.

Courtesy translation only, please refer to the German original.