Upadacitinib (1) – Rinvoq®

• Clinical trials
  • The benefit assessment is based on the Phase III SELECT COMPARE trial submitted by the pharmaceutical manufacturer. This is a three-arm, randomised, double-blind trial comparing upadacitinib with adalimumab and placebo, each in combination with MTX.
  • The benefit assessment is based on the Phase III SELECT CHOICE trial submitted by the pharmaceutical manufacturer. This is a randomised, double-blind trial comparing upadacitinib with abatacept, each in combination with csDMARD treatment.

a1) Adult patients with moderate to severe active rheumatoid arthritis who do not have any unfavourable prognostic factors and who have responded inadequately to, or are intolerant of, prior treatment with a disease-modifying antirheumatic drug (conventional DMARDs, including methotrexate (MTX)) or who have not tolerated such treatment; upadacitinib as monotherapy

• For adult patients with moderate to severe active rheumatoid arthritis 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 (conventional DMARDs, including methotrexate (MTX)) or have been unable to tolerate such treatment; the additional benefit of upadacitinib (as monotherapy or in combination with MTX) compared with the appropriate comparator therapy is not proven.
• The dossier did not provide any data for the assessment of the additional benefit of treatment with upadacitinib as monotherapy compared with the appropriate comparator therapy.

a2) Adult patients with moderate to severe active rheumatoid arthritis who do not have any unfavourable prognostic factors and who have responded inadequately to previous treatment with a disease-modifying antirheumatic drug (conventional DMARDs, including methotrexate (MTX)) or have not tolerated it; upadacitinib in combination with MTX

• For adult patients with moderate to severe active rheumatoid arthritis 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 (conventional DMARDs, including methotrexate (MTX)) or have been unable to tolerate such treatment; the additional benefit of upadacitinib (as monotherapy or in combination with MTX) compared with the appropriate comparator therapy is not proven.
• The dossier did not provide any data for the assessment of the additional benefit of treatment with upadacitinib in combination with MTX compared with the appropriate comparator therapy.

b1) Adult patients with moderate to severe active rheumatoid arthritis for whom first-line treatment with biotechnologically produced DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) is indicated; upadacitinib as monotherapy

• For adult patients with moderate to severe active rheumatoid arthritis for whom first-line treatment with biotechnologically produced DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) is indicated, the additional benefit of upadacitinib as monotherapy compared with the appropriate comparator therapy is not proven.
• The dossier did not provide any data for the relevant patient population b1 to assess the additional benefit of treatment with upadacitinib as monotherapy compared with the appropriate comparator therapy.

b2) Adult patients with moderate to severe active rheumatoid arthritis for whom first-line treatment with biotechnologically produced DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) is indicated; Upadacitinib in combination with MTX

• Overall, at week 26, the advantages of upadacitinib + MTX on morbidity and on health-related quality of life (SF-36 physical summary score) without any disadvantages in terms of side effects compared with the appropriate comparator therapy, and is 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 upadacitinib in combination with MTX compared with the appropriate comparator therapy, adalimumab + MTX, for the treatment of adult patients with moderate to severe rheumatoid arthritis, who are eligible for bDMARD or tsDMARD therapy for the first time, is classified as considerable.
• There is a hint that there is an additional benefit.
• mortality
  • For the endpoint of all-cause mortality, a statistically significant advantage was observed at week 26 in favour of upadacitinib + MTX compared with adalimumab + MTX.
  • Given the small number of events that occurred by week 26 and, furthermore, taking into account the fact that there were no significant differences in mortality at week 48, the proof for the effect on all-cause mortality is classified as not sufficiently strong.
• Morbidity – Remission (CDAI ≤ 2.8; SDAI ≤ 3.3; Boolean definition according to ACR/EULAR)
  • Remission – assessed using the Clinical Disease Activity Index (CDAI) – is considered to be clinically relevant.
  • At week 26, a statistically significantly higher number of patients achieved remission with upadacitinib + MTX compared with treatment with adalimumab + MTX.
  • For the endpoint of remission at week 26, both the operationalisation as SDAI ≤ 3.3, as well as the operationalisation using the Boolean definition according to ACR-EULAR, confirm the statistically significant advantage of upadacitinib + MTX over adalimumab + MTX observed for the operationalisation defined as CDAI ≤ 2.8.
  • Overall, therefore, an advantage for upadacitinib + MTX over adalimumab + MTX is inferred for the endpoint of disease remission.
• Health-related quality of life – Health Survey Short Form 36 (SF-36) (improvement in SF-36 of ≥ 5 points)
  • For the SF-36v2 physical summary score, the analyses of the proportion of patients showing an improvement of ≥ 5 points reveal a statistically significant advantage in favour of upadacitinib + MTX.
  • The sensitivity analysis did not confirm the statistical significance of the effect.
  • For the mental health total score of the SF-36v2, however, no statistically significant difference was observed between the treatment groups.
• Side effects – severe adverse events (SAEs), discontinuation due to adverse events (AEs)
  • For the endpoints of SAE and discontinuation due to AEs, the SELECT COMPARE study showed no statistically significant advantages or disadvantages of upadacitinib + MTX compared with adalimumab + MTX at week 26.
• Overall assessment
  • In summary, within the morbidity endpoint category, statistically significant advantages were observed for upadacitinib + MTX compared with adalimumab + MTX for both remission and low disease activity, which were confirmed across all operationalisations.
  • In particular, for the endpoints of remission and low disease activity, the demonstrated effects of upadacitinib + MTX compared with adalimumab + MTX are classified as considerable in extent.
  • A statistically significant, clinically relevant advantage for upadacitinib + MTX over adalimumab + MTX can also be inferred for the morbidity endpoint of fatigue.
  • For physical functional status (HAQ-DI), there is a statistically significant advantage for upadacitinib + MTX compared with adalimumab + MTX, which is not confirmed in the sensitivity analysis.
  • For the morbidity endpoints number of tender joints, pain, patient-reported disease activity and severity of morning stiffness, there are statistically significant effects in favour of upadacitinib + MTX in each case; however, it cannot be concluded that the effect is clinically relevant in each instance.
  • For the endpoints of health status, number of swollen joints and duration of morning stiffness, there were no statistically significant differences between upadacitinib + MTX and the appropriate comparator therapy, adalimumab + MTX.
  • In the quality of life category, there was a statistically significant advantage for upadacitinib + MTX in the physical domain total score of the SF-36v2, which was not confirmed in the sensitivity analysis; by contrast, no differences were observed between the treatment groups in the mental health summary score of the SF-36v2 at week 26.
  • In the category of side effects, no overall advantages or disadvantages can be identified for upadacitinib + MTX compared with the appropriate comparator therapy, adalimumab + MTX, at week 26.
  • Overall, at week 26, upadacitinib + MTX showed exclusively advantages in terms of morbidity and health-related quality of life (SF-36 physical summary score), with no disadvantages in other categories to offset these.
  • Consequently, for adult patients with moderate to severe rheumatoid arthritis who are eligible for bDMARD or tsDMARD therapy for the first time, there is a hint of considerable additional benefit for upadacitinib in combination with MTX compared with the appropriate comparator therapy, adalimumab + MTX.

c1) Adult patients with moderate to severe active rheumatoid arthritis who have responded inadequately to, or have been unable to tolerate, prior treatment with one or more bDMARDs and/or tsDMARDs; upadacitinib as monotherapy

• For adult patients with moderate to severe active rheumatoid arthritis who have responded inadequately to, or are intolerant of, prior treatment with one or more bDMARDs and/or tsDMARDs, The additional benefit of upadacitinib as monotherapy compared with the appropriate comparator therapy is not proven.
• The dossier did not provide any data in the relevant patient population c1 for the assessment of the additional benefit of treatment with upadacitinib as monotherapy compared with the appropriate comparator therapy.

c2A) Adult patients with moderate to severe active rheumatoid arthritis who have responded inadequately to, or have been unable to tolerate, previous treatment with one or more bDMARDs and/or tsDMARDs; Upadacitinib in combination with MTX; patients with high disease activity [DAS28 CRP > 5.1]

• For adult patients with moderate to severe active rheumatoid arthritis who have responded inadequately to, or are intolerant of, prior treatment with one or more bDMARDs and/or tsDMARDs, there is evidence of a minor additional benefit for upadacitinib in combination with MTX compared with the appropriate comparator therapy, abatacept + MTX, for patients with high disease activity at the start of the study (DAS28 [CRP] > 5.1).
• Overall, in the relevant patient population, upadacitinib + MTX showed exclusively positive effects compared with abatacept + MTX at week 24, with no associated disadvantages.
• 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 upadacitinib in combination with MTX compared with the appropriate comparator therapy, abatacept + MTX, for the treatment of adult patients with moderate to severe rheumatoid arthritis, who have responded inadequately to or are intolerant of prior treatment with one or more bDMARDs and/or tsDMARDs, for patients with high disease activity at the start of the study (DAS28 [CRP] > 5.1), is classified as minor.
• It is assumed that there is a hint of additional benefit.

Courtesy translation only, please refer to the German original.