Baricitinib (1) – Olumiant®

• Clinical trials
  • In its benefit assessment dossier pursuant to Section 35a of the German Social Code, Book V (SGB V), the pharmaceutical manufacturer has presented the results of the JADV (RA-BEAM) study for patients with moderate to severe rheumatoid arthritis.

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 MTX)

• For 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 MTX), the additional benefit of baricitinib (as monotherapy or in combination with MTX) there is no proof that it is better than the appropriate comparator therapy.
• No study has been submitted that would have been suitable for assessing the additional benefit of treatment with baricitinib (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: - Evidence of autoantibodies (e.g. rheumatoid factors, high levels of antibodies against citrullinated peptide antigens) - High disease activity (as demonstrated by DAS or the DAS28 scoring system, swollen joints, acute-phase reaction parameters such as C-reactive protein and erythrocyte sedimentation rate) - Early onset of joint erosions - Baricitinib as monotherapy

• For bDMARD-naive 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 not tolerated it, as well as patients who have responded inadequately to or have not tolerated previous treatment with multiple disease-modifying antirheumatic drugs (conventional DMARDs, including MTX)), The additional benefit of baricitinib (as monotherapy or in combination with MTX) compared with the appropriate comparator therapy, adalimumab, is not proven.
• No data were submitted for the assessment of the additional benefit of baricitinib as monotherapy compared with the appropriate comparator therapy; consequently, the additional benefit of baricitinib as monotherapy is not proven.

b2) bDMARD-naive patients for whom first-line treatment with bDMARDs is indicated: - Evidence of autoantibodies (e.g. rheumatoid factors, high levels of antibodies against citrullinated peptide antigens) - High disease activity (as demonstrated by DAS or the DAS28 scoring system, swollen joints, acute-phase reaction parameters such as C-reactive protein and erythrocyte sedimentation rate) - Early onset of joint erosions - Baricitinib 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 have been unable to tolerate it, as well as patients who have responded inadequately to or been unable to tolerate prior treatment with multiple disease-modifying antirheumatic drugs (conventional DMARDs, including MTX)), The additional benefit of baricitinib (as monotherapy or in combination with MTX) compared with the appropriate comparator therapy, adalimumab, is not proven.
• mortality
  • Overall mortality did not differ statistically significantly between the two treatment groups, baricitinib+MTX and adalimumab+MTX.
• Morbidity – Remission (SDAI ≤ 3.3)
  • Remission – assessed using the Simplified Disease Activity Index (SDAI) – is considered clinically relevant.
  • At week 52, 22.6% of patients in the baricitinib+MTX arm and 17.9% in the adalimumab+MTX arm achieved an SDAI ≤ 3.3. There was no statistically significant difference between the treatment groups.
  • In the JADV study, the endpoint ‘remission’ was also assessed using the CDAI and the Boolean definition according to ACR-EULAR. For none of the operationalisations presented was there a statistically significant difference between the treatment arms.
• Morbidity – low disease activity (DAS28-hsCRP ≤ 3.2)
  • Low disease activity – as assessed using the DAS28-hsCRP – represents a patient-relevant endpoint.
  • For the endpoint of low disease activity (DAS28-hsCRP ≤ 3.2), no statistically significant difference was observed between the intervention arms (RR 1.14 [95% CI 1.00; 1.30]; p-value = 0.059).
  • In the JADV study, the endpoint ‘low disease activity’ was also assessed using the CDAI and SDAI. When low disease activity was defined as a CDAI ≤ 10, there was no statistically significant difference between the treatment groups (RR 1.14 [95% CI 1.00; 1.29]; p-value = 0.055). However, for the alternative definition of disease activity as SDAI ≤ 11, a statistically significant effect in favour of baricitinib can be observed (RR 1.16 [95% CI 1.01; 1.32]; p-value = 0.031).
• Morbidity – number of joints with tenderness
  • Twenty-eight joints were assessed for tenderness. The degree of tenderness in the joints was determined using a 2-point scale. A statistically significant difference was observed between baricitinib+MTX and adalimumab+MTX in terms of the mean change for the patient-relevant endpoint ‘number of joints tender to pressure’ (-10.0 vs. -9.0; LSMD -0.9 [95% CI -1.6; -0.1]; p-value = 0.032). However, the clinical relevance of this effect cannot be conclusively assessed, as the 95% confidence interval for the standardised mean difference does not lie entirely outside the irrelevance range of -0.2 to 0.2 (Hedges’ g: -0.1 [–0.3; 0.0]).
• Quality of life – Health Survey Short Form 36 (SF-36) – physical summary score
  • Analysis of the proportion of patients who achieved an improvement of ≥ 5 points in the SF-36v2akut physical total score at week 52 suggests a statistically significant effect in favour of baricitinib+MTX compared with adalimumab+MTX (60.0% vs. 51.8%; RR = 1.14 [95% CI 1.00; 1.29]; p-value = 0.047).
• Side effects – severe adverse events (SAEs)
  • For the SAE endpoint, a statistically significant disadvantage of baricitinib+MTX compared with adalimumab+MTX was observed in the overall population (7.8% vs. 3.9%; RR 1.98 [1.07; 3.66], p = 0.027). For this endpoint too, in line with the morbidity endpoint ‘disease activity (VAS)’, an effect modification was observed based on the joint erosion status, so that, for SAE, a statistically significant difference to the detriment of baricitinib+MTX compared with adalimumab+MTX is observed only in patients with ≥ 3 joint erosions (RR 2.81 [95% CI 1.32; 5.96]), whereas for patients with 1–2 joint erosions and seropositivity, the analyses did not reveal any statistically significant advantage or disadvantage.
• Overall assessment
  • For bDMARD-naive patients who are being considered for a biotechnological DMARD for the first time, an overall assessment is carried out.
  • In summary, both positive and negative effects are observed for patients who are being considered for bDMARD therapy for the first time.
  • In the morbidity endpoint category, based on physical functional status (HAQ-DI) and low disease activity (SDAI ≤ 11), a statistically significant advantage for baricitinib+MTX over the appropriate comparator therapy, adalimumab+MTX. It should be noted that further statistically significant advantages emerge in other morbidity endpoints for the overall population of patients being considered for bDMARD therapy for the first time, even though a definitive assessment of the clinical relevance of these additional positive effects is not possible.
  • In the quality of life category, a statistically significant effect in favour of baricitinib+MTX was observed for the physical summary score of the SF-36 (v2 acute).
  • In the category of serious SAEs, population b2 showed a higher incidence of harm with baricitinib+MTX compared with adalimumab+MTX.
  • Overall, in the study’s total population presented here, the advantages in the endpoint categories of morbidity and quality of life are repealed by the disadvantages in terms of side effects, meaning that the additional benefit of baricitinib+MTX compared with the specified appropriate comparator therapy, adalimumab+MTX, is not proven. Based on these considerations, the information in the dossier, the results of the benefit assessment and the addendum, the G-BA considers that the additional benefit of baricitinib 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.

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 previous treatment with one or more bDMARDs, the additional benefit of baricitinib (as monotherapy or in combination with MTX) 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 baricitinib (as monotherapy or in combination with MTX) compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.