Mirikizumab (2) – Omvoh®

• Clinical trials
  • The VIVID-1 trial is a double-blind RCT comparing mirikizumab with ustekinumab or placebo in adults with moderate to severe active Crohn’s disease who have had an inadequate response to, no longer respond to, or are intolerant of conventional therapy (with corticosteroids, azathioprine, 6-mercaptopurine or methotrexate), a TNF-α antagonist or an integrin inhibitor, or who no longer respond to such treatment or are intolerant of it.

a) Adults with moderate to severe active Crohn’s disease who have had an inadequate response to, no longer respond to, or are intolerant of conventional therapy

• The additional benefit is not proven.
• mortality
  • No statistically significant difference was observed between the treatment arms for the endpoint ‘overall mortality’.
• Morbidity – Clinical remission (PRO2)
  • The endpoint ‘clinical remission’ was operationalised using PRO2. In accordance with the predefined criteria established during study planning, remission as measured by PRO2 was defined as an unweighted daily average stool frequency (CDAI-SF) ≤ 3 and, simultaneously, an unweighted daily average abdominal pain score (CDAI-AP) ≤ 1 (each averaged over a period of 7 days) at week 52. Neither value was permitted to be worse than at the start of the study.
  • For the endpoint of clinical remission, assessed using the PRO2, there was no statistically significant difference between the treatment arms.
• Morbidity – corticosteroid-free clinical remission (PRO2)
  • The endpoint of corticosteroid-free clinical remission was defined as clinical remission as assessed by the PRO2 at week 52, with no use of corticosteroids between weeks 40 and 52.
  • For the endpoint of corticosteroid-free clinical remission, assessed using the PRO2, there was no statistically significant difference between the treatment arms.
• Morbidity – Bowel symptoms (IBDQ)
  • For the endpoint ‘intestinal symptoms’, assessed using the corresponding subscore of the IBDQ, there was no statistically significant difference between the treatment arms.
• Morbidity – Systemic symptoms (IBDQ)
  • For the endpoint ‘systemic symptoms’, assessed using the relevant subscore of the IBDQ, there was no statistically significant difference between the treatment arms.
• Morbidity – Remission of urgent bowel movements (Urgency NRS)
  • The Urgency Numerical Rating Scale is a patient-reported single-item scale that assesses the severity of urgency (sudden and/or immediate urge) to defecate within the last 24 hours using an 11-point scale ranging from 0 (no urgency) to 10 (highest possible urgency).
  • For the endpoint of remission of imperative urge to defecate, as assessed using the Urgency NRS, there was no statistically significant difference between the treatment arms.
• Morbidity – extraintestinal manifestations
  • The endpoint ‘extraintestinal manifestations’ is generally considered to be patient-relevant. The endpoint is operationalised as the proportion of patients with extraintestinal manifestations (arthralgia, arthritis, iritis, uveitis, erythema nodosum, pyoderma gangraenosum and aphthous stomatitis) at the start of the study, in whom these had resolved by week 52. The analyses therefore do not include patients in whom extraintestinal manifestations first occurred during the course of the study. This is considered inappropriate, as not all patients included in the study are included in the analysis.
  • Consequently, no suitable data are available for the endpoint of extraintestinal manifestations.
• Morbidity – Fistulas
  • The endpoint ‘fistulas’ is considered to be patient-relevant. The endpoint is operationalised as the proportion of patients with draining skin fistulas at the start of the study and the closure of all draining skin fistulas by week 52. The analyses therefore do not take into account patients in whom draining skin fistulas only developed during the course of the study. As previously explained for the endpoint ‘extraintestinal manifestations’, this is deemed inappropriate.
  • Consequently, no suitable data are available for the ‘fistulas’ endpoint.
• Morbidity – Fatigue (FACIT Fatigue)
  • The fatigue endpoint was assessed in this study using the ‘Functional Assessment of Chronic Illness Therapy-Fatigue’ (FACIT-Fatigue) questionnaire.
  • There was no statistically significant difference between the treatment arms in the proportion of patients showing a clinically relevant improvement in FACIT-Fatigue of ≥ 8 points.
• Health-related quality of life – Inflammatory Bowel Disease Questionnaire (IBDQ) – total score
  • The IBDQ is a widely used and validated disease-specific instrument for the indication of Crohn’s disease. The IBDQ comprises a total of 32 questions on aspects of inflammatory bowel disease. The questionnaire comprises 4 domains: 10 questions on gastrointestinal symptoms, 5 questions on systemic symptoms, 12 questions on emotional functioning and 5 questions on social functioning. Each question can be rated on a scale of 1 to 7, with higher scores indicating a better state of health. The total score (IBDQ total score) ranges from 32 to 224 points.
  • No statistically significant difference was observed between the treatment arms in terms of health-related quality of life, as measured by the IBDQ total score.
• Side effects – Serious adverse events (SAE)
  • No statistically significant difference was observed between the treatment arms for the SAE endpoint.
• Overall assessment
  • In the mortality category, there was no statistically significant difference between the treatment arms for the endpoint of overall mortality.
  • In the morbidity category, there were no statistically significant differences between the treatment arms for the endpoints clinical remission (PRO2), corticosteroid-free clinical remission (PRO2), bowel symptoms (IBDQ), systemic symptoms (IBDQ), remission of the urge to defecate (Urgency NRS), fatigue (FACIT Fatigue) and health status (EQ-5D VAS), there were no statistically significant differences between the treatment arms. No suitable data are available for the endpoints extraintestinal manifestations, fistulas and impairment of activity (WPAI-CD Item 6).
  • In the health-related quality of life category, there were no statistically significant differences for the endpoints IBDQ total score, SF-36 physical composite score (PCS) and SF-36 mental composite score (MCS).
  • In the ‘Side effects’ category, there were no statistically significant differences between the treatment arms in the overall rates of SAEs and discontinuation due to AEs, nor in the specific AE ‘infections’ when examined in detail.
  • In the overall analysis of the results, there are therefore no statistically significant differences between the treatment arms across all categories. Consequently, no additional benefit of mirikizumab over ustekinumab can be established in adults with moderate to severe active Crohn’s disease who have responded inadequately to conventional therapy, are no longer responding to it, or have shown intolerance to it.

b) Adults with moderate to severe active Crohn’s disease who have responded inadequately to a biologic (TNF-α antagonist, integrin inhibitor or interleukin inhibitor), no longer respond to it, or are intolerant to it

• An additional benefit is not proven.
• mortality
  • For the endpoint ‘all-cause mortality’, there is no statistically significant difference between the treatment arms.
• Morbidity – Clinical remission (PRO2)
  • The endpoint ‘clinical remission’ was operationalised using PRO2. In accordance with the predefined criteria established during study planning, remission as measured by PRO2 was defined as an unweighted daily average stool frequency (CDAI-SF) ≤ 3 and, simultaneously, an unweighted daily average abdominal pain score (CDAI-AP) ≤ 1 (each averaged over a period of 7 days) at week 52. Neither value was permitted to be worse than at the start of the study.
  • For the endpoint of clinical remission, assessed using the PRO2, there was no statistically significant difference between the treatment arms.
• Morbidity – corticosteroid-free clinical remission (PRO2)
  • The endpoint of corticosteroid-free clinical remission was defined as clinical remission as assessed by the PRO2 at week 52, with no use of corticosteroids between weeks 40 and 52.
  • For the endpoint of corticosteroid-free clinical remission, assessed using the PRO2, there was no statistically significant difference between the treatment arms.
• Morbidity – Bowel symptoms (IBDQ)
  • For the endpoint ‘bowel symptoms’, assessed using the relevant subscore of the IBDQ, there was no statistically significant difference between the treatment arms.
• Morbidity – Remission of urgent bowel movements (Urgency NRS)
  • The Urgency Numerical Rating Scale is a patient-reported single-item scale that assesses the severity of urgency (sudden and/or immediate urge) to defecate within the last 24 hours using an 11-point scale ranging from 0 (no urgency) to 10 (maximum urgency).
  • For the endpoint of remission of imperative urge to defecate, as assessed using the Urgency NRS, mirikizumab demonstrated a statistically significant advantage over ustekinumab.
• Health-related quality of life – Inflammatory Bowel Disease Questionnaire (IBDQ) – total score
  • The IBDQ is a widely used and validated disease-specific instrument for the present indication of Crohn’s disease. The IBDQ comprises a total of 32 questions on aspects of inflammatory bowel disease. The questionnaire comprises 4 domains: 10 questions on gastrointestinal symptoms, 5 questions on systemic symptoms, 12 questions on emotional functioning and 5 questions on social functioning. Each question can be rated on a scale of 1 to 7, with higher scores indicating a better state of health. The total score (IBDQ total score) ranges from 32 to 224 points.
  • No statistically significant difference was observed between the treatment arms in terms of health-related quality of life, as measured by the IBDQ total score.
• Side effects – Serious adverse events (SAE)
  • No statistically significant difference was observed between the treatment arms for the SAE endpoint.
• Overall assessment
  • In the mortality category, there was no statistically significant difference between the treatment arms for the endpoint of all-cause mortality.
  • In the morbidity category, a statistically significant advantage of mirikizumab over ustekinumab was observed for the endpoint ‘remission of urgent bowel movements’ (Urgency NRS). For the endpoints clinical remission (PRO2), corticosteroid-free clinical remission (PRO2), bowel symptoms (IBDQ), fatigue (FACIT Fatigue) and health status (EQ-5D VAS), there were no statistically significant differences between the treatment arms. For the endpoint ‘systemic symptoms’ (IBDQ), there was also no statistically significant difference between the treatment arms overall. However, there was an effect modification by the characteristic ‘CDAI total score’ (< 300/≥ 300) at the start of the study. For patients with a CDAI total score < 300, mirikizumab showed a statistically significant advantage over ustekinumab. No suitable data are available for the endpoints ‘Extraintestinal Manifestations’, ‘Fistulas’ and ‘Activity Impairment’ (WPAI-CD Item 6).
  • In the health-related quality of life category, there were no statistically significant differences for the endpoints IBDQ total score, SF-36 physical composite score (PCS) and SF-36 mental composite score (MCS).
  • In the ‘Side effects’ category, there were no statistically significant differences between the treatment arms in the overall rates of SAEs or discontinuation due to AEs. In detail, a statistically significant advantage of mirikizumab was observed for the specific AE ‘infections’. An overall review of the results in the ‘Side Effects’ category does not indicate any additional benefit of mirikizumab compared with ustekinumab.
  • Subgroup analyses based on the characteristic ‘geographical region’ reveal numerous significant effect modifications, almost all of which relate to key endpoints. Statistically significant advantages are observed exclusively in the ‘other’ region, which comprises approximately 80 per cent of patients in Asia. For the regions of Europe and North America, however, the effects are not statistically significant. The situation is very similar for the characteristic ‘ancestry/ethnicity’ as it is for the characteristic ‘geographical region’.
  • Taking the results as a whole, there is therefore a statistically significant advantage of mirikizumab over ustekinumab in one morbidity endpoint (remission of the urgent need to defecate). However, given the effect modification observed across endpoints in relation to the characteristic ‘geographical region’, it is questionable whether the results are transferable to the German healthcare context. Therefore, on balance, no additional benefit of mirikizumab over ustekinumab is identified in adults with moderate to severe active Crohn’s disease who have had an inadequate response to a biologic (TNF-α antagonist, integrin inhibitor or interleukin inhibitor), no added benefit of mirikizumab over ustekinumab is identified.

Courtesy translation only, please refer to the German original.