Risankizumab (3) – Skyrizi®

• Clinical trials
  • The SEQUENCE study is an ongoing, open-label RCT comparing risankizumab with ustekinumab in adult patients with active moderate to severe Crohn’s disease who have responded inadequately to TNF-α antagonists or have been unable to tolerate them.

a) Adults with moderate to severe active Crohn’s disease who have responded inadequately to conventional therapy, lost response to it, or are unable to tolerate it

• The pharmaceutical manufacturer has not submitted any (comparative) studies for the assessment of the additional benefit of risankizumab in adults with moderate to severe active Crohn’s disease who have responded inadequately to, lost response to, or are intolerant of conventional therapy.
• As no data are available, additional benefit for patient population a is not proven.

b) Adults with moderate to severe active Crohn’s disease who have responded inadequately to, lost response to, or are unable to tolerate a biologic (TNF-α antagonist, integrin inhibitor or interleukin inhibitor)

• Taking an overall view of the positive effects, whilst accounting for the uncertainties mentioned, the G-BA identifies a hint of a minor additional benefit.
• mortality
  • No deaths occurred in either treatment arm.
• Morbidity – Clinical remission (PRO-2)
  • In this assessment, the endpoint of clinical remission as measured by PRO-2 (comprising the symptoms of stool frequency and abdominal pain reported in a patient diary on a scale of 0 = none, 1 = mild, 2 = moderate, 3 = severe), operationalised as an average stool frequency of ≤ 2.8 per day and an average abdominal pain score of ≤ 1 per day, with neither being worse than at baseline, at week 24.
  • For the endpoint of clinical remission, assessed using the PRO-2, a statistically significant advantage was observed between the treatment groups in favour of risankizumab compared with ustekinumab.
• Morbidity – Steroid-free remission (PRO-2)
  • The endpoint of steroid-free remission was defined as an average daily bowel movement frequency of ≤ 2.8 and an average daily abdominal pain score of ≤ 1, with both being no worse than at baseline, whilst remaining steroid-free at week 24.
  • For the endpoint of steroid-free remission, assessed using the PRO-2, there was a statistically significant advantage for risankizumab compared with ustekinumab.
• Morbidity – hospitalisation (disease-specific hospitalisation and total hospitalisation)
  • Overall, it is not sufficiently certain that the endpoint ‘disease-specific hospitalisation’ actually reflects predominantly severe events caused by Crohn’s disease. It is therefore not used for the assessment in this case.
  • Furthermore, it must be assumed that data from follow-up therapy were also included in the analyses, although it remains unclear whether hospitalisations may also have occurred in connection with the initiation of follow-up therapies. Both of these issues also affect the ‘total hospitalisation’ endpoint, which is why it cannot be meaningfully interpreted and is therefore not used in this case either.
• Morbidity – Bowel symptoms (IBDQ)
  • For the endpoint ‘intestinal symptoms’, assessed using the corresponding IBDQ subscore, there is a statistically significant advantage for risankizumab compared with ustekinumab.
• Morbidity – Systemic symptoms (IBDQ)
  • For the endpoint ‘systemic symptoms’, assessed using the corresponding subscore of the IBDQ, there was no statistically significant difference between the treatment groups.
• Health-related quality of life – Inflammatory Bowel Disease Questionnaire (IBDQ)
  • 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 bowel 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.
  • With regard to health-related quality of life, as measured by the IBDQ total score, there is a statistically significant advantage for risankizumab over ustekinumab.
• Health-related quality of life – SF-36 Physical Composite Score (PCS)
  • For health-related quality of life, as measured by the SF-36 Physical Component Summary (PCS), there is a statistically significant advantage for risankizumab compared with ustekinumab. The 95% confidence interval for the standardised mean difference lies entirely outside the non-significant range [−0.2; 0.2]. This is interpreted as a clinically relevant effect.
• Health-related quality of life – SF-36 mental health summary score (MCS)
  • With regard to health-related quality of life, as assessed using the SF-36 Mental Health Subscale (MCS), there is a statistically significant advantage for risankizumab compared with ustekinumab. However, the 95% confidence interval for the standardised mean difference does not lie entirely outside the non-significant range [−0.2; 0.2]. It cannot therefore be concluded that the observed effect is clinically relevant.
• Side effects
  • No suitable data are available for the side effect endpoints. This is because, on the one hand, the selection of events that the pharmaceutical manufacturer considers to be disease-related does not appear to be exhaustive, and, on the other hand, it remains unclear on what clinical grounds the pharmaceutical manufacturer selected the relevant events.
• Overall assessment
  • For the benefit assessment, the ongoing, open-label SEQUENCE trial, which is currently ongoing, is available for the benefit assessment; this trial compares risankizumab with ustekinumab in adult patients with active moderate-to-severe Crohn’s disease who have responded inadequately to or are intolerant of TNF-α antagonists.
  • No deaths occurred.
  • In the morbidity category, statistically significant advantages in favour of risankizumab were observed for the endpoints clinical remission (PRO-2), steroid-free remission (PRO-2) and bowel symptoms (IBDQ).
  • In the health-related quality of life category, statistically significant and clinically relevant advantages in favour of risankizumab were observed for the endpoints IBDQ total score and the SF-36 physical summary score.
  • No suitable data are available for the side effects category.
  • An overall review of the results shows that, based on the positive effects of risankizumab in the endpoint categories of morbidity (clinical remission, steroid-free remission, bowel symptoms) and health-related quality of life (IBDQ total score, SF-36 physical summary score), a moderate improvement over the appropriate comparator therapy that has not been achieved previously, such that, overall, a minor additional benefit for risankizumab compared with ustekinumab is inferred.

Courtesy translation only, please refer to the German original.