FDA grants approval to first specific IL-23 inhibitor risankizumab for CD

Risankizumab receives an additional third indication approved by the United States (US) Food andDrug Administration (FDA) for the treatment of moderately to severely active Crohn’s disease (CD) inadult patients, supported by data from 2 induction clinical trials, namely ADVANCE and MOTIVATE;and 1 maintenance clinical trial called FORTIFY.1,2 Risankizumab is an interleukin-23 (IL-23) antagonistwhich targets IL-23A, directly inhibiting the IL-23-specific pathway.3 Though previous studies of IL-23inhibitors, such as ustekinumab, demonstrated efficacy and safety in treating CD, they were not superiorto the anti-tumor necrosis factor (TNF) antibody adalimumab, and that severely active CD patients maynot respond to the treatment.3 Thus, exploration of treatment options against IL-23A is on the rise.3

Genome-wide association studies showed that IL-23 receptor genepolymorphisms were strongly correlated to the development of CD,in which the pro-inflammatory cytokine IL-23 was responsible fortriggering a Th17 cell-related autoimmune response, causing intestinalinflammation.1-4 The humanized monoclonal antibody risankizumabinhibited the IL-23 cytokine via targeting the p19 subunit, and blockadeof IL-23 was shown to have therapeutic effects in adult patients withCD vs. placebo.1,2,4

ADVANCE and MOTIVATE were phase 3, placebo-controlled, multicenter,randomized and double masked induction clinical trials, which includeda 35-day screening period, a 12-week induction period, a 12-weekprolonged induction period, and a 140-day follow-up period.1 Patientsenrolled in the ADVANCE trial were intolerant or showed poor responseto biologic or conventional therapies without bio-failure; whereas theMOTIVATE trial only enrolled patients who have experienced bio-failure.1The enrolled patients were randomized into 3 groups to receive:1) 600mg risankizumab administered intravenously, 2) 1,200mgrisankizumab administered intravenously, and 3) placebo: 2:2:1 inADVANCE and 1:1:1 in MOTIVATE.1

Efficacy of risankizumab in the induction trials was determined byco-primary endpoints at week 12, including endoscopic response andclinical remission, and determined by the CD Activity Index (CDAI)or patient-reported outcome criteria, which were met in all trials andboth doses of risankizumab.1 In ADVANCE, the endoscopic response ratewas 40% with 600mg risankizumab, 32% with 1,200mg risankizumabvs. 12% with placebo, while the clinical remission rate was 45% with 600mg risankizumab, 42% with 1,200mg risankizumab vs. 25% withplacebo.1 In MOTIVATE, the endoscopic response rate was 29% with600mg risankizumab, 34% with 1,200mg risankizumab vs. 11% withplacebo, while the clinical remission rate was 42% with 600mgrisankizumab, 40% with 1,200mg risankizumab vs. 20% with placebo.1A significantly larger proportion of patients achieved the co-primaryendpoints endoscopic response and clinical remission, receiving either doses of risankizumab vs. placebo, also showing the clinical efficacyof risankizumab as induction therapy.1

The incidence of adverse events (AEs), abnormal findings duringphysical examinations, changes in vital signs, and clinical laboratoryparameters were considered at weeks 4, 8 and 12, when determiningthe safety of using risankizumab.1 The occurrence of AEs of safetyinterest was similar in all groups across ADVANCE and MOTIVATE,with the exception of serious infections, where the placebo grouppatients showed a slightly higher incidence rate.1 The findings in these 2 trials aligned with the known risk-benefit profile of risankizumab,showing that there were no safety risk or dose-dependent safetyconcern observed.1

On the other hand, risankizumab demonstrated its clinical efficacyand safety as a maintenance therapy for CD in the 52-week phase3 maintenance withdrawal study FORTIFY, which enrolled patientswho showed response to risankizumab in ADVANCE or MOTIVATE,and randomly assigned 1:1:1 to receive either risankizumab 180mg,risankizumab 360mg or placebo respectively.2 The co-primary endpointsof FORTIFY were the same as the induction studies, i.e., endoscopicresponse and clinical remission, which were met at week 52 for groupswith both doses.2 Safety assessment was also concluded, with no newsafety risk or dose-dependent pattern discovered.2 The findings ofthe FORTIFY trial aligned with those from ADVANCE and MOTIVATE,showing the benefit of continuing risankizumab as a maintenancetherapy after successful induction in patients.2

Of note, the trials did not evaluate small bowel lesions, except terminalileum and anal lesions, which are closely associated with the diseaseoutcome.3 Thus, further studies should investigate this area to understandmore about patient response to risankizumab.3 As the FDA approvedrisankizumab as the first and only IL-23 inhibitor for moderately toseverely active CD in adults, it is anticipated that there will be morepossibilities for future treatment of CD.

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