IL-23 inhibition is a promising therapeutic approach for IBD treatment. Refractory moderate to severe CD and UC patients, with no other treatment alternatives, were given risankizumab as a compassionate treatment. These patients were prospectively followed up for up to 52 weeks as part of a multicenter real-world study. In spite of their history of anti-TNF and other biologics failure, over 60% of CD patients achieved clinical remission as soon as week 12, and 100% of CD and 80% of the UC cohort achieved clinical response at week 26, which were maintained throughout the follow-up period.
The ADVANCE, MOTIVATE induction studies, and the FORTIFY study included bio-naïve patients as well as bio-exposure (most of them were only anti-TNF failures, while the minority were also exposed to other biologics including ustekinumab). (9, 10). In order to receive this experimental treatment outside of a clinical trial setting, patients in our cohort had to be refractory to all available biologic therapies including three anti-TNFs, as well as to both ustekinumab and vedolizumab for CD and vedolizumab and tofacitinib for UC patients. Therefore, our study population represents a cohort of continuously refractory patients. For instance, disease duration in years in our cohort was greater than the average in the FORTIFY trial (10.1 years vs. 16 years, FORTIFY vs. our cohort, respectively), with more patients having ileocolonic localization (47% vs. 75%, FORTIFY vs. our cohort, respectively). SES-CD scores, however, were similar between the cohorts.
Nevertheless, our results support the observed efficacy with risankizumab in patients with previous bio-failure in both induction studies and FORTIFY. In our cohort, we found that 62.5% of the CD patients given the lower, 180 mg dose, achieved clinical remission at week 12, which was maintained during the follow-up period. These findings are similar to the open-label trial that showed 53% of 101 patients treated with 600 mg risankizumab were in clinical remission at week 26 (2), and to a recent report by Oliver et al. (11). Moreover, 81.3% of patients achieved clinical response in this group. These results are in accordance with the induction study results (9) that showed significantly more patients with moderate to severe active CD who had an inadequate response or intolerance to conventional and/or biologic therapy treated with risankizumab 600 mg IV or 1200 mg IV at weeks 0, 4, and 8 achieved clinical remission and endoscopic response at week 12 compared with placebo.
Our cohort included a similar induction period at the same time points, with doses that varied between 600 to 1800 mg IV, for up to three time points. Since there were no clear guidelines, doses were modified according to the latest published recommendations. Interestingly, the 180 mg dosage group showed better outcomes than the 360 mg group. These findings may correlate to the published FORTIFY trial, that showed no superiority to the higher induction dosage (1200 mg induction) group, despite higher serum concentrations with the higher dose. Authors suggested that a plateau of the exposure-response curve near the maximum for efficacy was reached by fully saturating the target at the site of action (10).
Demonstration of treatment efficacy now requires both symptomatic relief, as determined by patient-reported outcome measures, and (more objectively) improvement of mucosal disease as measured by endoscopy (12). Since this was a real-world setting, for simplicity purposes, our study included HBI scoring for CD (13), which is less cumbersome than the commonly used Crohn's disease activity index (CDAI). The use of this score allowed for easier follow-up and eliminated the use of the diary card (patient pre-assessment) and stool frequency measurements. In addition, we performed laboratory tests to monitor CRP, hemoglobin and fecal calprotectin at weeks 12, 26 and 52. Laboratory parameters correlated with HBI scores and showed an improvement in CRP and calprotectin levels at both doses, starting from week 12.
In the ADVANCE trial, higher efficacy was observed in the subpopulation of patients with no previous failure of biologics versus the subpopulation with previous bio-failure, for both doses of risankizumab (9). Our cohort has shown high rate of efficacy even in very experienced biologic exposure patients. These results are encouraging and may allow more patients to receive this promising treatment even in a very progressive and refractory disease. Moreover, risankizumab was shown to have superior efficacy over ustekinumab in psoriasis, indicating potential benefits of selective IL23 inhibition (14, 15). These comparative trials are currently being conducted in CD as well (the SEQUENCE trial, NCT04524611).
Our cohort included five patients with UC. To the best of our knowledge, this is among the first reports of UC patients receiving this treatment (outside clinical trial setting), except for a report by Ziv et al, who reported on one patient with UC who received risankizumab after failure with ustekinumab, with promising results (16). Our cohort of patients showed nearly significant improvement by a reduction in Mayo severity score at 12 weeks with the 180 mg dose (p = 0.13) and at 26 weeks (p = 0.07), despite the small numbers and the further division into two dosage groups. For most of the UC patients (3/5) we also had results of endoscopic scores, all ranging from 1–2 at week 12, in comparison to 3 at baseline. These scores were maintained in week 52, with 3 endoscopies ranging from 0–2 (average score 1). The use of risankizumab for UC is currently being tested in a randomized, double-blind, placebo-controlled induction sub-study (NCT03398148).
Real-world evidence is limited. Data from a refractory cohort of 12 relatively severe CD patients treated with risankizumab showed similar results to our data (17). They also reported no serious AEs, except for two patients who experienced mild headaches. Overall, risankizumab in our cohort appears safe with zero rates of treatment-emergent SAEs, including serious infections, and with no AEs leading to hospitalization/ death in both risankizumab groups. Low rates of AEs and SAEs were also reported during the 12-week induction period of the ADVANCE, MOTIVATE trials.
Our study has limitations. Since this was a real-world multi-center study of refractory patients receiving the treatment as part of a compassionate use, discrepancies between dose regimes were noted, and the number of subjects is relatively small. Additionally, some data was missing, as not all patients were evaluated by endoscopy throughout the trial at the specified time-points. However, our results correlate with previous publications and support the effectiveness of risankizumab for refractory IBD patients.
In conclusion, our results support the efficacy and safety of risankizumab in real-world practice as treatment option for multiple-biologic refractory patients. We show a favorable safety profile of risankizumab that is consistent with previously published studies. Long-term effects in refractory CD, as well as UC patients should be further evaluated.