Y-ECCO Literature Review: James Gauci

Newer therapies have focussed on inhibition of the interleukin-23 (IL-23)-dependent pathway, which also contributes to inflammatory cytokine production. These drugs have shown efficacy in clinical trials for the treatment of psoriasis [1] and are now being studied in Crohn’s Disease. Ustekinumab, for example, downregulates both IL-12- and IL-23-mediated inflammation. Its efficacy in induction and maintenance of remission in Crohn’s Disease has been proven [2].

Risankizumab is a novel agent which selectively antagonises IL-23. As IL-12 plays a role in infection and cancer immunity, such a selective approach might be advantageous [3,4]. A double-blind phase 2 induction study carried out in 2017 showed that induction therapy with this drug was superior to placebo in achieving clinical and endoscopic remission at week 12 [5]. Hence followed the project discussed in this literature review – an open-label extension study that aimed to assess the efficacy and safety of extended intravenous induction and subcutaneous maintenance therapy with risankizumab.

Methods

The study population consisted of all 108 patients who completed the phase 2 induction trial. Most of these patients had originally failed TNF antagonists [4].

Patients who had not achieved deep (clinical and endoscopic) remission at week 12 received open-label intravenous risankizumab (600 mg every 4 weeks) for 12 weeks. Patients in deep remission at week 12 entered a 12-week washout phase. Clinical remission was defined as a Crohn's Disease Activity Index (CDAI) score <150, while endoscopic remission was defined as a Crohn's Disease Endoscopic Index of Severity (CDEIS) score ≤4, or ≤2 for patients with isolated ileitis.

Following this extended intravenous induction phase, patients in clinical remission at 26 weeks were invited to participate in the maintenance phase. This involved the administration of open-label subcutaneous risankizumab (180 mg every 8 weeks) for 26 weeks. 

Efficacy endpoints at 26 weeks were assessed. These included the proportion of patients who achieved clinical remission or clinical response (either CDAI score of <150 or a reduction from baseline of >100). These endpoints were re-assessed at 52 weeks, together with the proportion of patients who achieved endoscopic remission or endoscopic response (>50% reduction in CDEIS score from baseline), mucosal healing and deep remission. Safety was assessed in all patients.

Key findings

Six of the 108 patients who had completed the phase 2 induction study were in deep remission and were enrolled in the 12-week washout phase. The remaining 102 patients were not in clinical remission. Of these, 101 received 12 weeks of 600 mg risankizumab, while one patient opted out of the study. At week 26, 53% of these (n=54) were found to be in clinical remission. Maintenance treatment with risankizumab was administered to all these 54 patients, together with the six patients who had achieved deep remission at week 12, as well as another patient due to a protocol violation. 

At week 52, clinical remission was maintained in 71% (n=44), while a clinical response was seen in 81% (n=50). Additionally, 35% (n=22) were in endoscopic remission, while 55% (n=34) showed an endoscopic response. Mucosal healing (absence of mucosal ulceration) was noted in 24% (n=15) of patients while deep remission was achieved in 29% (n=18).

The drug showed a favourable safety profile. It was well tolerated, with the most common treatment-emergent adverse events being arthralgia (22%; n=25), headache (20%; n=23) and abdominal pain (18%; n=21). No treatment-related deaths occurred.

Conclusion

Despite advances in treatment, existing therapies in moderate to severe Crohn’s Disease are still associated with high rates of failure. This open-label study demonstrates the efficacy of risankizumab in improving remission rates at week 26, as well as maintaining remission until week 52. Such results assert the role of selective IL-23 blockade as a promising solution in refractory Crohn’s Disease.

References

1. Campa M, Mansouri B, Warren R, Menter A. A review of biologic therapies targeting IL-23 and IL17 for use in moderate-to-severe plaque psoriasis. Dermatol Ther. 2016;6:1–12.
2. Feagan B, Sandborn W, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s Disease. N Engl J Med. 2016;375:1946–60.
3. Brunda MJ, Luistro L, Warrier RR, et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med. 1993;178:1223–30. 
4. Stobie L, Gurunathan S, Prussin C, et al. The role of antigen and IL-12 in sustaining Thl memory cells in vivo: IL-12 is required to maintain memory/effector Thl cells sufficient to mediate protection to an infectious parasite challenge. Proc Natl Acad Sci USA. 2000;97:8427–32.
5. Feagan B, Sandbom W, Geert D'Haens, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017;38:1699–709.

James Gauci is a trainee in Gastroenterology and Hepatology at Mater Dei Hospital, Malta. He is interested in the new emerging therapeutic agents in Iinflammatory Bowel Diseases, and is keen to further his studies in this field.