Skyrizi outperforms Stelara in endoscopic remission at week 48 in Crohn’s disease
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Key takeaways:
- Risankizumab was noninferior to ustekinumab in clinical remission at week 24 (58.5% vs. 39.5%).
- However, risankizumab demonstrated superiority in endoscopic remission at week 48 (31.8% vs. 16.2%).
Although Skyrizi was noninferior to Stelara in clinical remission at week 24, it was superior in endoscopic remission at week 48 in patients with moderate to severe Crohn’s disease, according to data from the SEQUENCE trial.
“In head-to-head trials directly comparing their efficacy in psoriasis, risankizumab was superior to ustekinumab, which suggests greater efficacy with p19 blockade than with p40 blockade,” Laurent Peyrin-Biroulet, MD, PhD, professor of gastroenterology at Nancy University Hospital in France, and colleagues wrote in The New England Journal of Medicine. “The relative efficacy of risankizumab and ustekinumab in inflammatory bowel disease has not been established.”
In the phase 3b, multicenter SEQUENCE trial, Peyrin-Biroulet and colleagues assessed the safety and efficacy of Skyrizi (risankizumab, AbbVie) vs. Stelara (ustekinumab, Janssen) in 520 adult patients with moderate to severe CD and a history of unacceptable side effects or inadequate response to anti-tumor necrosis factor therapy.
Patients were randomly assigned to risankizumab (n = 255; mean age, 38 years; 46.7% women) or ustekinumab (n = 265; mean age, 38.3 years; 50.6% women). Those receiving risankizumab received the 600 mg IV induction dose at weeks 0, 4 and 8 and subcutaneous 360 mg as maintenance every 8 weeks from weeks 12 to 48. Patients receiving ustekinumab received a single weight-based IV induction dose at week 0 (260 mg-520 mg), followed by subcutaneous 90 mg maintenance dosing at week 8, repeated every 8 weeks.
Coprimary endpoints were clinical remission at week 24, defined as a CD Activity Index score less than 150, analyzed in the first 50% of patients, and endoscopic remission at week 48, defined as a Simple Endoscopic Score for CD of 4 or less with a decrease of at least two points from baseline, analyzed in 100% of patients.
Researchers noted more patients in the risankizumab group completed all assigned treatments compared with the ustekinumab group (90.2% vs. 72.8%).
According to results, risankizumab demonstrated noninferiority to ustekinumab in clinical remission at week 24 (58.6%; 95% CI, 50.1-67.1 vs. 39.5%; 95% CI, 31.3-47.7), with an adjusted difference of 18.4 percentage points (95% CI, 6.6-30.3). Conversely, risankizumab demonstrated superiority in endoscopic remission at week 48 (31.8%; 95% CI, 26.1-37.5 vs. 16.2%; 95% CI, 11.8-20.7), with an adjusted difference of 15.6 percentage points (95% CI, 8.4-22.9).
Risankizumab also achieved superiority across multiplicity-adjusted secondary endpoints of endoscopic response at weeks 24 (45.2% vs. 26.4%) and 48 (45.1% vs. 21.9%), as well as glucocorticoid-free endoscopic remission (31.4% vs. 15.5%) and clinical remission (60.8% vs. 40.4%) at week 48.
Researchers reported that the proportion of patients who experienced any adverse event was similar between treatment groups (85.1% vs. 82.6%).
“In patients with moderate to severe Crohn’s disease who had had an inadequate response to anti-TNF therapy or unacceptable side effects with such therapy, risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 and superior with respect to endoscopic remission at week 48,” Peyrin-Biroulet and colleagues wrote. “No new safety risks were identified in association with risankizumab in this trial.”
Perspective
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Shubha Bhat, PharmD, MS, FCCP, BCACP
The SEQUENCE trial, which compared risankizumab with ustekinumab in the treatment of moderate to severe CD, was a welcomed addition within the IBD community. Upon risankizumab’s initial FDA approval, two notable distinctions from ustekinumab were observed: selective interleukin-23 inhibition (in contrast to dual IL-12/23 inhibition) and a higher dosing regimen.
The study results are clinically important, as achieving endoscopic healing is a critical treatment goal as outlined in the STRIDE II guideline, given the associated improved outcomes with this target once reached.
However, certain trial limitations should be noted, such as the exclusion of specific patient populations, including those with previous use of advanced therapies beyond anti-tumor necrosis factors; presence of short bowel, ostomy or anal pouch; the use of higher dose with risankizumab (360 mg) without permitting for ustekinumab dose escalation; the open-label design, which may introduce biases; and the higher dropout rates with ustekinumab (28%) vs. risankizumab (10%) due to lack of efficacy.
Furthermore, the study’s findings may not be applicable to patients with ulcerative colitis or bio-naive CD.
In clinical practice, risankizumab may be best utilized as a second-line agent, rather than ustekinumab, among patients with moderate to severe CD previously treated with anti-TNF therapies. However, payer acceptance of risankizumab may be slow, particularly with the anticipated introduction of multiple ustekinumab biosimilars in 2025. Additionally, ustekinumab is one of the first 10 drugs to be impacted by the Inflation Reduction Act of 2022’s Medicare Drug Price Negotiation Program.
While the clinical implications of the SEQUENCE findings are yet to be fully determined in this context, this head-to-head study represents a significant milestone in IBD research.
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