Marla Dubinsky, MD: Clinical Outcomes with Risankizumab Versus Ustekinumab in SEQUENCE

Findings from a post-hoc analysis of the head-to-head SEQUENCE trial are providing additional insight into the efficacy of risankizumab versus ustekinumab for achieving clinical remission and other symptomatic improvements in patients with Crohn disease (CD) refractory to anti-tumor necrosis factor (TNF) therapy.¹

Results were presented at the European Crohn’s and Colitis Organisation Congress annual meeting in Stockholm, Sweden, this weekend and showed improvements in CD activity index (CDAI), stool frequency, and abdominal pain scores were greater with risankizumab than ustekinumab over 48 weeks of treatment.¹

Both interleukin-23 (IL-23) inhibitors, risankizumab and ustenkinumab received initial approvals from the US Food and Drug Administration FDA in 2019 and 2009, respectively. The pair eventually earned indications in CD as well, in 2016 for risankizumab and in 2016 for ustekinumab.²

SEQUENCE was an open-label, multicenter, randomized, efficacy assessment-blinded study in patients with moderate to severe CD refractory to anti-TNF therapy. Risankizumab and ustekinumab were compared head-to-head in patients with a confirmed diagnosis of CD for ≥ 3 months prior to baseline who had a CDAI score of 220-450 and demonstrated intolerance or inadequate response to ≥ 1 anti-TNF therapy.^1,2

“The importance is just really about using what we have available to us to help us make decisions,” Marla Dubinsky, MD, chief of the division of pediatric gastroenterology at Mount Sinai Kravis Children’s Hospital, explained in an interview with HCPLive. “This is really straight through head-to-head, no placebo, no withdrawal if you're doing well. The reason why this is important is in clinical practice, if someone is doing well, they typically stay on the drug. We don't tell them ‘Now it's time to come off,’ so the real application of the way these drugs actually are prescribed and designed in our practice is really what the head-to-head clinical trial design helps us learn from.”

Patients in the primary efficacy analysis set (n = 527) were randomized in a 1:1 ratio to receive an intravenous 600mg induction of risankizumab at baseline, week 4, and week 8, then 360mg subcutaneous maintenance every 8 weeks starting at week 12, or ustekinumab at a single weight-based intravenous induction followed by a 90mg subcutaneous maintenance every 8 weeks starting at week 8 up to week 48. A mandatory steroid taper began at week 2, and randomization was stratified by baseline steroid use and the number of failed anti-TNFs.¹

Prespecified, non-ranked endpoints included CDAI clinical response and stool frequency/abdominal pain score clinical remission. CDAI clinical remission at week 48 was a ranked secondary endpoint. Results for the primary endpoints and key secondary endpoints were previously presented at United European Gastroenterology Week 2023. CDAI clinical remission at weeks 8 and 24, and changes from baseline in average daily abdominal pain score, stool frequency, and CDAI were evaluated post-hoc.^1,2

Dubinsky highlighted the importance of endoscopic outcomes and endoscopic remission, but also pointed to the need for symptomatic measures as well: “There is really significant importance around why we care about endoscopy. However, taking a step back, it is also important for our communication with our patients why clinical outcomes are important.”

Results showed greater rates of CDAI clinical remission at week 24 were observed among patients taking risankizumab (59.6%) compared to ustekinumab (42.6%; P = .0001). Risankizumab also outperformed ustekinumab for stool frequency/abdominal pain score clinical remission (55.7% vs 41.1%; P < .001) and CDAI clinical response (69.8% vs 54.3%; P < .001) at week 24, with similar results observed at week 48.¹

The mean baseline abdominal pain score was 1.9 in both groups, although stool frequency and CDAI were both slightly lower in the risankizumab group (5.5 and 309.4, respectively) compared to the ustekinumab group (5.6 and 310.1, respectively). The least square mean changes from baseline across all 3 measures were greater with risankizumab than with ustekinumab and were observed as early as week 8 (P <.001 for abdominal pain score and stool frequency; P <.05 for CDAI).¹

“I think we use this to help start the dialogue around where we're moving. Realistically, we are moving into an era of IL-23, so we will continue to have more IL-23s in this space. The critical nature of us moving from an IL-12/23 world to a targeted IL-23 world, this was the beginning of that dialogue,” Dubinsky concluded.

References:

1. ^{Dubinsky MC, D’Haens G, Atreya R, et al. Risankizumab Versus Ustekinumab for the Achievement of Clinical Outcomes and Symptom Improvement in Patients With Moderate To Severe Crohn’s Disease: Results From the Phase 3b SEQUENCE Trial. Paper presented at: European Crohn’s and Colitis Organisation Congress 2024; February 21 - 24; Stockholm, Sweden. Accessed February 24, 2024.}
2. ^{Brooks, A. Risankizumab Achieves Primary Endpoints over Ustekinumab in SEQUENCE Trial. HCPLive. October 16, 2023. Accessed February 23, 2023. https://www.hcplive.com/view/risankizumab-achieves-primary-endpoints-over-ustekinumab-in-sequence-trial}