Remission Doubled With Risankizumab vs Ustekinumab in CD

COPENHAGEN, Denmark — Risankizumab (Skyrizi, AbbVie) shows noninferiority for clinical remission at week 24, and superiority of endoscopic remission at week 48 when compared with ustekinumab (Stelara) in patients with moderately to severely active Crohn's disease (CD) who have failed one or more antitumor necrosis factor (anti-TNF) therapies, according to the results of the phase 3 SEQUENCE trial.

Secondary endpoints — presented for the first time here at the United European Gastroenterology (UEG) Week 2023 — also showed superiority of risankizumab, an IL-23 inhibitor, over ustekinumab, an IL-12 and IL-23 inhibitor, for clinical remission at week 48 (60.8% vs 40.8%) and a statistically significant endoscopic response also favoring risankizumab at weeks 24 and 48.

"With endoscopic remission we see that with a single agent we have doubled the endoscopic remission rate by moving from 16% to 31% with risankizumab [at week 48]," said Laurent Peyrin-Biroulet, MD, a gastroenterologist specializing in inflammatory bowel disease at Nancy University Hospital, Nancy, France. "Superiority for sure was met."

"This sort of thing happens once in your career," noted Peyrin-Biroulet, who presented the results of the study at the meeting. "It's totally amazing that everything you see here was in favor of risankizumab.

"Already we see the efficacy signal in the proportion of premature discontinuations at 2% vs 13% due to lack of efficacy [in risankizumab and ustekinumab, respectively]," he said. "This is due to drug failure."

Risankizumab is an IL-23 inhibitor that selectively blocks the cytokine IL-23, thought to be linked to a number of chronic immune-mediated diseases, by binding to its p19 subunit. It is the first IL-23 inhibitor to receive approval from the US Food and Drug Administration in June 2022 for moderately to severely active CD based on data from the ADVANCE, MOTIVATE, and FORTIFY trials.

Risankizumab and Ustekinumab Head-to-Head

The phase 3, open-label, multicenter, randomized, clinical trial evaluated risankizumab vs ustekinumab through week 48 in patients with moderately to severely active CD.

Participants were required to have a CD Activity Index (CDAI) score of 220 to 450 at baseline, a Simple Endoscopic Score for Crohn's Disease (SES-CD) of 6 or more for ileocolonic or colonic disease (and of 4 or more for isolated ileal disease), excluding the presence of a narrowing component, plus an average daily stool frequency of four or more and/or average daily abdominal pain score of 2 or more. They were also required to have previously failed one or more anti-TNF therapies.

Randomization was stratified by the number of anti-TNF therapies failed (one or more than one), and steroid use at baseline; steroids were then tapered from week 2. Two primary endpoints comprised clinical remission at week 24 (defined as CDAI < 150, noninferiority margin within 10% of risankizumab vs ustekinumab in 50% of participants), and also endoscopic remission (SES-CD of 4 or less, and at least a 2-point reduction vs baseline and no subscore greater than 1 in any individual component) at week 48 demonstrating superiority of risankizumab vs ustekinumab.

Secondary endpoints included clinical remission at week 48, endoscopic response at weeks 48 and 24, steroid-free endoscopic remission at week 48, and steroid-free clinical remission at week 48 (all tested for superiority of risankizumab vs ustekinumab).

Intravenous risankizumab at 600 mg was given at weeks 0, 4 , and 8 followed by subcutaneous risankizumab at a 360 mg maintenance dose every 8 weeks through week 48 (n = 255). Participants who completed the week 48 visit continued on subcutaneous risankizumab for up to an additional 220 weeks. Ustekinumab was given as a weight-based, intravenous induction dose at week 0 followed by a 90 mg subcutaneous dose every 8 weeks, starting at week 8 through week 48 (n = 265). Participants received open-label drug administration but efficacy assessment was blinded.

Superiority of Risankizumab

Both primary endpoints were met. For clinical remission at week 24, in half of the patients enrolled, rates were 58.6% (75/128) for risankizumab and 39.5% (54/137) for ustekinumab, for a difference of 18.4% [95% CI, 6.6 - 30.3], meaning that noninferiority was met within the predefined margin of 10%. The second primary endpoint of endoscopic remission at week 48 showed rates of 31.8% (81/255) for risankizumab and 16.2% (43/265) for ustekinumab (P < .0001 for superiority).

Risankizumab was found to be superior to ustekinumab for all secondary endpoints (all with P < .0001). Steroid-free endoscopic remission at week 48 showed a 16% difference, and steroid-free clinical remission at week 48 showed a 20% difference — both in favor of risankizumab.

In addition, more participants on risankizumab completed the study (89.4%) than those on ustekinumab (74.0%), Peyrin-Biroulet reported.

Adverse event rates (events per 100 person years) were comparable between the two drugs at 341.2 for risankizumab and 282.7 for ustekinumab. For risankizumab, no new safety risks were observed, and of those recorded, they were consistent with the known safety profile. Serious adverse events occurred in 10% of risankizumab-treated patients, and 17% of ustekinumab-treated patients.

"We know the safety of IL-23 inhibitors is good," said Peyrin-Biroulet. "If we look at all adverse events there was no difference across arms and in terms of serious adverse events, it was in favor of risankizumab because a CD flare is considered a serious adverse event."

Session co-moderator, Alessandro Armuzzi, MD, head of the Inflammatory Bowel Disease Center at the IRCCS Humanitas Research Hospital in Milan, Italy, commented on the findings. "The results look in favor of risankizumab — all the endpoints were met, not only the co-endpoints but also the secondary endpoints too," he said.

These results, showing a preference for risankizumab, have value in helping clinicians with the sequence of therapies when patients with Crohn's disease have failed one or more TNF inhibitor, said Armuzzi.

No funding for this study was disclosed. Peyrin-Biroulet has disclosed receiving fees from Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index, Sandoz, Celgene, Biogen, SamsungBioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSEImmunotherapeutics, Enthera, Theravance, Pandion, Gossamer, Viatris, ThermoFisher, ONOPharma, Mopac, Cytoki, Morphic, Prometheus, and Applied MolecularTransport. Armuzzi disclosed consulting/advisory board fees from AbbVie, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, and Tillots Pharma; speaker's fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, and Takeda; and research grants from MSD, Takeda, Pfizer, and Biogen.

United European Gastroenterology (UEG) Week 2023: Abstract LB01. Presented October 15, 2023.

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