Skyrizi induction therapy bests placebo in refractory Crohn’s
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Crohn’s disease previously unresponsive to conventional and biologic therapies showed response to Skyrizi, achieving clinical remission in more than a third of patients regardless of dosing, according to a presentation at Digestive Diseases Week.
“In ADVANCE and MOTIVATE, significantly more patients achieved the co-primary endpoints of clinical remission – with different definitions – and endoscopic response with risankizumab vs. placebo at week 12,” Geert R. D’Haens, MD, from Amsterdam University Medical Center said in his presentation. “Risankizumab showed efficacy regardless of biologic exposure status by subgroup analysis in patients with moderate-to-severe Crohn’s in ADVANCE. The non-biologic exposed patients had numerically higher rates of efficacy vs. bio-exposed patients.”
Across two double-blind phase three studies, D’Haens and colleagues randomly assigned patients with inadequate response or intolerance to biologic therapy and/or conventional therapy to receive IV risankizumab (Skyrizi, AbbVie) at 600 mg or 1,200 mg or to receive a placebo treatment at weeks 0, 4 and 8. All participants were considered refractive to treatments and categorized as moderate to severe Crohn’s. The ADVANCE trial included both patients naive to biologic therapy and those that were exposed. MOTIVATE included only exposed patients.
More than 95% of patients finished the 12-week dosing schedule and there were no COVID-19 infections, he said.
When looking at the ADVANCE trial, D’Haens showed that only 25.2% of the placebo recipients reached Crohn’s disease activity index (CDAI) remission compared with 45.2% of those receiving 600 mg of risankizumab and 41.6% of those receiving 1,200 mg (P < .001 for both). In looking at remission defined by stool frequency and abdominal pain score (SF/APS), 43.5% of the 600 mg group and 41% of the 1,200 mg group achieved the goal vs 21.7% of the placebo group (P < .001 for both). Endoscopic response was also similar with 40.3% of the 600 mg group and 32.2% of the 1,200 mg achieving remission vs. 12% in placebo (P < .001 for both).
In MOTIVATE, the results were very similar: 19.8% of placebo recipients reached CDAI clinical remission while 42.5% of those in the 600 mg group and 40.3% of those in the 1,200 mg group achieved that goal (P < .001 for both). For SF/APS clinical remission, 19.3% in the placebo group reached remission vs. 34.6% in the 600 mg group and 39.3% in the 1.200 mg group (P < .001 for both). Endoscopic response was shown in 11.2% of placebo recipients vs. 28.8% of the 600 mg group and 34.2% of the 1,200 mg group.
“There is clearly no dose-dependent effect,” D’Haens said.
Adverse events were “numerically higher” in the placebo group, D’Haens said, attributing them to uncontrolled activity of Crohn’s disease.
“Risankizumab intravenously at 600 and 1,200 mg at weeks 0, 4 and 8 was more effective than placebo at inducing clinical remission and endoscopic response at week 12 and both doses of risankizumab were generally well tolerated and safe,” he said.
Perspective
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Risankizumab is one of several novel biologics targeting interleukin-23. The data presented at DDW from the ADVANCE and MOTIVATE trials demonstrate 12-week induction benefits for both biologic naive and biologic experienced patients. Endpoints included the Crohn’s disease activity index (CDAI) and individual patient reported outcome (PRO) scores (mandated by some regulatory authorities) for stool frequency (SF) and abdominal pain (AP) as well as endoscopic responses.
As expected, outcomes were somewhat less for patients with prior biologic exposure, which is becoming an important group of patients given the abrogated long-term persistence of patients who start biologic therapies with TNF inhibitors. Most recently, AbbVie has also presented a press release from the 53-week maintenance extension study (FORTIFY).
Researchers re-randomized subcutaneous risankizumab 360 mg or 180 mg every 8 weeks or placebo for patients completing the 12-week induction. Of interest, the control group (placebo) responses were higher than anticipated at 52-weeks for patients achieving response at 12-weeks, which may represent the longer half-lives of the newer generation biologics compared with TNF inhibitors. There were no new safety signals for this class of agents that look to be promising as first- or second-line biologics.
My personal impression, which is reflected in the new AGA guidelines for moderate–severe Crohn’s disease is that we should be bypassing “conventional agents” (aminosalicylates, steroids, thiopurines) for patients with moderate–severe disease severity (based on young age, presence of extraintestinal manifestations, deep ulcers or evidence of transmural disease at diagnosis) and move directly to safe and effective long-term strategies which, at present, primarily include TNF inhibitors, anti-IL-12/23, anti-IL 23 or vedolizumab. The positioning of IL-23 inhibitors vs. IL-12/23 inhibitors will depend on more head-to-head and/or real-world data.
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D’Haens GR. Abstract 775a. Presented at: Digestive Disease Week; May 21-24, 2021 (virtual meeting).
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