Risankizumab SC Induction: Phase 3 Endoscopic Signal Is Real, But Comparator Silence Is the Defining Risk

AbbVie's SKYRIZI Shows Strong Endoscopic Outcomes in Crohn's Disease

AbbVie announced new findings from the Phase 3 AFFIRM study, demonstrating significant clinical and endoscopic outcomes with subcutaneous SKYRIZI (risankizumab-rzaa) in adults with moderately to severely active Crohn's disease. Presented at the American College of Gastroenterology 2026 Annual Scientific Meeting, the data showed that 35.8% of patients achieved endoscopic remission and 36.6% achieved ulcer-free endoscopy by Week 24. Among advanced therapy-naïve patients, these rates were even higher, reaching 45.1% for endoscopic remission and 49.0% for ulcer-free endoscopy. These results support the ongoing regulatory applications to the U.S. Food and Drug Administration and European Medicines Agency for a subcutaneous induction dosing regimen.

• The Phase 3 AFFIRM study revealed substantial endoscopic improvements with subcutaneous SKYRIZI in patients with moderately to severely active Crohn's disease. At Week 24, 35.8% of patients treated with SKYRIZI achieved endoscopic remission, defined as healing of the intestinal lining with little to no visible inflammation. Additionally, 36.6% achieved ulcer-free endoscopy, signifying the complete absence of ulcers, demonstrating SKYRIZI's potential for deeper disease control.
• SKYRIZI demonstrated consistent efficacy across diverse patient populations, including those who were advanced therapy-naïve and those who had previously experienced an inadequate response to advanced therapies. Notably, advanced therapy-naïve patients exhibited the highest rates of endoscopic improvement, with 45.1% achieving endoscopic remission and 49.0% achieving ulcer-free endoscopy at Week 24. This broad effectiveness provides crucial evidence for clinicians making treatment decisions.
• The safety profile of risankizumab through Week 24 in the AFFIRM study was consistent with previously known data, with lower rates of treatment-emergent adverse events observed in the risankizumab groups compared to placebo. No new safety signals were identified. These positive efficacy and safety findings bolster the regulatory applications for subcutaneous SKYRIZI induction in moderately to severely active Crohn's disease, which are currently under review by the U.S. Food and Drug Administration and European Medicines Agency.

AFFIRM's Endoscopic Remission and Ulcer-Free Outcomes for Crohn's Disease

Several recent studies have advanced the evidence base for moderately to severely active Crohn's disease. The GALAXI-1 trial evaluated guselkumab, an IL-23 inhibitor, across three intravenous induction regimens transitioning to subcutaneous maintenance through week 48. At week 48, CDAI clinical remission was achieved in 64% of patients in the guselkumab 200→100 mg group, 73% in the 600→200 mg group, and 57% in the 1200→200 mg group, with endoscopic response rates of 44%, 46%, and 44%, respectively. Endoscopic remission ranged from 17% to 33% across guselkumab arms. Adverse event frequencies in the three guselkumab groups combined reached 74% of 220 patients (353.1 events per 100 patient-years), with nasopharyngitis and upper respiratory infections as the most frequently reported infections. No active tuberculosis, opportunistic infections, or deaths occurred through week 48.

The VIVID-2 open-label extension study assessed long-term outcomes with mirikizumab, an anti-IL-23p19 monoclonal antibody, in patients who had completed the VIVID-1 trial. At week 104, 60.5% (modified non-responder imputation) of the efficacy population achieved endoscopic response, 37.9% achieved endoscopic remission, and 73.4% achieved CDAI remission. Among week 52 endoscopic responders who had achieved the specified endpoint at week 52, 81.8% maintained endoscopic response and 86.9% maintained CDAI remission at week 104. Among week 52 endoscopic non-responders, 30.9% achieved endoscopic response at week 104 following reinduction. During the second year of treatment, 64.7% of patients experienced treatment-emergent adverse events and 7.7% had serious adverse events, consistent with the known mirikizumab safety profile.

The ADVANCE and MOTIVATE phase 3 induction trials evaluated risankizumab, an IL-23 p19 inhibitor, at doses of 600 mg and 1200 mg intravenously at weeks 0, 4, and 8. All co-primary endpoints were met in both trials. In ADVANCE, CDAI clinical remission was achieved in 45% of patients receiving risankizumab 600 mg and 42% receiving 1200 mg, versus 25% with placebo; endoscopic response rates were 40% and 32%, respectively, versus 12% with placebo. In MOTIVATE, CDAI clinical remission rates were 42% and 40% for the 600 mg and 1200 mg doses versus 20% with placebo, and endoscopic response rates were 29% and 34% versus 11% with placebo. The overall incidence of treatment-emergent adverse events was similar across treatment groups in both trials, and the one death in a risankizumab-treated patient was deemed unrelated to the study drug.

Unpacking the AFFIRM Study Design for Crohn's Disease

Several pivotal trials have evaluated advanced therapies in moderately to severely active Crohn's disease (CD), employing randomized, double-blind, placebo-controlled or active-comparator designs with both induction and maintenance phases. Across these studies, primary endpoints consistently encompass clinical remission, clinical response, and endoscopic outcomes, with patient-reported outcomes (PROs) increasingly integrated as secondary measures.

• GALAXI-1 (Guselkumab, Phase 2): A randomized, multicentre, double-blind trial enrolling adult patients with moderately to severely active CD. Five treatment arms were evaluated in a treat-through design: three guselkumab intravenous induction doses (200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8) transitioning to subcutaneous maintenance at week 12, a ustekinumab reference arm (approximately 6 mg/kg intravenous at week 0, then 90 mg subcutaneous every 8 weeks), and a placebo arm. Key endpoints assessed at week 48 included CDAI remission (CDAI score <150), endoscopic response (≥50% improvement from baseline in SES-CD or SES-CD score ≤2), and endoscopic remission (SES-CD score ≤2). The primary efficacy analysis population comprised all randomised patients who received at least one dose of study drug, excluding those discontinued during a temporary study pause (NCT03466411).

• Risankizumab Phase 2 Open-Label Extension: Patients who achieved clinical response (decrease in CDAI from baseline ≥100) without clinical remission (CDAI <150) at week 26, or clinical response and/or remission at week 52 in the parent phase 2 study, were enrolled. All patients received open-label subcutaneous risankizumab 180 mg every 8 weeks; four patients who had lost response were first reinduced with risankizumab 600 mg every 4 weeks (three infusions). Efficacy outcomes included proportions of patients with clinical remission and endoscopic remission (observed analysis), sustained over a median of 33 months (167.0 patient-years). Safety endpoints included rates of serious adverse events, serious infections, opportunistic infections, and immunogenicity (NCT02513459).

• Risankizumab vs. Ustekinumab Matching-Adjusted Indirect Comparison (Phase 3 Trials): This indirect comparison drew on individual patient-level data from three risankizumab phase 3 trials (NCT03104413; NCT03105128; NCT03105102) and published aggregated data from three ustekinumab phase 3 trials (NCT01369329; NCT01369342; NCT01369355). During induction, patients received risankizumab 600 mg intravenous at weeks 0, 4, and 8, or a single dose of ustekinumab 6 mg/kg intravenous at week 0. During maintenance, patients received risankizumab 180 or 360 mg subcutaneous or ustekinumab 90 mg subcutaneous every 8 or 12 weeks to 52 weeks. Endpoints included proportions achieving CDAI response (decrease of ≥100 points or total score <150), CDAI remission (CDAI ≤150), endoscopic response (≥50% reduction from baseline in SES-CD), and endoscopic remission (SES-CD ≤2).

• Budesonide CIR (Phase 3, US): A multicenter, double-blind, randomized, placebo-controlled trial enrolling 200 patients with mild to moderate CD (CDAI between 200 and 450) involving the distal ileum and/or ascending colon. Patients received budesonide controlled ileal release 9 mg once daily, 4.5 mg twice daily, or placebo for 8 weeks. The primary endpoint was remission defined by a CDAI of 150 or less. Secondary measures included mean change from baseline CDAI and adverse event profiles, including plasma cortisol levels.

• Semapimod (CD04/CD05): A randomized, double-blind, placebo-controlled trial (CD04) followed by an open-label extension (CD05) in patients with moderate to severe CD (CDAI 250–400). Intravenous semapimod 60 mg was administered for 1 or 3 days versus placebo. The open-label extension allowed up to five additional semapimod HCl 60 mg daily doses administered three times every 6–8 weeks. Primary outcome measures were CDAI, IBDQ, Crohn's Disease Endoscopic Inflammation Score (CDEIS), and serum C-reactive protein concentration.

• Adalimumab Long-Term (CHARM/ADHERE): CHARM early responders randomised to adalimumab were followed for up to 4 years. Endpoints included remission (CDAI <150), response (CR-100), corticosteroid-free remission, and fistula healing. Analyses employed as-observed, last observation carried forward, and a hybrid nonresponder imputation approach for year 4 (hNRI). Adverse event incidence rates were tracked across the full treatment period (NCT00077779).

• Placebo Rate Meta-Analysis (Induction and Maintenance): A meta-analysis of phase 2/3 placebo-controlled trials (2010–2021) using individual patient data from 8 induction (n = 1147) and 4 maintenance (n = 524) trials quantified placebo clinical response and remission rates. Overall placebo induction response was 27% (95% CI, 23%–32%) and remission 10% (95% CI, 8%–14%); maintenance placebo response was 32% (95% CI, 23%–42%) and remission 22% (95% CI, 14%–33%). Patient-level factors—including baseline CRP, albumin, BMI, CDAI, and 2-item PRO scores—were evaluated as predictors of placebo outcomes via regression analyses.

Addressing Unmet Needs in Moderately to Severely Active Crohn's Disease

Despite meaningful advances in biologic and small-molecule therapies, substantial gaps persist in the management of moderately to severely active Crohn's disease. Refractory populations — those who have failed multiple lines of therapy — continue to drive research into novel combinations, alternative mechanisms, and precision sequencing strategies.

• Refractory and multi-biologic-failure patients: A significant proportion of patients with CD fail to achieve or sustain remission on biologic monotherapy, with sub-optimal response and remission rates documented across anti-TNF, vedolizumab, and ustekinumab. Real-world cohorts have enrolled patients exposed to three or more prior biologics, underscoring the need for effective options in this heavily pre-treated population. Dual biologic therapy (DBT) — specifically the combination of ustekinumab and vedolizumab — has been explored as a strategy to address this gap, with 76% of refractory patients achieving disease remission at week 52 in one retrospective cohort.

• Optimising biologic sequencing after anti-TNF failure: Real-world evidence from 13,222 IBD patients demonstrates that non-anti-TNF biologics are superior to a second anti-TNF after first-line anti-TNF failure in CD, yet treatment selection in this setting remains an active area of investigation. The SEQUENCE trial showed superiority of risankizumab over ustekinumab for disease response in patients who had previously failed an anti-TNF agent, and ustekinumab persistence was evaluated following the approval of risankizumab and upadacitinib, reflecting ongoing efforts to define optimal sequencing.

• Perianal and fistulising Crohn's disease: Perianal fistulas affect 13%–39% of patients with CD and carry therapy failure rates exceeding 50%. Anti-TNF agents are preferred for this subpopulation, with combined seton placement and anti-TNF allowing wound healing in 40%–70% of cases, yet no curative treatment exists. Emerging investigational approaches — including mesenchymal stem cell-derived extracellular vesicles delivered via nanofiber-hydrogel composites, allogeneic adipose-derived stromal cell injection (AlloFIST trial), and rhPDGF-BB-enhanced collagen plugs — are being evaluated to address the persistent unmet need for durable fistula closure.

• Paediatric patients with refractory or severe disease: The incidence of IBD among children and adolescents in Europe is approximately 10 per 100,000 per year, with 10%–40% experiencing primary non-response to anti-TNFα and a further 5%–20% per year experiencing secondary treatment failure. Ustekinumab (approved for CD in patients ≥2 years of age) and vedolizumab (currently off-label in paediatrics) represent the best-established options following anti-TNF failure, with reported clinical remission rates of 51% at week 52 for ustekinumab. The UNITI Jr phase 3 study reported 52.1% clinical remission at week 8 in paediatric patients weighing at least 40 kg, while evidence for IL-23p19 antibodies, JAK inhibitors, and S1P receptor modulators in this population remains predominantly derived from adult studies.

• Transmural healing as a treatment target: The optimal treatment target in CD remains undefined. Targeting transmural healing (TMH) may be associated with a lower risk of complications than clinical and endoscopic outcomes alone. The VECTORS phase 4 randomised controlled trial — enrolling approximately 304 adult patients with moderately to severely active CD — is prospectively evaluating whether a treatment strategy targeting corticosteroid-free intestinal ultrasound-based response or TMH plus clinical and biomarker remission is superior to targeting corticosteroid-free clinical and biomarker remission alone, with the primary efficacy outcome of corticosteroid-free endoscopic remission at week 48.

• Nutritional and dietary therapy as an underutilised strategy: Exclusive enteral nutrition (EEN) is established as a first-line induction therapy in paediatric CD, achieving remission rates comparable to corticosteroids while supporting growth and promoting mucosal healing, yet its use in adults remains selective. Structured exclusion diets such as the Crohn's Disease Exclusion Diet (CDED) and partial enteral nutrition offer feasible long-term approaches, particularly for patients with stricturing disease, malnutrition, or intolerance to pharmacologic agents — a population for whom pharmacologic options may be limited or poorly tolerated.

SKYRIZI's Subcutaneous Leap: Elevating Crohn's Remission and Convenience

The latest findings from the Phase 3 AFFIRM study for subcutaneous SKYRIZI (risankizumab-rzaa) in Crohn's disease represent a significant step towards a more patient-centric treatment paradigm. By demonstrating robust clinical and endoscopic outcomes with a subcutaneous induction regimen, particularly in advanced therapy-naïve patients, risankizumab is poised to offer a fully subcutaneous treatment pathway from initiation through maintenance. This shift is critical, as patient preference for self-administration, especially via convenient on-body injectors, is high and can significantly impact adherence and overall treatment success.

The emphasis on achieving endoscopic remission and ulcer-free endoscopy is paramount. Research consistently shows that these objective measures of mucosal healing are strongly associated with improved long-term outcomes, including reduced rates of hospitalization and surgery. The high rates observed in the AFFIRM study, particularly in patients new to advanced therapies, underscore risankizumab's potential to alter the natural course of the disease, aligning with the growing understanding that earlier, effective intervention leads to better patient prognoses.

However, the competitive landscape for inflammatory bowel disease therapies is dynamic. While risankizumab has shown favorable comparative efficacy, particularly in endoscopic outcomes against ustekinumab, other IL-23 inhibitors are also emerging with strong profiles. Sustained differentiation will be key. Furthermore, while the 24-week induction data is promising, the long-term durability of remission initiated solely via subcutaneous induction will be an important area for continued observation. Translating these impressive trial results into consistent real-world effectiveness will also require careful consideration of diverse patient populations and adherence challenges. Ultimately, a fully subcutaneous risankizumab regimen offers a compelling new option that could enhance patient experience and drive deeper, more durable remission in Crohn's disease.