SC Home Induction Wins FDA Nod but Payer Parity and Head-to-Head Gaps Cap Upside

FDA Approves Subcutaneous SKYRIZI Induction for Crohn's Disease

The U.S. FDA has approved a subcutaneous (SC) induction regimen for AbbVie's SKYRIZI (risankizumab-rzaa) for adults with moderately to severely active Crohn's disease. This approval allows patients to initiate treatment at home using an on-body injector (OBI) induction pack, continuing with OBI for maintenance every eight weeks. The decision is supported by positive Phase 3 AFFIRM trial results, where SC SKYRIZI demonstrated superior clinical remission and endoscopic response at week 12 compared to placebo. Efficacy was particularly strong in advanced therapy-naïve patients, with 74% achieving clinical remission and 60% achieving endoscopic response, significantly higher than placebo. The safety profile was consistent with previous findings, with no new risks identified.

• The Phase 3 AFFIRM trial showed subcutaneous SKYRIZI achieved superior co-primary endpoints of clinical remission (CDAI < 150) and endoscopic response (SES-CD > 50% reduction) at week 12 compared to placebo. Notably, 74% of advanced therapy-naïve patients achieved clinical remission (vs. 27% placebo) and 60% achieved endoscopic response (vs. 15% placebo), demonstrating market-leading outcomes in this subpopulation.
• The approval introduces a fully self-administered subcutaneous induction regimen (720 mg at weeks 0, 2, 4, 8) via an on-body injector (OBI), offering greater flexibility for patients to start treatment at home. This builds on the OBI's established user experience, with 88% of Crohn's disease patients in a real-world survey reporting it easy to use, enhancing treatment adherence and quality of life.
• Alongside the new induction regimen, the FDA also approved an update to SKYRIZI's U.S. Prescribing Information regarding tuberculosis (TB) testing. This revision allows healthcare providers to use clinical judgment when determining the necessity of TB evaluation prior to treatment initiation across all approved indications, providing greater flexibility in patient assessment.

Addressing Key Challenges in Moderately to Severely Active Crohn's Disease

Current approaches for moderately to severely active Crohn's disease are limited by suboptimal durability and escalating therapeutic demands. Despite established efficacy of advanced therapies, real-world studies reveal suboptimal treatment persistence and limited endoscopic healing.

• Inadequate response and loss of response drive discontinuation: Many patients with inflammatory bowel disease show an inadequate response or experience a loss of response to advanced therapies. Up to a third of patients show primary nonresponse to antitumor necrosis factor biological therapy, and of those who respond, up to 40% develop secondary loss of response. The median (95% CI) time to permanent discontinuation of first-line treatment was 12.3 (10.9, 13.6) months in patients with Crohn's disease, with lack of efficacy the most cited reason for switching to a different therapy.

• Long-term persistence declines despite optimization: The cumulative event-free rates at 1, 2, 5, and 10 years were 83.3%, 75.1%, 37.4%, and 23.3%, respectively, with incidence of loss of response of 10.6% per patient-year of follow-up. First-line advanced treatments were optimized in 191 (58.1%) Crohn's disease patients prior to permanent discontinuation, and second-line therapy was typically from a different class compared with the first-line treatment choice.

• Frequent need for dose escalation with disease-specific predictors: Dose escalation occurred in 69 (41.8%) of Crohn's disease patients on ustekinumab. In Crohn's disease, prior biologic use (OR 3.05; 95% CI: 1.31-7.14; p = 0.01) and prior immunomodulator use (OR 2.07; 95% CI: 1.00-4.29; p = 0.05) were significantly associated with escalation, and longer disease duration was also observed in escalated patients (median 6 vs. 4 years, p = 0.003). Immunogenicity is a major reason for secondary loss of response to infliximab.

• Limited mucosal, endoscopic, and fistula healing: Current medical and surgical approaches achieve long-term fistula healing in only approximately 50% of patients with perianal fistulizing Crohn's disease. More than 90% of patients undergo multiple operative interventions, and more than 50% of patients lose response over time to anti-tumor necrosis factor agents, particularly infliximab, which remain the cornerstone of medical therapy.

• Safety burden including infections and hepatic events: Long-term use of infliximab in Crohn's disease patients has a high risk of infections, with failure in mucosal healing and increased concomitant use of systemic corticosteroids as independent risk factors of infections during infliximab therapy. Reported risks include tuberculosis and hepatitis B virus reactivation, liver dysfunction observed in 23 of 134 (17.2%) HBsAg-positive patients with prolonged immunosuppression (>3 months) as an independent predictor (odds ratio [OR] 3.06; 95% confidence interval [CI] 1.02-9.16), and severe mixed hepatocellular and cholestatic liver injury progressing to acute liver failure requiring transplantation.

Pivotal AFFIRM Data for SKYRIZI Subcutaneous Induction in Crohn's

In the phase 3 induction trials U-EXCEL and U-EXCEED, patients with moderate-to-severe Crohn's disease were randomly assigned to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks, with 526 patients undergoing randomization in U-EXCEL and 495 in U-EXCEED. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks, and at week 52 a higher percentage had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons).

In the phase 3 induction studies ADVANCE and MOTIVATE, patients with moderately to severely active Crohn's disease received intravenous risankizumab (600 mg or 1200 mg) or placebo at weeks 0, 4, and 8. In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo, and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo, and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. In the phase 3 FORTIFY maintenance withdrawal study, 542 patients with clinical response to risankizumab were randomly assigned to subcutaneous risankizumab 180 mg, risankizumab 360 mg, or placebo every 8 weeks, with CDAI clinical remission reached in 74 (52%) of 141 patients with 360 mg risankizumab vs 67 (41%) of 164 patients with placebo (adjusted difference 15% [95% CI 5-24]) and endoscopic response in 66 (47%) of 141 patients vs 36 (22%) of 164 patients (adjusted difference 28% [19-37]).

Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib. For risankizumab induction, the overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials, and three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). For risankizumab maintenance, maintenance treatment was well tolerated, adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache.

SKYRIZI's Role in the Evolving Crohn's Disease Treatment Landscape

The treatment landscape for moderately to severely active Crohn's disease has expanded with interleukin-23 p19 inhibitors demonstrating efficacy in both biologic-naive and biologic-experienced populations. In the phase 3 ADVANCE and MOTIVATE induction trials, risankizumab 600 mg and 1200 mg achieved CDAI clinical remission rates of 45% and 42% versus 25% with placebo in ADVANCE and 42% and 40% versus 20% with placebo in MOTIVATE, with endoscopic response rates of 40% and 32% versus 12% in ADVANCE and 29% and 34% versus 11% in MOTIVATE. In the phase 2 GALAXI-1 trial, guselkumab 200→100 mg, 600→200 mg and 1200→200 mg achieved CDAI clinical remission at week 48 in 39 (64%), 46 (73%) and 35 (57%) patients compared with 37 (59%) in the ustekinumab group, with endoscopic response in 27 (44%), 29 (46%), 27 (44%) and 19 (30%), respectively, and endoscopic remission in 11 (18%), 11 (17%), 20 (33%) and four (6%), respectively. Long-term guselkumab treatment showed sustained efficacy through week 240, with 97.7% (n = 85 of 87) achieving clinical remission, 71.3% (n = 62 of 87) achieving endoscopic response, and 51.7% (n = 45 of 87) achieving endoscopic remission as observed.

Oral small molecules have emerged as a distinct class, culminating in the approval of upadacitinib for moderate to severe active Crohn's disease in adult patients since April 2023 by EMA/FDA based on two induction studies and a maintenance study showing superiority to placebo. Upadacitinib is the first and only JAK inhibitor approved in patients with CD and provides the first advanced oral treatment option for patients with CD. In CD, JAK inhibitor therapy was superior to placebo for induction of clinical remission [risk ratio [RR] 1.53, 95% confidence interval [CI] 1.19-1.98; I2 = 31%], and endoscopic remission [RR 4.78, 95% CI 1.63-14.06; I2 = 43%]. Within the class, tofacitinib demonstrates limited efficacy in Crohn's disease management, filgotinib initially showed clinical remission in phase 2 trials while its subsequent phase 3 studies failed to demonstrate consistent endoscopic improvement, and upadacitinib achieved notable clinical remission rates during both induction and maintenance phases of phase 2 trials.

Comparative and head-to-head trial data have refined positioning of biologics alongside newer mechanisms. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4.53 [95% CI 1.49-13.79]), infliximab combined with azathioprine (7.49 [2.04-27.49]), adalimumab (3.01 [1.25-7.27]), and ustekinumab (2.63 [1.10-6.28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol, while infliximab and azathioprine combination therapy was also associated with significantly higher odds than vedolizumab (3.76 [1.01-14.03]). In the SEAVUE phase 3b trial in biologic-naive patients, 124 (65%) of 191 patients in the ustekinumab group versus 119 (61%) of 195 in the adalimumab group were in clinical remission at week 52 (between-group difference 4%, 95% CI -6 to 14; p=0.42). In BERGAMOT, etrolizumab 210 mg did not achieve co-primary induction endpoints at week 14 with clinical remission in 48 (33%) of 145 versus 28 (29%) of 96 on placebo (adjusted treatment difference 3.8% [95% CI -8.3 to 15.3]; p=0.52) and endoscopic improvement in 40 (27%) versus 21 (22%) (5.8% [-5.4 to 17.1]; p=0.32), but maintenance etrolizumab achieved clinical remission in 76 [35%] of 217 versus 52 [24%] of 217 on placebo (11.3% [95% CI 2.7-19.7]; p=0.0088) and endoscopic improvement in 51 [24%] versus 26 [12%] (11.5% [4.1-18.8]; p=0.0026) at week 66.

SKYRIZI's SC Induction: Reshaping Crohn's Disease Patient Care

The recent FDA approval for a subcutaneous induction regimen of risankizumab in moderately to severely active Crohn's disease marks a pivotal moment for patient care, emphasizing convenience and accessibility. This decision allows patients to initiate treatment at home using an on-body injector (OBI), a significant shift from traditional intravenous induction. This patient-centric approach is poised to enhance adherence, a critical factor in managing a chronic, relapsing condition like Crohn's disease, ultimately leading to more sustained clinical and endoscopic remission.

Risankizumab, as a selective interleukin-23 (IL-23) p19 inhibitor, targets a key pathway in Crohn's disease pathogenesis, offering a potent mechanism of action. Clinical trials have consistently demonstrated its efficacy in inducing and maintaining remission, even in patients who have failed previous advanced therapies. This positions risankizumab as a strong contender in the evolving therapeutic landscape, offering a differentiated profile, particularly against broader IL-12/23 inhibitors like ustekinumab, with some indirect comparisons suggesting superior induction outcomes.

However, strategic considerations must account for the need for direct comparative efficacy data against other established biologics to fully define its optimal placement in treatment algorithms. While the on-body injector has shown high acceptability and a favorable safety profile in short-term studies, ongoing real-world evidence will be crucial to monitor long-term adherence rates and any potential device-related challenges. As the armamentarium for Crohn's disease expands, integrating risankizumab effectively will require a nuanced understanding of patient profiles, prior treatment histories, and the potential for biomarker-guided personalized medicine to maximize therapeutic success.