Tag Archives: Ustekimuab

Ustekinumab in Pediatric Crohn’s Disease: Efficacy and Safety

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EB Mitchell et al. JPGN 2025;80:653–663. Ustekinumab is safe and effective in pediatric patients with Crohn’s disease

This was a retrospective longitudinal cohort study of 101 children with CD treated with ustekinumab from two large centers between 2015 and 2020. The median follow-up time on ustekinumab was 16.6 months. 

Key findings:

  • Fifty-nine patients were in steroid-free clinical remission at 1 year.
  • Higher baseline disease activity (odds ratio [OR]: 0.91 (p = 0.01) and stricturing/penetrating disease phenotype (OR: 0.14 p = 0.02) were associated with decreased likelihood of steroid-free clinical remission at 1-year
  • Ustekinumab drug escalation occurred in 70% of patients, and after escalation, 50 (70%) achieved clinical remission, and 49 (69%) achieved steroid-free remission at the last follow-up
  • Adverse events were rare and did not require therapy discontinuation

My take: More pediatric data showing efficacy for ustekinumab is important. My sense, though, is that newer IL-23 specific agents are going to eclipse ustekinumab in pediatrics as they are doing in adults.

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Efficacy of Mirikizumab in Moderate-to-Severe Crohn’s Disease (VIVID-1 Study)

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M Ferrante et al. The Lancet 2024; https://doi.org/10.1016/S0140-6736(24)01762-8. Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn’s disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study

Methods: VIVID-1 was a global phase 3, randomized, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study which enrolled 1150 patients with moderate-to-severe Crohn’s disease. There were three treatment groups: mirikizumab group, ustekinumab group, and placebo group. In each group, 48-49%were considered “biologic-failures” including 45-46% who were anti-TNF failures.

Key findings:

Discussion points:

Early treatment effect: “Symptomatic improvement was evident as early as week 4 accompanied by a statistically significant reduction in high-sensitivity CRP and faecal calprotectin, and endoscopic response was seen at week 12.”

Compared to ustekinumab: “Mirikizumab reached non-inferiority versus ustekinumab for clinical remission by CDAI at week 52…mirikizumab showed statistically significantly greater improvements from baseline in fecal calprotectin and CRP compared to ustekinumab.
In addition, a greater percentage of patients reached the combination endpoint of endoscopic response and clinical remission by CDAI at week 52.”

Comparison across treatment trials: “. At week 52, 45∙4% of patients treated with mirikizumab met the endpoint of clinical remission by CDAI in the treat-through analysis with composite endpoint, 54∙1% met the endpoint in the treat-through analysis, and 64∙3% met the endpoint in the responder analysis. This example, with a range of nearly 20% percentage points depending on analysis type, shows the profound limitations in comparing
unadjusted outcomes across phase 3 trials.” The authors note other differences in trial design between VIVID-1 and SEQUENCE (risankizimab) and state “no conclusions on
relative efficacy can be drawn.”

My take: This study shows that mirikizumab is effective in adults with moderate-to-severe Crohn’s disease with and without prior biologic treatments. Pediatric studies are underway.

Pediatric Data for Ustekinumab Therapy in Crohn’s Disease

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D Turner et al. JPGN 2024; 79:315–324. Ustekinumab in paediatric patients with moderately to severely active Crohn’s disease: UniStar study long-term extension results

Dosing: “Patients were randomised 1:1 and stratified by body weight (<40 or ≥40 kg) to receive a single induction dose of lower- or higher-dose IV ustekinumab (lower dose: 3 mg/kg [<40 kg] and 130 mg [≥40 kg]; higher dose: 9 mg/kg [<40 kg] and 390 mg [≥40 kg]). Doses specified as higher were selected to deliver ustekinumab exposure comparable to a reference adult population with CD.7, 12 At Week 8, patients received a single SC maintenance dose of ustekinumab (2 mg/kg [<40 kg]; 90 mg [≥40 kg]).”

Key findings:

  • Of the 34 patients who entered the LTE, 25 patients with evaluable data completed Week 48, and 41.2% (14/34) achieved clinical remission at Week 48
  • Efficacy and PK through 1 year in ustekinumab-treated paediatric patients were comparable to those previously reported in adults. No new safety or immunogenicity signals were reported through 4 years of ustekinumab treatment.

My take (borrowed in part from authors): “Overall, long-term data support the SC dose regimens of 90 mg as maintenance therapy for the treatment of CD for a paediatric population with ≥40 kg body weight. A phase 3 study of ustekinumab (ClinicalTrials.gov Identifier: NCT04673357) is ongoing to further evaluate dose regimens for paediatric patients <40 kg and ≥40 kg.” This type of data is essential to support the use of advanced therapies like ustekinumab until they receive specific regulatory approval for children (often 8-10 years after approval in adults).

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Risankizumab Outperforms Ustekinumab

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L Peyrin-Biroulet et al. NEJM 2024; 391:213-223. Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease

Background: “Interleukin-23 is a heterodimeric proinflammatory cytokine comprising a p40 subunit shared with interleukin-12 and a unique p19 subunit that plays a key role in skin, joint, and gastrointestinal inflammation.16 Ustekinumab and risankizumab are humanized IgG1 monoclonal antibodies; ustekinumab selectively binds p40, and risankizumab selectively binds p19…In head-to-head trials directly comparing their efficacy in psoriasis, risankizumab was superior to ustekinumab, which suggests greater efficacy with p19 blockade than with p40 blockade.”

This “SEQUENCE” trial was a phase 3b, multicenter, open-label, randomized controlled trial with 527 patients with moderate-to-severe Crohn’s disease who either had an inadequate response or had intolerance to anti-TNF agents, received either risankizumab or ustekinumab.

Key Findings:

  • A higher percentage of patients in the risankizumab group than in the ustekinumab group completed all the assigned treatment (90.2% [230 of 255 patients] vs. 72.8% [193 of 265 patients]).  The primary reason for discontinuation of risankizumab was an adverse event (3.1% [8 of 255 patients]), and the primary reason for discontinuation of ustekinumab was lack of efficacy (13.2% [35 of 265 patients]
  • Clinical remission at 48 weeks was 60.8% with risankizumab and 40.8%% with ustekinumab (P<0.001); there were similar rates of glucocorticoid-free clinical remission, 60.8% vs 40.4% respectively. Endoscopic response at 48 weeks was 45.1% and 21.9% respectively.

My take: These head-to-head results showed the superiority of risankizumab over ustekinumab across numerous clinical and endoscopic end points, including glucocorticoid-free clinical remission and endoscopic remission. However, it is still concerning to me that endoscopic remission rates were only 32% at 1 year and that less than half had an endoscopic response.

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Upadacitinib vs Ustekinumab for Ulcerative Colitis

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RS Dalal et al. Clin Gastroenterol Hepatol 2024; 22: 666-668. Comparative Effectiveness of Upadacitinib vs Ustekinumab for Ulcerative Colitis: A Multicenter Retrospective Cohort Study

This was a multicenter retrospective cohort study of adults with ulcerative colitis comparing upadacitinib (n=70) to ustekinumab (n=148). The upadacitinib-treated patients were all bio-exposed, had more advanced therapy failures, and higher baseline SCCAI (simple clinical colitis activity index).

Key findings:

  • Upadacitinib-treated patients had better outcomes: Clinical response of 82.9% vs. 63.5%, Steroid-free clinical remission 62.1 % vs. 34.7%, improvement in arthralgia 64.3% (9 of 14) vs 23.4% (11 of 47), and endoscopic remission 37.5% (9 of 24) compared with 15.9% (7 of 44).
  • The odds ratio (OR) after inverse probability of treatment-weighting were in favor of upadacitinib: Clinical response OR 2.39, SFCR OR 3.17, and endoscopic remission OR 5.10
  • Similar amounts of adverse effects were reported in each group

My take: Upadacitinib had better response rates within 52 weeks even though the patients receiving this medication had more advanced therapy failures. However, it is important to keep in mind the limitations of this retrospective study. The improved outcomes are in contrast to a study comparing another JAK inhibitor (tofacitinib) to ustekinumab in which the outcomes appeared equivalent (Tofacitinib vs Ustekinumab -Which is Better for Ulcerative Colitis?).

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Heron at Azalea Park (Sandy Springs, GA)