Summary

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• A phase 1 study (UNISTAR) evaluated the efficacy and safety of STELARA in pediatric patients with moderately to severely active Crohn’s disease (CD).^1,2
• Additionally, a prospective study, 2 retrospective studies, and 2 registries evaluated the use of STELARA in pediatric patients with CD.^3-10

CLINICAL DATA

Phase 1 Clinical Study

Rosh et al (2021)¹ evaluated the pharmacokinetics (PK), efficacy and safety of STELARA in pediatric patients with moderately to severely active CD or fistulizing CD for ≥3 months in a phase 1, multicenter, 16-week, double-blind induction dose-ranging study (UNISTAR).

Study Design/Methods

• Patients with moderately to severely active CD who were 2 to <18 years of age (body weight ≥10 kg) were included. Additionally, patients also had a Pediatric Crohn’s Disease Activity Index (PCDAI) score >30 and at least an abnormal C-reactive protein (CRP; >0.3 mg/dL) or fecal calprotectin (FCP; >250 µg/g), or ulcerations in the ileum and/or colon.
• All patients received previous or current treatment for CD, including oral corticosteroids (CSs) and/or immunomodulators (eg, azathioprine, 6-mercaptopurine, methotrexate); however, they were required to be stable prior to study start. Patients who failed or were intolerant to anti-tumor necrosis factor (TNF) therapy were also allowed to participate.
• Randomization (1:1) was performed for induction to 1 of 2 weight-based intravenous (IV) doses:
  • Lower IV induction dose: 3 mg/kg if body weight 10 kg to <40 kg or 130 mg if body weight ≥40 kg
  • Higher IV induction dose: 9 mg/kg if body weight 10 kg to <40 kg or 390 mg if body weight ≥40 kg
• At week 8, patients received a single subcutaneous (SC) maintenance dose of STELARA 2 mg/kg if body weight 10 kg to <40 kg or 90 mg if body weight ≥40 kg.

Results

Baseline Characteristics

• A total of 44 patients were randomized to either the lower dose STELARA IV induction (n=23) or the higher dose STELARA IV induction (n=21). The median age was 13 years (interquartile range [IQR], 12-16); 59% of patients had a body weight ≥40 kg and 91% had prior exposure to biologics (infliximab, adalimumab, and vedolizumab).
• A total of 73% (32/44) of patients were receiving ≥1 concomitant medications for CD at baseline which included immunomodulators (39%), oral CSs (32%), oral aminosalicylates (21%), and antibiotics (5%).
• Through week 16, 9.1% (4/44) of patients discontinued STELARA due to adverse events (AEs; worsening of CD [n=2] and lack of efficacy per the investigator [n=2]).

Pharmacokinetics

• Mean serum ustekinumab concentrations (SUC) were 51.3 μg/mL, 7.7 μg/mL, 3.0 μg/mL, and 1.6 μg/mL at weeks 0 (after infusion), 3, 6, and 8, respectively, for the lower induction dose group. Mean SUC for the higher induction dose group at the same time points were 149.0 μg/mL, 23.7 μg/mL, 9.1 μg/mL, and 4.8 μg/mL, respectively.

Clinical and Endoscopic Outcomes

• Clinical and endoscopic outcomes (clinical response, clinical remission, endoscopic response, and endoscopic remission) from week 3, week 8, and week 16 are shown in Table: Summary of Clinical Outcomes at Weeks 3, 8, and 16.

CS Use

• Steroid use from baseline to week 16 decreased in both lower (30% to 13%) and higher dose groups (33% to 19%).
  • At weeks 8 and 16, 22% (5/23) of patients in the lower dose group were in steroid-free clinical remission; in the higher dose group, 10% (2/21) and 24% (5/21) of patients were in steroid-free clinical remission at weeks 8 and 16, respectively.

Inflammatory Biomarkers

• In the lower dose group, 16.7% (3/18) of patients had normalized CRP levels at weeks 8 and 16, while in the higher dose group, 28.6% (4/14) and 21.4% (3/14) of patients had normalized CRP levels at weeks 8 and 16, respectively.
• Median (IQR) change in CRP concentration from baseline at week 8 vs change from baseline at week 16 was -0.7 (-8.0 to 0.1) mg/L vs 0 (-9.3 to 0) mg/L in the lower dose group and -0.3 (-14.4 to 0.3) mg/L vs -0.8 (-8.7 to 0) mg/L in the higher dose group, respectively.
• Median (IQR) change in FCP concentration from baseline at week 8 vs change from baseline at week 16 was 0 (-2395.0 to 418.0) mg/kg vs 0 (-3438.0 to 190.0) mg/kg in the lower dose group and -37.0 (-1347.0 to 553.0) mg/kg vs 0 (-‍1126.0 to 654.0) mg/kg in the higher dose group, respectively.

Clinical Outcomes and PK

• Clinical response at week 8 was achieved in 63.2% (12/19) of patients in the higher SUC group (>1.38 μg/mL) and 45% (9/20) of patients in the lower SUC group (≤1.38 μg/mL).
• Median improvement from baseline in PCDAI score at week 8 was 20 for patients in the higher SUC group (>1.4 μg/mL) and 17.5 for patients in the lower SUC group (≤1.4 μg/mL).
• There was no observable correlation between SUC and clinical remission at week 8.

Safety

• A total of 73% of patients reported ≥1 AE through week 16 which included 83% in the lower dose group and 62% in the higher dose group.
• Serious adverse events (SAEs) were reported in 16% of patients (lower dose group, 26%; higher dose group, 5%) with CD exacerbation being the most frequent (lower dose group, 9%; higher dose group, 5%).
• Infections (upper respiratory tract infection, anal abscess, Clostridium difficile, eczema infected, gastroenteritis, gastroenteritis viral, and nasopharyngitis) were reported in 39% of patients (lower dose: 39%, n=9; higher dose: 38%, n=8).
• A total of 2 patients discontinued treatment due to AEs (n=1, each dosing group) and no malignancies, deaths, injection-site reactions, anaphylaxis, serum sickness-like events, opportunistic infections, or antibodies to STELARA were reported through week 16.

Long Term Extension of UNISTAR

Turner et al (2024)² evaluated the PK, immunogenicity, efficacy, and safety of STELARA in pediatric patients with moderately to severely active CD in the long-term extension (LTE) of the UNISTAR study through week 240.

Study Design/Methods

• Patients who responded to STELARA, at the opinion of the investigator, at week 16 entered LTE and were continued on SC STELARA maintenance therapy every 8 weeks (q8w) up to week 240.
• Clinical efficacy and inflammatory biomarkers were evaluated from enrollment in LTE (week 16 of UNISTAR) through week 224.
  • Clinical remission was evaluated using PCDAI (PCDAI score ≤10 points), which was assessed q8w from weeks 24 to 48 and every 24 weeks from week 56 through the end of the study.
  • CRP was evaluated q8w from weeks 24 to 48 and approximately every 24 weeks thereafter.
  • Stool FCP and lactoferrin were evaluated every 24 weeks from week 24.
• SUC and antibodies were measured q8w through week 56, every 24 weeks thereafter, and at early termination and safety follow‐up visits.

Results

Baseline Characteristics

• Among the patients (N=44) who received STELARA, 34 were enrolled in LTE at week 16 and 8 completed the LTE.

Clinical Outcomes

• At weeks 16 and 48, 25% (11/44) and 41.2% (14/34) of patients achieved clinical remission, respectively.
• At week 48, 38.2% (13/34) of patients were in CS-free clinical remission and 90.0% (9/10) of patients who were in clinical remission at week 8 were still in clinical remission.

Inflammatory Biomarkers

• Among 17 patients with abnormal CRP values at week 0 and available CRP data at week 48, 41.2% (7/17) achieved normalization of CRP at week 48.
• Among 24 patients with abnormal CRP values at week 0 and assuming that patients with missing data did not achieve CRP normalization, 29.2% (7/24) achieved normalization of CRP at week 48.
• Among patients with abnormal FCP values at week 0 and available data at week 48, 36.8% (7/19) achieved normalization of FCP and 30.0% (6/20) achieved normalization of fecal lactoferrin at week 48.

Health-Related Quality of Life

• The mean (standard deviation [SD]) IMPACT-III score at week 0 was 107.9 (17.2). The mean (SD) IMPACT-III score at week 48 was 131.1 (22.8), showing a mean (SD) change of 23.9 (25.4) from baseline

PK and Immunogenicity

• Antibodies to STELARA were observed in one patient randomized to the lower induction dose with a peak titer of 1:100 and tested positive for neutralizing antibodies.

Safety

• Safety events from enrollment in the LTE through the final safety follow-up at week 240 is presented in Table: Safety Events in the LTE Period Through Week 240.

Prospective Study

Keller et al (2023)⁴ evaluated the association between ustekinumab trough levels (UTLs) and sonographic transmural healing in pediatric patients with inflammatory bowel disease (IBD) treated with STELARA.

Study Design/Methods

• The study included patients with IBD (aged ≤18 years) receiving maintenance STELARA treatment, who underwent intestinal ultrasound (IUS) examination and serum UTLs at a tertiary center.
• Patients with IUS and UTL performed on 2 events >6 months apart were included in a per-event analysis.
• The primary outcome was the comparison of UTL between patients with and without transmural healing (defined as bowel wall thickness <3 mm and no hyperemia [bowels with hyperemia] on color Doppler, using the Mann-Whitney U test).
• Secondary outcome was the comparison of UTL for each IUS parameter.

Results

• Among 44 children with IBD, 34 had CD.
• The baseline characteristics of patients with CD were as follows:
  • Median age: 14.9 years (IQR, 12.9-16.6)
  • Median disease duration: 3.83 years (IQR, 1.76-5.07)
  • Median time between UTL and IUS: 0 days (IQR, 0-26.5)
• Overall, 18 (53%) patients with CD achieved transmural healing.
  • Higher UTL was associated with transmural healing (11.7 [5.3-17.0] µg/mL) vs without transmural healing (5.5 [4.2-11.0] µg/mL; P=0.013).
• Optimal UTL cut-point for transmural healing detection was 11.4 ug/mL for patients with CD (AUROC, 0.661; sensitivity, 59%; specificity, 79%).

Retrospective Studies

Pujol-Muncunill et al (2024)³ evaluated the efficacy and safety of STELARA in pediatric patients with CD in a multicenter, retrospective study (STEP-CD Study) from the pediatric IBD Porto group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

Study Design/Methods

• Children with CD (2-18 years of age) from 23 centers worldwide who were treated with STELARA monotherapy or with STELARA combined with other medications were included in the study.
• The primary outcome was the proportion of patients who achieved CS- and exclusive enteral nutrition (EEN)-free clinical remission (defined by weighted Pediatric Crohn’s Disease Activity Index [wPCDAI] <12.5) or clinical remission by Physician Global Assessment (PGA) at week 12 without the need for any IV, oral, or topical CS at the time of assessment or ≥25% of the daily energy intake from a partial exclusive nutrition formula.
• Secondary outcomes were CS- and EEN-free sustained remission at week 52; CS-, EEN-, and surgery-free remission at week 52; rate of response (defined by wPCDAI >17.5) or remission (defined by wPCDAI <12.5) after STELARA dose optimization; rate of deep remission (defined as clinical remission, FCP <100 µg/g, and CRP <5 mg/L).

Results

Baseline Characteristics

• A total of 101 patients with a mean age of 15.4 years (IQR, 12.7-17.2) were included.
• The median wPCDAI at treatment initiation was 38.7 (IQR, 25-57.5).
• Baseline patient characteristics are presented in Table: Select Baseline Demographics and Clinical Characteristics.

• The recommended induction and maintenance dosing for STELARA in adult patients (~6 mg/kg) was used in 87% (88 patients) and 79% of patients, respectively.
• The intention-to-treat CS- and EEN-free response rate at week 12 was 72.9% (95% CI, 61.9-81.7). Among these patients (n=74), remission was observed in 30 patients (40.5%; 95% CI, 30.1-51.9) and complete deep remission was observed in 8 patients (10.8%; 95% CI, 5.6-19.9).
• At week 52, 30 of 74 patients were in CS- and EEN-free clinical remission (40.5%; 95% CI, 30.1-51.9), and 16 of 74 patients were in sustained CS-, EEN-, and surgery-free remission (21.6%; 95% CI, 13.7-32.2).
• The remission rate was similar between patients on combination therapy (corticosteroids and/or thiopurines) and those on monotherapy at weeks 12 (27.6% vs 47.2%; P=0.086) and 52 (58.8% vs 48.4%; P=0.349).
• Data on predictive factors associated with STELARA-induced clinical remission at week 12 are presented in Table: Multivariate Analyses of STELARA Response.

• At 52 weeks of follow-up, 51 of 74 patients (68.9%) remained on STELARA treatment (median duration of 10.6 months [IQR, 6.0-12.0]).
• A total of 23 patients (22.7%) were discontinued from the STELARA treatment due to lack of response, n=21; lingual vasculitis as a suspected AE of STELARA, n=1; and death nonrelated to STELARA therapy, n=1.
• STELARA treatment was ceased in 4 patients (5.4%) and 23 patients (31.1%) within 12 weeks and 1 year, respectively.
• Six patients (6%) required surgical treatment during the 12 months of treatment (intestinal resection, n=4; endoscopic dilatation, n=1; and surgical treatment for perianal disease, n=1) at a median time of 6.9 months (IQR, 3.5-9.6). All the patients continued on STELARA treatment after surgery.
• At 12 months of follow-up, 7 mild to moderate AEs (probably drug related) were reported: 3 cases of infections (herpes zoster, axillary abscess, and appendicitis), 2 cases of abnormal blood monitoring tests (1 case of hepatic enzyme elevation and 1 case of lymphopenia not requiring discontinuation), 1 case of eczema, and 1 case of lingual vasculitis. No malignancies or serious drug-related AEs were reported.

Koudsi et al (2023)⁵ conducted a retrospective, multicenter study assessing the effectiveness and safety of STELARA in pediatric patients with CD at pediatric IBD centers in France affiliated with Groupe d’Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID).

Study Design/Methods

• The study included patients aged ≤18 years who had received STELARA.
• All patients received the initial STELARA IV dose (6mg/kg), followed by a 90 mg SC dose after 8 weeks.
• Disease activity was assessed using the Pediatric Crohn Disease Activity Index (PCDAI), categorized as remission (<10), mild (<30), moderate (≥30-40), and severe (≥40) disease. A clinically significant response to therapy was defined as a score change of ≥12.5 points.

Results

Baseline Characteristics

• A total of 53 children with IBD were included, of whom 48 (90.6%) patients had CD.
• The median follow-up duration was 10.5 months (range, 1-51).
• Among the 48 patients with CD, 30 (65.2%) had ileocolonic disease, 11 (23.9%) had colonic disease, and 5 (10.9%) had an isolated ileal inflammation.
• Mean PCDAI at baseline was 28.7 in 35 patients, <15 in 9 patients, and >45 in 6 patients.

Effectiveness

• At 3 months postinduction, compared to baseline among CD and ulcerative colitis (UC) patients:
  • Mean weight increased significantly from 45 kg (21.5-70.5) to 49 kg (23.3-73), P<0.001.
  • Body mass index (BMI) increased from 19 kg/m² (13-32.6) to 20 kg/m² (15.7-33.6), P<0.001.
  • CRP levels significantly decreased at 3 months (P<0.05) and at the last follow-up (P<0.001).
  • Blood albumin levels significantly increased at 3 months (P<0.005) and at the last follow-up (P<0.001).
  • The erythrocyte sedimentation rate was significantly lower (P<0.001) and hematocrit rate was significantly higher (P<0.005) at the last follow-up.
• PCDAI score significantly decreased at 3 months (P<0.05) with 17 (48%) patients achieving a PCDAI <15, increasing to 20 (57%) patients at the last follow-up.
• Among CD and UC patients at baseline, 9 (16%) patients were steroid-free, increasing to 31 (58%) at 3 months and 33 (62%) at the last follow-up.
• Among the 20 (42%) patients with perineal CD at baseline, 9 had active perineal lesions at STELARA induction, with 1 patient developing perineal inflammation during treatment. Improvement in lesions was observed in 5 (50%) patients with STELARA treatment.
• Among 20 patients with perianal and nonperianal CD, the mean PCDAI at induction was 25.6 (range, 5-55) and 30.8 (range, 5-85), respectively.
  • After 3 months of treatment, these values were 22.5 (range, 2.5-75) and 14.3 (range, 0-37.5), respectively (P=0.17).
  • At the last follow-up, the values were 19 (range, 0-60) and 8.5 (range, 0-35), respectively (P=0.04).

Safety

• At 13-month follow-up among CD and UC patients, 9 patients experienced AEs, with fatigue (n=3 [3%]) and headache (n=3 [3%]) being more frequent. Treatment was discontinued in 1 patient due to recurrent respiratory tract infections.

Registry-Based Studies

REALITI

Adler et al (2024),⁶ Saeed et al (2024)⁷ and Steiner et al (2024)⁸ reported results from a real-world evidence study (REALITI) that evaluated the effectiveness and safety of STELARA in pediatric patients with CD using data from ImproveCareNow (ICN) registry.

Study Design/Methods

• The study included pediatric patients, aged 2 to <18 years, with reference data from young adults (aged 18-25 years) with CD.
• Three readers independently scored reports blinded to clinical information and each other's scores.⁶
• Demographic and clinical data, recorded prospectively in ICN, were summarized, and compared between patients with and without endoscopy.⁶
• Clinical remission was defined as short Pediatric Crohn’s Disease Activity Index (sPCDAI) ≤10 and endoscopic remission as Simplified Endoscopic Mucosal Assessment of Crohn’s Disease (SEMA-CD) ≤1.

Results

Baseline Characteristics

• A total of 479 patients with CD treated with STELARA were included (n=348, pediatric patients; n=131, young adults).

Assessment of Mucosal Inflammation

• A total of 114 pediatric patients with moderate to severe CD (sPCDAI ≥30) were analyzed at week 52 (n=77, with endoscopic assessment; n=37, without endoscopic assessment).⁶
• At baseline, the median age for all patients was 16.0 years (IQR, 15-16).⁶
• Patients with endoscopic assessments vs patients without were predominantly female (56% vs 41%) and had more ileocolonic disease activity (73% vs 54%), perianal disease (39% vs 35%), and stricturing phenotype (B2; 10% vs 5%), respectively.⁶
• At baseline, the median sPCDAI was 40 (IQR, 35-50) in all 114 patients and the median SEMA-CD was 8.5 (IQR, 5-13) in 38 patients.⁶
• A total of 77 patients had ≥1 report during the study and 20 patients had a report at week 52.⁶
• At week 52, endoscopic remission was achieved by 4/20 (20%) patients (95% CI, 8.1-41.6) with lower remission rates were observed in patients with baseline endoscopic assessments (n=17/77 [22.1%]; 95% CI, 14.3-32.5) compared to those without (n=10/37 [27.0%]; 95% CI, 15.4-43.0).⁶

Pediatric Patients vs Young Adults

• An analysis of pediatric patients (n=348) compared to young adults (n=131) was conducted.⁷
• At baseline, the majority of pediatric patients (98.9%) and young adults (95.4%) had received prior biologic therapy, with approximately half (47.1% and 50.4%, respectively) also receiving CSs.⁷
• A total of 49.7% of pediatric patients, compared to 44.8% of young adults had moderate to severe CD (sPCDAI ≥30).⁷
• At week 52, clinical remission was achieved in 105/348 (30.2%) pediatric patients (95% CI, 25.6-35.2) vs 37/131 (28.2%) young adults (95% CI, 21.2-36.5).⁷
• At week 52, the rates of discontinuation were similar in pediatric patients (21.0%) and young adults (22.9%).⁷
• When comparing pediatric patients to young adults, IBD-related hospitalizations were reported in 31.9% vs 19.8% of patients, IBD-related surgery occurred in 16.1% vs 9.2% of patients, serious infections occurred in 7.5% vs 3.8% of patients, and the rates of opportunistic infections were 1.4% vs 0%.⁷
• There were no events of tuberculosis, malignancy, or anaphylaxis requiring STELARA discontinuation.⁷
• One death was reported among pediatric patients, which was considered as unrelated to IBD or STELARA treatment by investigators; no deaths were reported among young adults.⁷

Pediatric Patients vs Young Adults Weighing >40 Kg

• An analysis was conducted on 114 pediatric patients who weighed >40 kg with a sPCDAI ≥30, compared to 51 young adults with moderately to severely active CD.⁸
• All pediatric patients were treatment refractory (99.1%, no response to prior biologics; <1%, biologic naïve).⁸
• At week 52, clinical remission was achieved in 26/114 (22.8%) pediatric patients (95% CI, 16.1-31.3) vs 11/51 (21.6%) young adults (95% CI, 12.5-34.6).⁸
• At week 52, the rates of discontinuation were similar in pediatric patients (25.4%) and young adults (25.5%).⁸
• When comparing pediatric patients to young adults, IBD-related hospitalizations were reported in 36.0% vs 21.6% of patients, IBD-related surgery occurred in 14.0% vs 11.8% of patients, serious infections occurred in 9.6% vs 3.9% of patients, and the rates of opportunistic infections were 1.8% vs 0%.⁸
• There were no reports of tuberculosis, malignancy, or anaphylaxis requiring STELARA discontinuation. No deaths were reported in either group.⁸

DEVELOP

Koletzko et al (2024)⁹ assessed STELARA safety in pediatric patients with CD using data from DEVELOP, a multicenter, global, prospective, observational, longitudinal registry of long-term safety of infliximab (and other treatments) in pediatric patients with IBD.

Study Design/Methods

• The study included pediatric patients aged <18 years.
• Patients were categorized into 2 groups based on weight: <40 kg group and ≥40 kg group.

Results

Baseline Characteristics

• A total of 150 patients were included (n=31, <40 kg group; n=119, ≥40 kg group).
• Most of the treated patients were between 12 and 17 years old (92.0%). About 91% of patients initially received STELARA q8w. At the last known dose, 64% received STELARA q8w, and 22% received STELARA every 4 weeks.
• Overall, 65.3% of patients had prior IBD surgery, 98% received prior biologic therapy and 72% received ≥2 biologics prior to STELARA.

Safety

• During follow-up, 37 patients (24.7%) discontinued STELARA, with a mean (SD) time to discontinuation of 16.7 (17.00) months, while 84 patients (56.0%) were exposed to STELARA for ≥24 months.
• Rates (events per 100 patient-years) of AEs, SAEs, serious infections, CD-related hospitalizations, and IBD-related surgeries are shown in Table: Rates of AEs, SAEs, Serious Infections, CD-Related Hospitalizations, and IBD-Related Surgeries Among STELARA Treated Patients.
• One malignancy (malignant carcinoid tumor) was reported in an 18-year-old female in the ≥40kg group, with a history of prior therapy with vedolizumab, methotrexate, and 6-mercaptopurine. There were no reports of deaths or opportunistic infections.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 23 January 2025.

Summarized in this response are data from UNISTAR, prospective studies, registries, and retrospective studies with a sample size of ≥50 patients.