SUMMARY

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• Please refer to the local labeling for relevant information on dosage and administration for STELARA.
• Phase 3 clinical trials of STELARA in the treatment of Crohn’s disease (CD) did not evaluate subcutaneous (SC) induction dosing.¹
• A phase 2a induction trial,² 2 prospective cohort studies,^3,4 1 retrospective study,⁵ and 3 nonrandomized open-label studies^6-8 evaluated induction dosing with SC STELARA in CD and are summarized below.

CLINICAL DATA

Phase 2a Induction Trial

Sandborn et al (2008)² conducted a phase 2a multicenter, randomized, double-blind, placebo-controlled, cross-over study to evaluate the efficacy and safety of STELARA in patients with moderate to severe CD (≥6 weeks duration; Crohn’s Disease Activity Index [CDAI] ≥220 and ≤450) through 28 weeks. Concurrently, an open-label study was conducted evaluating the safety and efficacy of either 4 SC injections of STELARA administered weekly or 1 intravenous (IV) infusion of STELARA in patients considered to be primary or secondary nonresponders to infliximab.

Study Design/Methods

• A total of 104 patients with moderately to severely active CD despite treatment with at least 1 of the following: 5-aminosalicylates (5-ASA), antibiotics, corticosteroids, azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX); submaximal infliximab doses or regimens (ie, only 1-2 induction doses of infliximab 5 mg/kg, or maintenance doses of 5 mg/kg every 8 weeks without shortening the dosing interval or escalating to 10 mg/kg, or intolerance to infliximab); or other anti-tumor necrosis factor (TNF) agents (population 1) were enrolled in a double-blind study.
• Patients in population 1 were randomized to 1 of the following 4 treatment groups:
  • SC placebo at weeks 0, 1, 2, and 3 and SC STELARA 90 mg at weeks 8, 9, 10, and 11 (n=26).
  • SC STELARA 90 mg at weeks 0, 1, 2, and 3 and SC placebo at weeks 8, 9, 10, and 11 (n=25).
  • IV placebo at week 0 and IV STELARA 4.5 mg/kg at week 8 (n=27).
  • IV STELARA 4.5 mg/kg at week 0 and IV placebo at week 8 (n=26).
• The open-label study included moderately to severely active CD patients who did not respond to a 3-dose induction of infliximab 5 mg/kg or initially responded but lost response during every-8-week maintenance therapy despite dose escalation to 10 mg/kg (population 2).
• Twenty-seven patients were randomized to receive IV STELARA 4.5 mg/kg at week 0 (n=13) or SC STELARA 90 mg at weeks 0, 1, 2, and 3 (n=14).
• No additional treatment was administered at week 8.
• Concomitant use of 5-ASA, antibiotics, prednisolone (maximum 20 mg/day), AZA, 6-MP, or MTX was permitted in both studies provided that all medication doses remained constant, with the exception of corticosteroids, which could be tapered by 2.5 mg/week after week 8.
• The primary endpoint for the double-blind study was clinical response, defined as a reduction in baseline CDAI ≥25% and ≥70 points, at week 8 in the combined SC and IV STELARA groups.
• Secondary endpoints included clinical response at weeks 4 and 6, and clinical remission (CDAI<150).

Results

Efficacy

• Rates of clinical response and clinical remission are described in Table: Primary and Secondary Efficacy Results through Week 8.

Safety

• Adverse events (AEs) reported through week 8 in population 1 were similar between groups, excluding the incidence of nausea, worsening CD, and fatigue, which were slightly higher in patients in the placebo group, and the frequency of pruritus and anxiety, which were slightly higher in patients in the STELARA group.
• Serious AEs were reported in 3 patients (6%) in the combined placebo group (small intestinal stenosis and nonsteroidal anti-inflammatory drug [NSAID]-induced gastrointestinal ulceration, worsening CD and erythema nodosum, worsening CD and small intestinal obstruction) and 2 patients (4%) in the combined STELARA group (small intestinal obstruction and coronary artery disease).
• No patients in either group experienced serious infections, opportunistic infections, or malignancy through week 8.
• Through week 28, serious AEs were reported in 6 patients (6%) in (worsening CD [n=2], colonic stenosis and pneumothorax, small intestinal obstruction [n=2], and prostate cancer).
• Squamous and basal cell skin carcinomas were diagnosed in 1 patient (SC STELARA group), after week 28.
• In population 2, serious AEs were reported in 4 patients (15%; viral gastroenteritis, nephrolithiasis, worsening CD, and disseminated histoplasmosis, worsening CD, and syncope).

Prospective Cohort Studies

Painchart et al (2020)⁴ evaluated the association between ustekinumab trough levels, the presence of antibodies, and the clinical response in patients with refractory CD who received STELARA for induction and maintenance treatment.

• One of the cohorts included in this study was a longitudinal induction cohort which evaluated patients who initiated treatment with STELARA SC.
• In the induction cohort, patients were treated with STELARA 90 mg SC at weeks 0, 4, and 12, and then every 8 weeks. Ustekinumab trough levels and anti-drug antibodies were assessed at the end of the induction phase at week 12, and during the maintenance phase at week 28.
• Patients were evaluated for clinical and biologic response.
  • Clinical response was defined as a 3-point reduction in the Harvey Bradshaw Index (HBI) or the physician global assessment (PGA) if the HBI was not applicable.
  • Clinical remission was defined as an HBI score below 5.
  • Biological response (remission) was defined as a C-reactive protein (CRP) of <5 mg/L during follow-up.
• A total of 23 patients were included in the induction cohort.
  • Three patients in the induction cohort discontinued STELARA before week 28 due to treatment failure.
• A clinical response was observed in 57% (13/23) of patients at the end of the induction phase (week 12) and in 75% (15/20) of patients at week 28.
• A biological response was observed in 48% (11/23) of patients at the end of the induction period (week 12) and in 40% (8/20) of patients at week 28.

Rowan et al (2018)³ prospectively evaluated ustekinumab trough concentrations and clinical response using the STELARA SC formulation for induction for the treatment of adult patients with CD in a pilot study.

• SC induction was given as 360 mg in 3 divided doses: 180 mg at week 0, 90 mg at week 1 and 90 mg at week 2, with corresponding ustekinumab trough concentrations assessed to week 8. This equaled a median induction dose of 6.3 mg/kg (interquartile range [IQR], 5.3-6.7 mg/kg) for the treated patients.
• The interval between subsequent maintenance doses was at the discretion of the treating physician who was blinded to the results of ustekinumab levels. Following induction, maintenance doses of STELARA 90 mg SC were given at intervals of every 4 weeks, every 6 weeks, or every 8 weeks.
• At each study visit, clinical symptoms were recorded utilizing the HBI along with biological measures, including hemoglobin, albumin (Alb), CRP, and fecal calprotectin (FCP).
• The primary outcomes were trough serum ustekinumab levels and clinical remission (defined as HBI ≤4) at week 8 following SC STELARA induction. Secondary outcome measures included: ustekinumab trough levels at weeks 1 and 2, and changes in Alb, CRP, and FCP at week 8 compared to baseline.
• A total of 19 patients were included in the study; however, the induction treatments with STELARA were successfully completed in 17/19 patients who each received their first maintenance dose at week 8. The other 2 patients didn’t complete the induction protocol due to disease worsening requiring surgical resection in one patient and a breast abscess occurring in another patient. All patients had been exposed to anti-TNFs and 1 had received an integrin receptor antagonist prior to initiating STELARA therapy.
• There was a significant improvement in HBI from week 0 (median HBI=5) to week 8 (median HBI=1; P=0.002) with 84.2% (n=16/19) in clinical remission (HBI ≤4) by week 8.
• Median ustekinumab trough concentrations for the 17 patients who completed induction were: 16 µg/mL (IQR, 14.5-20 µg/mL) at week 1; 20 µg/mL (IQR, 16-20.5 µg/mL) at week 2; and 6.1 µg/mL (IQR, 4-9.8 µg/mL) at week 8.
• There was a significant change in median FCP levels at week 8 compared to baseline while there were no significant changes in CRP or Alb levels.
• STELARA treatment with SC induction was reported as well tolerated. There was a total of 2 patients (10.6%) who reported mild local skin reactions at the injection site and 1 patient (5.3%) on combination therapy with AZA who developed varicella zoster during induction (resolved with anti-viral therapy without treatment discontinuation).

Retrospective Study

Mccrossan et al (2023)⁵ conducted a pilot study that retrospectively evaluated the association between treatment failure/loss of response and serum drug concentrations and antibody levels in patients with CD receiving STELARA SC induction therapy.

• Patients who received STELARA SC induction therapy after exhibiting loss of response to anti-TNF therapy for CD and who had follow-up data for 74 months were enrolled.
• Among the 10 patients included, 3 experienced treatment failure and 7 continued receiving STELARA. Treatment failure was defined as switching to another biologic and/or requiring surgery.
  • All the patients who failed treatment were switched to alternative biologics, and 1 required surgery.
• All patients required a dosing interval reduction of STELARA to every 4-week dosing.
• Median antibody levels were higher among patients who failed treatment vs those who did not (6.57 AU/mL vs 5.87 AU/mL; P=0.03).
  • Of the patients who failed treatment, 2 had lower serum trough levels than those who continued on STELARA while 1 patient had a higher serum trough level (median, 2.9 µg/mL vs 5.8 µg/mL; P=0.52).

Nonrandomized Open-Label Studies

Herrera et al (2015)⁶ analyzed CD activity prior to and post induction therapy with STELARA in patients with refractory disease.

• Patients on STELARA for refractory CD previously treated with at least 2 anti-TNF agents were enrolled.
• Patients received an induction dose of STELARA 3 mg/kg SC followed by a maintenance dose of 90mg every 8 weeks (4 patients received an extra dose of 90 mg at week 4).
• Clinical response (defined as a >70-point reduction from baseline CDAI) and clinical remission (defined as CDAI >150 points) were assessed at week 8 and at the end of follow-up.
• Eight patients received STELARA for refractory CD with clinical response to induction achieved in 7 out of 8 patients.
• At week 8, 3 patients (37.5%) were in clinical remission.
• During median follow-up at week 42, 6 patients were still receiving treatment and in clinical remission (75%).
• Arthralgia was the most common side-effect, and no serious AEs were reported.

Kopylov et al (2014)⁷ conducted a retrospective, observational, open-label study of STELARA for the treatment of patients with CD who were resistant to anti-TNF therapy.

• Thirty-eight CD patients were treated with STELARA SC after developing loss of response to 1 or more anti-TNF agents.
• Clinical response, defined as an improvement in symptoms and continued treatment with STELARA, was assessed at initial response, 6 months, 12 months and the last follow-up.
• Thirty-four out of 38 patients received an induction regimen and the other 4 patients received maintenance dosing from the start. See Table: Loading and Maintenance Doses of Subcutaneous STELARA for the dosing regimens used in this study.

• Eighteen patients (47.4%) required dose escalation, which was successful in 11/18 (61.1%).
• See Table: Clinical and Steroid-Free Response to STELARA in CD for the clinical and steroid-free response results reported.

• After the first STELARA dose, 1 patient with an initial clinical response after 4 months developed a clostridium difficile infection. The patient was treated with antibiotics and regained clinical response.
• No other serious AEs were reported.

Rosen et al (2011)⁸ described post marketing use of STELARA in patients with anti-TNF-alpha refractory moderate to severe CD from a single center.

• In an open-label study, patients received STELARA 45 mg or 90 mg SC at weeks 0 and 4, then at intervals of 8 or 12 weeks.
• The primary endpoint was clinical response, which was defined as a decrease in HBI ≤3 at week 12.
• Secondary endpoints included the ability to taper steroids at week 12 and remission (HBI ≤3).
• Thirteen patients met the inclusion criteria and 9 patients received STELARA ≥12 weeks.
• Clinical response was found in 7 out of 9 patients (77.8%; P<0.05) at week 12.
• Four out of 9 patients (44.4%) achieved clinical remission.
• Two patients were on steroids prior to initiation of STELARA treatment and were able to taper their steroid treatment. However, only one was able to discontinue steroids completely by week 8.
• No AEs were noted in the study.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 June 2024.