Summary

• Analyses of data from a subset of patients with active perineal fistulas from the phase 2b study (CERTIFI) and phase 3 induction studies (UNITI-1 and UNITI-2) demonstrated that among randomized patients with open perineal fistulas at baseline, a numerically higher proportion of patients in the combined STELARA groups in the studies achieved fistula response and resolution versus placebo at week 8, as did both patients receiving STELARA 1 mg/kg or 130 mg (low dose) and patients receiving STELARA 6 mg/kg (high dose) in the pooled set. Similarly, a numerically higher proportion of patients in the STELARA group achieved fistula response vs placebo in the CERTIFI maintenance phase as well as the phase 3 maintenance study (IM-UNITI).¹
• In the phase 3 UNITI induction (UNITI-1 and UNITI-2) and maintenance (IM-UNITI) studies conducted to evaluate the use of STELARA in adult patients with moderately to severely active Crohn’s disease (CD), patients randomized to STELARA treatments had numerically higher perianal fistula resolution compared to patients randomized to placebo during both induction and maintenance studies. Additionally, perianal fistula resolution did not appear to be associated with higher ustekinumab serum concentrations among randomized patients from the induction studies and nonrandomized and randomized patients from the maintenance study.² Among patients who had 1 or more open and draining fistula at induction and had available data at week 252, 77.4% (24/31) were in fistula response.³
• SEAVUE is a phase 3b, randomized study conducted to evaluate the efficacy and safety of STELARA and adalimumab in biologic-naïve adult patients with moderately to severely active CD. STARDUST is a phase 3b, open-label, randomized study in adult patients with moderately to severely active CD comparing a treat-to-target (T2T) maintenance strategy vs a standard of care (SoC) approach. Perianal fistula closure from SEAVUE and STARDUST are reported below.^4-7
  • Overall, 53.8% and 47.4% of patients treated with STELARA from the SEAVUE and STARDUST studies were in fistula response, respectively. In both studies, no relationship was observed between fistula resolution and ustekinumab serum concentrations.

CLINICAL DATA

Phase 2b/3 Clinical Trials

Sands et al (2017)¹ described fistula healing in subsets of adult patients with moderately to severely active CD with active perineal fistulas in the pivotal phase 2 and 3 studies.

Study Design/Methods

• The efficacy and safety of intravenous (IV) induction and subcutaneous (SC) maintenance therapy with STELARA in adult patients with moderately to severely active CD were evaluated in CERTIFI (phase 2b study), UNITI-1 & 2 (phase 3 induction studies), and IM-UNITI (phase 3 maintenance study).
• In the CERTIFI, UNITI-1, and UNITI-2 studies, almost 40% of patients had a history of fistulizing CD. However, only 10.8% to 15.5% of patients across the studies had active perineal fistulas at baseline.
• Patients had their fistulas assessed by physical exam (including gentle compression) at study visits and were analyzed for fistula response (≥50% reduction in draining fistulas) and complete fistula resolution (100% reduction).
• Due to small sample size, data from the final induction visit at week 8 from these patients were combined over the 3 studies and then evaluated.
• Observed data on fistula response were also reported from the IM-UNITI and CERTIFI maintenance studies.

Results

• Among randomized patients with open perineal fistulas at baseline, a numerically higher proportion of patients in the combined STELARA groups in the CERTIFI, UNITI-1, and UNITI-2 studies achieved fistula response versus placebo at week 8, as did both patients receiving STELARA 1 mg/kg or 130 mg (low dose) and patients receiving STELARA 6 mg/kg (high dose) in the pooled set. Please see Table: Fistula Assessments at Week 8 Among Randomized Patients with Open Perineal Fistulas at Baseline in CERTIFI, UNITI-1, and UNITI-2.

• In the CERTIFI maintenance phase, IV STELARA responder and nonresponder patients with open fistulas at week 0 were rerandomized to SC STELARA (n=24) or SC placebo (n=30) at week 8.
  • With data available at week 22, fistula response occurred in 47% (9/19) and 30% (6/20) of these patients, respectively.
• With data available at week 44 among randomized patients in IM-UNITI, a numerically higher proportion of patients also had fistula response in the combined STELARA maintenance group (80% [12/15]) versus the placebo group (45.5% [5/11]; P=0.64).

Phase 3 Clinical Trials

Sands et al (2019)² examined the relationship between perianal fistula resolution and serum ustekinumab levels in patients with CD during the phase 3 UNITI studies.

Study Design/Methods

• Patients in the phase 3, 8-week UNITI-1 and UNITI-2 induction studies were randomized to IV placebo, STELARA 130 mg IV, or STELARA ~6 mg/kg IV (weight-range-based doses of STELARA: 260 mg [weight ≤55 kg], 390 mg [weight >55 kg and ≤85 kg], and 520 mg [weight >85 kg]).
• Responders to STELARA IV induction therapy were randomized to placebo SC, STELARA 90 mg SC every 8 weeks (q8w), or STELARA 90 mg SC every 12 weeks (q12w) as part of the phase 3, 44-week, randomized withdrawal UNITI maintenance study (IM-UNITI). Patients who were nonresponders to placebo IV or STELARA IV were also eligible for IM-UNITI in the nonrandomized dosing arms and received STELARA.
• Patients with open, draining fistulas at baseline had their fistulas assessed by physical exam (including gentle compression).
• Patients were analyzed for complete perianal fistula resolution (100% reduction) at study visits.
• Perianal fistula resolution in randomized patients at induction week 8 (maintenance week 0) was analyzed based on induction week 8 (maintenance week 0) ustekinumab serum concentration quartiles.
• Perianal fistula resolution at maintenance week 44 was analyzed based on maintenance week 24 ustekinumab serum concentration quartiles. Both randomized and nonrandomized groups at maintenance week 0 were combined to increase the number of patients with fistulas for this analysis.
• Patients in fistula resolution with missing pharmacokinetic data were excluded from the analyses with perianal fistula resolution and ustekinumab serum concentrations.
• Patients were considered not to be in perianal fistula resolution if they started a prohibited medication (eg, another biologic).

Results

• In observed data, among randomized patients with open, draining perianal fistulas at baseline of the UNITI-1 and UNITI-2 studies, patients in the STELARA IV treatment groups achieved numerically higher fistula resolution at induction week 8 compared to patients randomized to placebo IV:
  • STELARA 130 mg IV: 27.5% (11/40); P=0.03
  • STELARA ~6 mg/kg IV: 23.7% (9/38); P=0.08
  • Placebo IV: 9.3% (4/43)
• Perianal fistula resolution at induction week 8 based on induction week 8 ustekinumab serum concentration quartiles did not show a clear exposure-response relationship among randomized patients:
  • STELARA 130 mg IV:
    • Quartile 1 (≤1.18 µg/mL): 33.3% (3/9)
    • Quartile 2 (>1.18 to ≤1.62 µg/mL): 11.1% (1/9)
    • Quartile 3 (>1.62 to ≤2.84 µg/mL): 44.4% (4/9)
    • Quartile 4 (>2.84 µg/mL): 33.3% (3/9)
  • STELARA ~6 mg/kg IV:
    • Quartile 1 (≤3.40 µg/mL): 44.4% (4/9)
    • Quartile 2 (>3.40 to ≤5.04 µg/mL): 12.5% (1/8)
    • Quartile 3 (>5.04 to ≤9.30 µg/mL): 11.1% (1/9)
    • Quartile 4 (>9.30 µg/mL): 25.0% (2/8)
• At week 44, patients randomized to STELARA maintenance (90 mg SC q8w or 90 mg SC q12w) had numerically higher perianal fistula resolution compared to patients randomized to placebo SC among patients with open, draining fistulas at baseline:
  • STELARA 90 mg SC q8w: 85.7% (6/7); P=0.15
  • STELARA 90 mg SC q12w: 71.4% (5/7); P=0.36
  • Placebo SC: 44.4% (4/9)
• Including all patients (randomized and nonrandomized) treated with STELARA SC maintenance, perianal fistula resolution occurred in 42% (21/50) of patients by week 44.
• Among randomized and nonrandomized patients, perianal fistula resolution at maintenance week 44 based on maintenance week 24 ustekinumab serum concentration quartiles did not show a positive exposure-response correlation in either the STELARA 90 mg SC q8w group or the STELARA 90 mg SC q8w and q12w combined dosing group:
  • STELARA 90 mg SC q8w:
    • Quartile 1 (≤1.34 µg/mL): 85.7% (6/7)
    • Quartile 2 (>1.34 to ≤1.99 µg/mL): 57.1% (4/7)
    • Quartile 3 (>1.99 to ≤3.01 µg/mL): 28.6% (2/7)
    • Quartile 4 (>3.01 µg/mL): 14.3% (1/7)
  • STELARA 90 mg SC q8w and STELARA 90 mg SC q12w:
    • Quartile 1 (≤1.25 µg/mL): 75.0% (9/12)
    • Quartile 2 (>1.25 to ≤2.31 µg/mL): 50.0% (6/12)
    • Quartile 3 (>2.31 to ≤3.47 µg/mL): 25.0% (3/12)
    • Quartile 4 (>3.47 µg/mL): 27.3% (3/11)

Sandborn et al (2022)³ reported final results through 5 years from the long-term extension (LTE) of the phase 3 IM-UNITI maintenance study evaluating long-term efficacy, safety, and immunogenicity of STELARA SC maintenance therapy in patients with CD.

Study Design/Methods

• Patients who completed safety and efficacy evaluations at week 44 of IM-UNITI and were expected to benefit from continued treatment, per the investigator, were allowed to participate in the LTE (272 weeks).
• At week 44, patients receiving STELARA were maintained at their current dosage in an open-label manner, and those receiving placebo discontinued the study.
• Efficacy assessments, including fistula response, (≥50% reduction in the number of draining fistulas) were conducted through week 252.

Results

• Among patients from the randomized and nonrandomized populations who received STELARA and entered the LTE (n=567):
  • 61 patients had ≥1 open and draining fistula at induction baseline.
    • At week 252, 77.4% (24/31) patients with data available were in fistula response.

Phase 3b Clinical Trials

Peyrin-Biroulet et al (2022)⁴ reported data on fistula resolution and relationship between fistula resolution and serum ustekinumab concentrations from the SEAVUE (phase 3b, randomized study that evaluated the efficacy and safety of STELARA and adalimumab in biologic-naïve adult patients with moderately to severely active CD)^5,6 and STARDUST (phase 3b, open-label, randomized study conducted in adult patients with moderately to severely active CD comparing a T2T maintenance strategy vs a SoC approach) studies.⁷

Study Design/Methods

SEAVUE

• Patients were randomly assigned 1:1 to receive IV STELARA (approximately 6 mg/kg at baseline followed by 90 mg SC q8w) or adalimumab (160 mg SC at baseline followed by 80 mg SC at week 2, and 40 mg SC every 2 weeks thereafter) per dosing regimens approved in the United States without dose modifications.^5,6
• Randomization was stratified according to use of steroids (yes or no), Crohn's Disease Activity Index (CDAI) score (≤300 or >300), and any ulcerations >5 mm at baseline (yes or no).^5,6
• Primary endpoint: Clinical remission (CDAI score <150) at week 52.^5,6
• Primary and major secondary endpoints were tested in a hierarchical fashion where formal testing for subsequent endpoints was only conducted if the preceding endpoint in the hierarchy demonstrated statistical significance between treatment groups.^5,6

STARDUST

• Biologic-naïve and biologic-failure patients with moderately to severely active CD received open-label STELARA ~6 mg/kg IV at baseline followed by 90 mg SC at week 8.^4,7
  • At week 16, patients who had a CDAI improvement of ≥70 points were randomized in a 1:1 ratio to either the T2T group or the SoC group through week 48.
    • In the T2T group, patients received 90 mg SC STELARA q8w or q12w based on a <25% or ≥25% improvement in the baseline Simple Endoscopic Score for Crohn’s Disease (SES-CD) score, respectively. Beginning at week 16, STELARA dosing frequency could be increased based on symptoms and biomarker control (eg, q12w increased to q8w and q8w increased to every 4 weeks [q4w]). Patients who did not achieve treatment targets despite receiving STELARA q4w were discontinued from the study at least 4 weeks after the dose escalation.
    • In the SoC group, patients received the STELARA maintenance dose based on the European Union Summary of Product Characteristics where the recommended dosing for patients with adequate response to induction is q12w. At week 16, patients with inadequate response received another dose of STELARA 90 mg SC. During the maintenance period, patients who lost response during q12w dosing could be escalated to q8w dosing.
  • Primary endpoint: endoscopic response at week 48 (SES-CD score ≥50% decrease from baseline)
• In SEAVUE and STARDUST, the number of open and draining perianal fistulas was evaluated at baseline and at the end of maintenance treatment (SEAVUE, at week 52; STARDUST, at week 48).
• Fistula resolution was defined as closure of all fistulas.

Results

• In SEAVUE, 7 out of 13 (53.8%) patients in the STELARA group and 6 out of 16 (37.5%) patients in the adalimumab group with active perianal fistulas at baseline had complete fistula resolution at week 52 and fistula resolution, respectively.
• In STARDUST, 9 out of 19 (47.4%) patients with active perianal fistulas at baseline had complete fistula resolution at week 48.
  • Among the 9 patients with fistula resolution, 2 were receiving STELARA q12w at week 48, 6 were receiving STELARA q8w, and 1 was receiving STELARA q4w.
  • Among the 10 patients without fistula resolution, 2 were receiving STELARA q12w at week 48, 3 were receiving STELARA q8w, 1 was receiving STELARA q4w, and 4 discontinued before week 48.
• In SEAVUE and STARDUST, fistula closure at week 52 and week 48, respectively, was not associated with higher ustekinumab serum concentrations at either week 16 or the end of maintenance treatment.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 06 February 2025.

Summarized in this response are relevant data from pivotal phase 2b (CERTIFI) and phase 3 clinical trials (UNITI-1, UNITI-2, IM-UNITI), and the open-label LTE as well as data from the phase 3b studies (SEAVUE and STARDUST).