Summary

• Summarized in this response are relevant clinical data from the pivotal phase 3 UNITI clinical trial program.
• In a substudy that evaluated endoscopic healing of STELARA treatment in the induction (UNITI-1 and -2) and maintenance (IM-UNITI) studies in patients with moderately to severely active Crohn's disease (CD), among the randomized patients, the mean change from baseline in Simplified Endoscopic Score for Crohn's disease (SES-CD) at week 8 of induction (primary endpoint) was significantly greater in the combined STELARA group vs the placebo group (-2.8 vs -0.7; P=0.012) and was numerically higher at week 44 of maintenance (-2.5 vs -1.9; P=0.176) for the combined STELARA group vs placebo, respectively.¹
• In a substudy that evaluated the efficacy of STELARA on histologic CD activity in the induction (UNITI-1 and -2) and maintenance (IM-UNITI) studies, a statistically significant histologic improvement was observed at week 8 in patients induced with STELARA, but not in the placebo group. In the primary randomized patient population, continued histologic improvement was reported in patients who received maintenance treatment with STELARA 90 mg subcutaneously (SC) every 8 weeks (q8w) but not in the STELARA 90 mg SC every 12 weeks (q12w) group or placebo group.²
• A post-hoc analysis of pooled data from GALAXI-1 (a phase 2b trial which studied the efficacy of guselkumab in patients with moderately to severely active CD) and IM-UNTI assessed the impact of endoscopic response at maintenance on long-term outcomes. At the end of maintenance (EOM), endoscopic response was significantly associated with higher odds for long term extension (LTE) clinical remission and Inflammatory Bowel Disease Questionnaire (IBDQ) remission (odds ratio [OR], 1.91 and 1.99, respectively) and lower odds for LTE C-reactive Protein (CRP) abnormality (OR, 0.46). A greater number of patients without endoscopic response experienced hospitalizations and/or surgeries compared to those with endoscopic response at EOM, though the difference was not significant due to low event counts (16.0% vs 9.0%).³

CLINICAL DATA

Phase 3 UNITI Trial Program Substudies: Endoscopic and Histologic Outcomes

UNITI Trials Overall Study Design

• The UNITI Trial program consisted of 3 randomized, placebo-controlled studies which evaluated the efficacy and safety of STELARA induction (UNITI-1 and UNITI-2) and maintenance (IM-UNITI) therapy in adult patients with moderately to severely active CD.^1,2
• Patients enrolled failed or were intolerant to 1 or more tumor necrosis factor (TNF) blockers (UNITI-1) or failed or were intolerant to conventional therapies (immunomodulators or corticosteroids), but never failed a TNF blocker (UNITI-2).¹
• UNITI-1 and UNITI-2 Induction Trials (Induction week 0)^1,2
  • Patients were randomized to a single intravenous (IV) dose (STELARA 130 mg, STELARA ~6 mg/kg, or placebo).
  • Patients were evaluated for clinical response at week 8.
• IM-UNITI Trial (Maintenance week 0 [i.e. induction week 8])
  • Primary randomized maintenance population:
    • STELARA induction responders were randomized to SC placebo or STELARA 90 mg SC q12w or 90 mg SC q8w (for 44 weeks of maintenance treatment).
  • Non-randomized maintenance groups^1,4
    • STELARA induction non-responders received STELARA 90 mg SC, and continued on STELARA 90 mg SC q8w if in clinical response at week 8 of maintenance (if not in clinical response then STELARA was discontinued).
    • Placebo induction nonresponders received STELARA 130 mg IV, and continued on STELARA 90 mg SC q12w if in clinical response at week 8 of maintenance (if not in clinical response then STELARA was discontinued).
    • Placebo induction responders received placebo throughout the study to week 44.

Endoscopic Healing Substudy - UNITI Trials

Rutgeerts et al (2018)¹ conducted a prospective substudy evaluating the efficacy of STELARA on endoscopic healing in the induction (UNITI-1 and -2) and maintenance (IM-UNITI) phase 3 studies.

Study Design/Methods

• Patients enrolled in the substudy had an ileocolonoscopy at week 0 and 8 (week 0 of maintenance) of induction, and week 44 of maintenance.
• To measure endoscopic disease activity and endoscopic healing of the mucosa after treatment, the SES-CD score and the detection of mucosal ulceration (presence/absence) were utilized.
• The SES-CD score is based on the evaluation of 4 endoscopic components (presence/size of ulcers, proportion of mucosal surface covered by ulcers, proportion of mucosal surface affected by any other lesions, and presence/type of narrowing/strictures) across 5 ileocolonic segments.
• Each endoscopic component is scored from 0 to 3 for each segment, and a total score is derived from the sum of all the component scores (range, 0 to 56).
• The primary endpoint was the change from baseline in SES-CD score at week 8 of induction.
• Major secondary endpoints included: change from baseline in the SES-CD score at week 44 of maintenance, mucosal healing at week 44, and mucosal healing at week 8. These were tested in this order, and the first major secondary endpoint was only tested if the primary endpoint was positive, and the subsequent endpoint was tested only if the preceding endpoint in the hierarchy was positive. P-values for the subsequent endpoint(s) are considered nominal and should be interpreted with caution when the preceding endpoint(s) in the hierarchy are not positive.
• Other secondary endpoints evaluated at week 8 of induction and week 44 of maintenance included endoscopic response, endoscopic remission, and clinically meaningful endoscopic improvement. P-values for these other secondary endpoints are considered nominal and should be interpreted with caution due to the fact that analyses of other secondary endpoints were to proceed regardless of the results of the hierarchical multiple-testing procedure.
• Mucosal healing was defined as complete absence of any mucosal ulcerations among patients who presented with ulceration in at least 1 ileocolonic segment at induction baseline; clinically meaningful improvement was defined as ≥3 point reduction in SES-CD compared to induction baseline; endoscopic response was defined as ≥50% reduction from the SES-CD score at induction-baseline; and endoscopic remission was defined as a SES-CD score of ≤2.
• Serum ustekinumab concentrations were evaluated at weeks 0, 3, 6, and 8 during induction and every 4 weeks during maintenance.

Results

Patient Characteristics

• Of the 334 enrolled patients in the substudy (UNITI-1, n=142; UNITI-2, n=192), 289 (86.5%) had evaluable endoscopy data (ie, at least one ileocolonic segment evaluated) at baseline.
• A total of 87.2% (252/289) of patients with evaluable endoscopy data had eligible SES-CD scores (baseline ≥3, excluding the contribution of the narrowing component score) or ulceration at baseline (placebo, n=97; combined STELARA group, n=155).
• A total of 70 randomized maintenance patients (placebo, n=24; combined STELARA group, n=46 [STELARA 90 mg SC q8w, n=29; STELARA 90 mg SC q12w, n=17]) participated in the endoscopy substudy.

Efficacy

Induction Data

• Primary endpoint: at week 8 among randomized patients with an eligible SES-CD score at baseline of the induction studies, treatment with STELARA (pooled group) IV induction had a significantly greater mean change from baseline in SES-CD vs placebo (-2.8 [n=155] vs -0.7 [n=97], P=0.012; respectively).
• At week 8 among randomized patients from both induction trials with eligible SES-CD score at baseline, the mean change in SES-CD from baseline in the STELARA 130 mg IV (n=72), STELARA ~6 mg/kg IV (n=83), and placebo (n=97) groups were -2.5 (P=0.096), -3.0 (P=0.009), and -0.7, respectively.
  • From the UNITI-1 study, the mean change in SES-CD from baseline at week 8 in the combined STELARA group (n=66) and placebo group (n=41) was -2.3 and 0.2 (P=0.010), respectively.
  • From the UNITI-2 study, the mean change in SES-CD from baseline at week 8 in the combined STELARA group (n=89) and placebo group (n=56) was -3.1 and -1.4 (P=0.234), respectively.
• Please see Table: Induction Week 8 (UNITI-1 and -2) - Randomized Patients for major and other secondary endpoint results at week 8 of the induction trials.

Maintenance Data

• At maintenance week 44 among randomized patients, mean reductions in the SES-CD from induction baseline (first major secondary endpoint) were greater in patients given STELARA SC (combined treatment groups, a reduction of 2.5; P=0.176) than patients given placebo (reduction of 1.9 points), but the treatment difference between groups was not statistically significant. Because this first major secondary endpoint was not statistically significant, P-values for all other major secondary endpoints are also not statistically significant; nominal P-values are provided for these endpoints (in addition to the other secondary endpoints).
  • In the subgroup analysis by dose group, change from baseline in SES-CD score for STELARA 90 mg SC q8w (n=29; -3.1, P=0.107) was numerically greater than STELARA 90 mg SC q12w (n=17; -1.6, P=0.637) and placebo (n=24; -1.9).
• At week 44 of maintenance, among randomized patients with eligible SES-CD scores or ulcerations at induction baseline:
  • The proportion of patients with mucosal healing (major secondary endpoint) was numerically greater in the combined STELARA SC group (13.0%) than in the placebo group (4.2%; P=0.409).
  • The proportion of patients with clinically meaningful endoscopic improvement was numerically greater in the combined STELARA SC group (37.0%) than in the placebo group (25.0%; P=0.312).
  • The rate of endoscopic response was numerically greater in the combined STELARA SC group (17.4%) than in the placebo group (4.2%; P=0.151).
  • The rate of endoscopic remission was numerically greater in the combined STELARA SC group than in the placebo group (10.9% vs 4.2%; P=0.656).
  • For some of these other secondary endpoints, please see Table: Maintenance Week 44 (IM-UNITI) - Randomized Patients for the proportion of patients by dosing group who achieved these other secondary endpoints at week 44 of maintenance.

• There was no association between serum ustekinumab concentration quartiles and clinically meaningful endoscopic improvement at week 8.
• At week 44, there was a trend for increasing rates of endoscopic response and remission with serum ustekinumab concentration quartiles.
• Patients with serum ustekinumab concentrations <0.5 µg/mL had substantially lower endoscopic response or remission.

Pooled Analysis of GALAXI-1 and IM-UNITI Trials: Endoscopic Response at 1 Year at EOM and Long-term CD Outcomes

Neff-Baro et al (2024)³ conducted a post-hoc analysis evaluating the impact of endoscopic response at 1 year (also known as EOM) on long-term outcomes using pooled data from the GALAXI-1 and IM-UNITI trials

Study Design/Methods

• Endoscopic response at EOM (~48 weeks) and outcomes during LTE (~96 weeks) were evaluated. Multivariate analyses were conducted and adjusted for the treatment arm during maintenance, clinical remission status at EOM, and endoscopic response at EOM.
• Data from two randomized clinical trials were pooled to assess the impact of endoscopic response at 1 year on long-term patient relevant outcomes including clinical response, clinical remission, quality of life (using the IBDQ), and risk of hospitalizations and/or surgeries.
• A total of 461 patients (IM-UNITI, n=177; GALAXI-1, n=284) had endoscopy and clinical remission data available at EOM. Data for LTE outcomes were available for IBDQ remission (n=290) and for clinical remission and clinical response (n=383).

Results

Endoscopic Response at EOM and Long-term Outcomes

• At EOM, endoscopic response was significantly associated with higher odds for LTE clinical remission and IBDQ remission (OR, 1.91 and 1.99, respectively) and lower odds for LTE CRP abnormality (OR, 0.46).
• A greater number of patients without endoscopic response experienced hospitalizations and/or surgeries than that of patients with endoscopic response at EOM, though the difference was not significant due to low event counts (16% vs 9%).
• For EOM endoscopic response and LTE patient relevant outcomes See Table: Relationship Between EOM Endoscopic Response and LTE Outcomes in Pooled Analysis.

Relationship Between EOM Endoscopic Response and LTE Outcomes in Pooled Analysis⁵

Histologic Disease Activity Substudy - UNITI Trials

Li et al (2019)² conducted a substudy evaluating the efficacy of STELARA on histologic CD activity in the induction (UNITI-1 and -2) and maintenance (IM-UNITI) phase 3 studies.

Study Design/Methods

• During endoscopies, 2 biopsies were collected from a subset of patients at induction week 0 and week 8 and at maintenance week 44 (up to 2 biopsies from these anatomic regions: terminal ileum, splenic flexure, rectum).
• All biopsies were blindly scored using the Global Histology Activity Score (GHAS) for each region to assess histologic activity. Minor adaptations were made for the circumstances of the substudy, one of which included that the single highest scoring biopsy from each of the anatomic regions was used as the final score for that region.
• Histologic features evaluated were: epithelial damage, architectural changes, infiltration of mononuclear cells into the lamina propria, infiltration of polymorphonuclear cells in the lamina propria, polymorphonuclear cells in the epithelium, and the presence of erosions/ulcers.⁴
• Histology data were evaluated from 251 patients with SES-CD ≥3 at induction baseline.²
• For each treatment group and comparing each group, histologic improvements (eg, change in GHAS from induction week 0 to week 8 and maintenance week 44) were assessed.

Results

Histologic Improvement During Induction Therapy

• From baseline to induction week 8, the overall total GHAS (mean±standard deviation) was significantly reduced in STELARA-treated patients (10.4±7.0 [week 0, n=123] to 7.1±5.9 [week 8, n=106]; P<0.001) but not in placebo-treated patients (9.2±6.4 [week 0, n=73] to 7.8±6.2 [week 8, n=68]; P=0.193).
• Of note, the results were generally consistent in the subgroup analyses by induction study and by induction dose.

Histologic Improvement During Maintenance Therapy:

• At maintenance week 44 in the randomized patient population, a continued decrease in overall total GHAS from induction week 8 was reported in the STELARA 90 mg SC q8w group (7.4±7.7 [n=23] to 6.1±4.7 [n=15]) but not in the STELARA 90 mg SC q12w group (increase from 5.3±3.9 [n=14] to 8.7±4.1 [n=6]) or placebo group (increase from 9.2±3.8 [n=16] to 10.9±7.1 [n=13]; all comparisons P>0.05).
• From induction week 8 in the pooled patient population (randomized and non-randomized), continued histologic improvement was also observed in the STELARA 90 mg SC q8w group (7.1±6.2 [n=56] to 5.2±4.2 [n=43]; P<0.0001), but not in the STELARA 90 mg SC q12w group (increase from 6.1±5.7 [n=37] to 7.2±5.1 [n=22]) or placebo group (increase from 8.2±4.2 [n=37] to 8.9±6.8 [n=26]).
• Among patients in the pooled population who had evaluable histology data at both induction baseline and week 44 of the maintenance study, the mean reduction in GHAS from baseline was numerically greater in the STELARA 90 mg SC q8w group (-4.1±5.6 [n=37]) vs placebo (-1.2±5.5 [n=23]). The mean reduction in the STELARA 90 mg SC q12w group (-1.0±7.8 [n=18]) was similar to placebo (n=23).
• At week 44 in the randomized maintenance population, a significantly larger proportion of patients in the STELARA 90 mg SC q8w group (50%; 6/12) achieved histologic response (≥50% decrease of overall GHAS from baseline) compared to patients who received placebo (0%; 0/11) (P=0.0137). In the STELARA 90 mg SC q12w group, 17% (1/6) achieved histologic response (P=0.3529). A similar pattern was seen in the pooled maintenance population.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 23 October 2024.

Summarized in this response are relevant clinical data from the pivotal phase 3 UNITI clinical trial program and from a post-hoc analysis of pooled data from the GALAXI-1 and IM-UNITI trials.