Summary

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• STARDUST is a phase 3b, multicenter, randomized study in adult patients with moderately to severely active Crohn's disease (CD) comparing a treat-to-target (T2T) maintenance strategy based on dose adjustment of STELARA at week 16 using endoscopy vs a standard-of-care (SoC) approach. The study consisted of an 8-week STELARA intravenous (IV) induction period followed by a STELARA subcutaneous (SC) maintenance period through week 48. From week 48, patients continued STELARA SC treatment in the long-term extension (LTE) up to week 104.^1-3
• Key efficacy (including endoscopic response, endoscopic remission, changes in intestinal ultrasound [IUS] parameters, mucosal healing, clinical response, clinical remission, corticosteroid-free remission, changes in biomarkers) and safety as well as subgroup analyses through week 48 are reported below.^1-4
• Results from the LTE, up to week 104, including the health-related quality of life (HRQoL) measures are also summarized below.^5-8

CLINICAL DATA

Phase 3b Study: STARDUST Trial

Danese et al (2020, 2022)^1-3 reported efficacy and safety results from an open-label, phase 3b, multicenter, randomized study in adult patients with moderately to severely active CD comparing a T2T maintenance strategy based on dose adjustment of STELARA at week 16 using endoscopy (followed by clinical and biomarker directed dose escalation) vs a SoC approach.

Study Design/Methods

• In the T2T group, beginning at week 16, the STELARA dosing frequency could be increased (eg, every 12 weeks [q12w] increased to every 8 weeks [q8w] and q8w increased to every 4 weeks [q4w]) for patients who did not achieve a Crohn’s Disease Activity Index (CDAI) score of <220 with a ≥70 point improvement from baseline and fecal calprotectin (FCal) levels ≤250 μg/g or C-reactive protein (CRP) levels ≤10 mg/L. 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 (90 mg SC q12w) based on the European Union Summary of Product Characteristics (EU SmPC) where the recommended dosing for patients with adequate response to induction is q12w. At week 16, patients with inadequate response could receive another dose of STELARA 90 mg SC. According to the EU SmPC, patients who lost response during q12w dosing could be escalated to treatment q8w.
• For the week 48 analysis, nonresponder imputation (NRI) and last observation carried forward (LOCF) were used for missing dichotomous and continuous variables, respectively. LOCF was also a preplanned sensitivity analysis for the primary endpoint.

Results

Patient Characteristics

• The randomized population included a total of 440 patients (n=219, T2T group; n=221, SoC group).³
• In the T2T and SoC groups, the median age was 36.0 and 34.0 years and 52% and 50% of patients were female, respectively.³
• In the T2T and SoC groups, 39% and 38% of patients were biologic-naïve and 61% and 62% had received ≥1 biologic therapy, respectively.³

Efficacy at Week 48

• At week 48, endoscopic response (primary endpoint) was achieved in 38% vs 30% of patients in the T2T group and SoC group, respectively (NRI analysis, P=not significant [NS]).³
• Other secondary endpoints did not differ significantly between treatment groups.³
• Results for endoscopic, clinical, and biomarker outcomes at week 48 are summarized in Table: Endoscopic, Clinical, and Biomarker Outcomes at Week 48, and results for mean changes in Simple Endoscopic Score for Crohn's Disease (SES-CD) score, CDAI score, and biomarkers levels at week 48 are presented in Table: Changes from Baseline in SES-CD Score, CDAI Score, FCal Levels, and CRP Levels at Week 48.

Subgroup Analysis Based on Baseline Demographics

• Subgroups of patients were evaluated based on baseline demographics.³
• For each subgroup, the odds ratio (OR) and 95% confidence interval (CI) of T2T vs SoC were provided based on the logistic regression model that included the treatment group and stratification factors (prior exposure to biologics [none or 1] and SES-CD score [≤16, >16] at baseline) as independent variables.³
• At week 48, among patients included in the subgroup analysis (T2T, n=219; SoC, n=221), patients in the T2T group were more likely to achieve endoscopic response vs patients in the SoC group if patients, at baseline, had³:
  • Longer disease duration (>median [79.1 months]; OR, 2.15 [95% CI, 1.17-3.94]; P=0.013)
  • Clinically moderate disease (CDAI ≤300; OR, 1.71 [95% CI, 1.04-2.80]; P=0.034)
  • Normal FCal (≤250 μg/g; OR, 3.03 [95% CI, 1.22-7.56]; P=0.017)
  • Endoscopically more active CD (SES-CD ≥4 for ileal or ≥6 for colonic and/or ileocolonic disease; OR, 1.80; [95% CI, 1.11-2.94]; P=0.018)
  • History or presence of strictures/fistula or occurrence of an intra-abdominal abscess, hospitalization, or surgery for CD at baseline (history of ongoing events, OR, 2.31; [95% CI, 1.06-5.01]; P=0.034; and ongoing events, OR, 3.46; [95% CI,
    1.07-11.19]; P=0.039).

Safety at Week 48

• Overall, treatment-emergent adverse events (TEAEs) were experienced by 188 (86%) patients in the T2T group and 179 (81%) patients in the SoC group.³
• For summary of safety events, see Table: TEAEs through Week 48.

• One patient in the T2T group reported basal cell carcinoma (not considered a serious adverse event [AE]) and 2 patients in the SoC group reported metastatic neuroendocrine carcinoma and invasive ductal breast carcinoma (both considered serious AEs). No patient developed lymphoma.³
• Two patients in the T2T group and 1 in the SoC group reported herpes zoster infections and one patient each in the SoC group reported disseminated cutaneous herpes zoster and cytomegalovirus syndrome. No patient developed tuberculosis.³
• Antibodies to ustekinumab (UST) through week 48 were detected in 9 (4%) patients in the T2T group (6 patients had neutralizing antibodies) and in 17 (8%) patients in the SoC group (12 patients had neutralizing antibodies).³

Kucharzik et al (2023)⁴ reported results from a substudy assessing changes in IUS parameters, including the transmural response to STELARA therapy.

Study Design/Methods

• Key IUS endpoints were assessed at weeks 0, 4, 8, 16, and 48 or upon early termination¹⁰:
  • Segmental IUS response was defined as a reduction of ≥25% in bowel wall thickness (BWT) of the target bowel segment.
  • Transmural remission was defined as normalization of all IUS parameters in the target bowel segment.
  • Segmental BWT: The mean of 4 measurements (2 in cross-section and 2 in longitudinal) of the most affected (ie, most inflamed) part of each segment. BWT was considered pathological if thickness was >2.0 mm in the terminal ileum and >3.0 mm in the colon.
  • Blood flow: Color Doppler signal: 0, no signal; 1, minimal pixels, scant; 2, increased signal limited to the wall; 3, signal is significant in the wall and mesentery. Normalization of color Doppler signal was defined as ≤1.
  • Bowel wall stratification: 0, normal/preserved echo-stratification; 1, uncertain presence of echo-stratification; or 2, focal disruption (<3 cm); 3, extensive disruption (≥3 cm). Normalization of bowel wall stratification was defined as normal/preserved echo-stratification.
  • Mesenteric inflammatory fat (i-Fat): 0, absent, no evidence of proliferative, mesenteric i-Fat; 1, uncertain (increased fat is possible - either the quality or the views are insufficient to determine the contribution); or 2, present. Normalization of mesenteric i-Fat was defined as absence of mesenteric i-Fat.
• For all IUS parameters, the most affected bowel segment at baseline was used.
• Obese patients or patients exhibiting other characteristics precluding IUS visualization of the affected bowel segment or with normal BWT (≤2.0 mm for the terminal ileum; ≤3.0 mm for the colon) in all segments at week 0 were excluded.

Results

• Among the 77 patients who had a baseline IUS assessment, 31 (40.3%) were
  biologic-naïve, and the most affected bowel segment at baseline was the terminal ileum (65.0%) and colon (35.0%).
• Changes in the IUS response and transmural remission rates based on the most affected bowel segment and biological treatment history per observed analysis are described in Table: IUS Response and Transmural Remission Over Time at Week 48 (Overall and by Bowel Segment and Biological Treatment History).

• Results for changes in BWT up to week 48 based on the most affected bowel segment and biological treatment history per observed analysis are reported in Table: Mean Percentage Changes in BWT from Baseline to Week 48 (Overall and by Bowel Segment and Biological Treatment History).

• According to the observed analysis, from baseline through week 48, the overall proportion of patients with normalized BWT, blood flow, bowel wall stratification (BWS), and mesenteric i-Fat increased progressively from 0% to 25.9%, 37.3% to 72.5%, 36.8% to 64.2%, and 25.0% to 55.6%, respectively.¹⁰
  • At week 48, normalization of IUS parameters was observed in the colon vs terminal ileum for BWT (50.0% vs 15.8%), blood flow (85.7% vs 67.6%), BWS (66.7% vs 63.2%), and mesenteric i-Fat (68.8% vs 50.0%).
  • At week 48, normalization of IUS parameters was observed in the biologic-naïve vs biologic-exposed patients for BWT (31.8% vs 21.9%), blood flow (70.0% vs 74.2%), BWS (76.2% vs 56.3%), and mesenteric i-Fat (63.6% vs 50.0%).

Long-Term Extension

Peyrin-Biroulet et al (2021, 2022, 2023)^5-8 evaluated the efficacy and safety of STELARA through week 104 of the STARDUST LTE.

Study Design/Methods

• From week 48 onwards, eligible patients in the T2T and SoC groups continued to receive STELARA SC up to week 104 with further protocol-guided dose adjustments.
• STELARA dose de-escalation was implemented starting at week 48 for patients with endoscopic remission at week 48 and corticosteroid-free clinical remission for ≥16 weeks:
  • Those receiving STELARA q8w were de-escalated to q12w.
  • Those receiving STELARA q4w were de-escalated to q8w and further de-escalated to q12w in patients with corticosteroid-free clinical remission and biomarker remission (CRP ≤10 mg/L and FCal ≤250 µg/g) at 2 consecutive visits 8 weeks apart.
• Results are presented for the NRI analysis only for patients entering the LTE.
• Efficacy of the T2T approach in modifying disease course with STELARA was evaluated by analyzing time to disease progression events up to week 104.
• Disease progression events included combined bowel damage events (defined as the development of new strictures/fistulae or the occurrence of an intra-abdominal abscess) or CD-related hospitalizations or surgeries based on the AE analysis.
• Time to first bowel damage event, CD-related surgery, CD-related hospitalization, and combined CD-related surgery and hospitalization were analyzed.
• HRQoL outcomes and the effect of STELARA on work productivity and activity impairment for the T2T and SoC groups were assessed at week 104. Changes from baseline were assessed using the following measures:
  • Inflammatory Bowel Disease Questionnaire (IBDQ)
  • European Quality of Life 5-Dimension 5-Level (EQ-5D-5L)
  • Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) tools
  • Hospital Anxiety and Depression Scale - Anxiety and Depression subscales (HADS-A and HADS-D, respectively)
  • Work Productivity and Activity Impairment (WPAI) questionnaire
  • Time lost from work, percentage of patients with an IBDQ response (≥16point improvement from baseline) and remission (IBDQ score ≥170) at week 104

Results

Patient Characteristics

• Among the 440 who were randomized at week 16, 323 entered LTE, of whom 20.1% discontinued before week 104.
  • Of the 147 patients in the T2T group and 176 patients in the SoC group, 119 (81.0%) and 139 (79.0%) patients, respectively, completed 104 weeks of study.

Endoscopic, Clinical, and Biomarker Outcomes

• Results for endoscopic and clinical outcomes through week 104 are summarized in Table: Endoscopic and Clinical Outcomes through Week 104 (NRI), and results for biomarker outcomes at week 104 are summarized in Table: Clinical, Endoscopic, and Biomarker Outcomes through Week 104 for Patients Entering LTE (as Observed).

Subgroup Analysis Based on Prior Biologic Exposure

• Results for endoscopic, clinical, and biomarker outcomes at week 104 in subgroups of patients who were biologic-naïve or biologic-experienced are summarized in Table: Endoscopic, Clinical, and Biomarker Outcomes at Week 104 in Patients Entering LTE Based on Prior Biologic Exposure (NRI).

Dose Distribution and Dose De-escalation

• For dose distribution and dose de-escalation in patients through week 104, see Table: Dose Distribution and De-escalation in Patients through Week 104.
• Of 62 patients who de-escalated their dose at least once, 7 (11.3%) patients escalated their dose after de-escalation and 3 patients were de-escalated after CD-related surgery.
• From week 48 through week 104, the overall median duration of corticosteroid-free clinical remission and biomarker remission after the first dose de-escalation was 24.00 weeks (95% CI, 12.14-35.29) and 24.00 weeks (95% CI, 14.57-32.86) in the T2T and SoC groups, respectively (hazard ratio, 1.028; 95% CI, 0.520-2.031).
• Among patients who completed LTE and remained on the same dose, endoscopic response and remission were achieved in ~50% and ~20% of patients, respectively, and clinical response and remission rates were >90% and >80%, respectively. Less than 10 patients remained on STELARA q4w dosing throughout the LTE period.

Disease Progression Events

• Disease progression events are reported in Table: Time to Disease Progression Event through Week 48 and Week 104 from Randomization.

Pharmacokinetics and Immunogenicity

• In patients who entered LTE, the median UST concentrations at week 104 were similar between the T2T (2.28 μg/mL) and SoC (2.20 μg/mL) groups.
• The incidence of antibodies to UST through week 104 was lower in the T2T vs SoC group (5/145 [3.4%] vs 13/176 [7.4%]).
• Among patients positive for antidrug antibodies through week 104, 3/5 (60.0%) patients in the T2T group and 10/13 patients (76.9%) in the SoC group were positive for neutralizing antibodies.
• Increases in endoscopic response and remission rates were observed with increasing UST concentrations at week 48 but not at week 104; see Table: Endoscopic Outcomes at Weeks 48 and 104 by Serum Concentrations.

Health-Related Quality of Life

• In the T2T vs SoC group, the percentage of patients with an IBDQ response (89.4% vs 84.8% of patients, respectively) and remission (76.1% vs 71.2% of patients, respectively) at week 104 were similar.
• Changes in HRQoL and WPAI measures from baseline to week 104 are reported in Table: Changes from Baseline in HRQoL and WPAI Measures at Week 104 (mRAS).
• Compared with baseline, patients in the T2T and SoC groups lost an average of 2.2 and 2.3 fewer days from work, respectively, due to CD at week 104.
• At week 104 vs baseline, 60.9% vs 61.6% patients in the T2T group and 68.7% vs 63.4% patients in the SoC group were in employment.

Safety through Week 104

• Overall, TEAEs were reported in 108 (73.5%) patients in the T2T group and 120 (68.2%) patients in the SoC group.
• For summary of safety events, see Table: TEAEs from Week 48 through Week 104 in Patients Entering LTE.

• One patient in the T2T group reported a nonserious basal cell carcinoma during the LTE.
• The most common TEAE leading to treatment discontinuation was CD (T2T group, 3 [2.0%]; SoC group, none).
• One patient each in the T2T group had a serious AE of a severe CD flare and a serious Campylobacter infection.
• TEAEs included 5 reports of malignancy: lung adenoma, plasma cell myeloma, and superficial spreading melanoma stage unspecified in the T2T group and cervical neoplasm and malignant melanoma in the SoC group.
  • The malignant melanoma was considered by the investigator to be related to STELARA and the cervical neoplasm was fatal.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 06 September 2024.