SUMMARY

• STELARA was evaluated in 3 randomized, double-blind, placebo-controlled, phase 3 clinical studies in adult patients with moderately to severely active Crohn’s Disease (CD). There were two 8-week intravenous (IV) induction studies (UNITI-1 and UNITI-2), followed by a 44-week subcutaneous (SC) randomized withdrawal maintenance study (IM-UNITI).¹ Analyses of efficacy based on disease location are reported below.^1–3
• The efficacy of STELARA vs adalimumab was evaluated in a randomized, double-blind, parallel-group, phase 3b trial. The proportion of patients achieving clinical remission based on baseline gastrointestinal (GI) involvement and ulceration are reported below.^4,5
• A prospective study, 3 retrospective studies, and 8 case reports evaluating the efficacy of STELARA based on disease location are also summarized in this response.^6–16

CLINICAL DATA

Pivotal Trial Program – UNITI/IM-UNITI

The efficacy and safety of STELARA was evaluated in 3 randomized, double-blind, placebocontrolled, phase 3 clinical studies in adult patients (aged ≥18 years) with moderately to severely active CD. There were two 8-week IV induction studies (UNITI-1 and UNITI-2), followed by a 44-week SC randomized withdrawal maintenance study (IM-UNITI), representing 52 weeks of therapy.¹

UNITI-1 and UNITI-2 Induction Studies

• In both studies, at week 0, patients were randomized in a 1:1:1 ratio to receive a single dose of IV placebo, IV STELARA 130 mg, or weight-based tiered IV STELARA dosing approximating 6 mg/kg (260 mg [weight ≤55 kg], 390 mg [weight >55 kg and ≤85 kg], 520 mg [weight >85 kg]).^1,17
• The primary endpoint was clinical response at week 6 (defined as a reduction from baseline in Crohn’s Disease Activity Index (CDAI) score of ≥100 points or a CDAI score of <150 points).¹
• At week 6, clinical response was observed in 34% (84/249) of patients treated with STELARA vs 21% (53/247) of patients in the placebo group for UNITI-1; P<0.01. For UNITI-2, the rates were 56% (116/209) vs 29% (60/209), respectively; P<0.001.
• A total of 741 patients were randomized in UNITI-1.^1,17 See Table: Clinical Response at Week 6 Based on Involved GI Area at Baseline: UNITI-1 for clinical response at week 6 based on the involved gastrointestinal (GI) area.²

• A total of 628 patients were randomized in UNITI-2.¹ See Table: Clinical Response at Week 6 Based on Involved GI Area at Baseline: UNITI-2 for clinical response at week 6 based on the involved GI area.²

IM-UNITI Maintenance Study

• Patients who were in clinical response at week 8 to IV STELARA during the UNITI-1 or UNITI-2 induction study were randomly assigned in a 1:1:1 ratio to receive placebo SC (n=133), STELARA 90 mg SC every 8 weeks (q8w; n=132), or STELARA 90 mg SC every 12 weeks (q12w; n=132).¹
• Of the 397 randomized patients, 388 patients were included in the efficacy analysis population for IM-UNITI.²
• The primary endpoint was clinical remission at week 44 (CDAI score <150 points).¹
• At week 44, clinical remission was observed in 53% (68/128) of patients treated with STELARA vs 36% (47/131) of patients in the placebo group; P<0.01.
• See Table: Clinical Remission at Week 44 Based on Involved GI Area at Baseline: IM-UNITI Maintenance Study for clinical remission at week 44 based on the involved GI area.²

UNITI/IM-UNITI - Post Hoc Analysis

• A post hoc analysis of the UNITI-1, UNITI-2, and IM-UNITI studies was conducted to evaluate the predictive performance of fecal calprotectin (FCal) for short- and long-term clinical and endoscopic outcomes. The analysis also included assessments in patients with isolated ileal disease and those with colonic or ileocolonic disease.³
• Clinical remission was defined as CDAI <150 points. Clinical response was defined as a reduction in CDAI of ≥100 points, endoscopic remission was defined as a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of <3, mucosal healing was defined as the absence of ulceration, and endoscopic response was defined as improvement in
  SES-CD of at least 50% from the baseline value.³
• Overall, 677 patients were treated with STELARA during induction and had evaluable data at week 6 and week 8.³
• Of the 677 patients, 134 (19.8%) had ileal, 65 (9.6%) had colonic, 478 (70.6%) had ileocolonic CD, and 157 (23.2%) had an involvement of the proximal GI tract.³
• Week 6 FCal <250 mg/kg did not predict any clinical (response and remission) or endoscopic outcome at weeks 8, 32, or 52 in patients with ileal CD; however, a trend for week 6 FCal <250 mg/kg predicting mucosal healing at week 8 was observed in patients with colonic or ileocolonic CD with poor accuracy.³
• Week 6 FCal <250 mg/kg showed a significant ability to predict week 52 endoscopic remission and mucosal healing with fair accuracy in patients with colonic or ileocolonic CD.³

Phase 3b Study - SEAVUE Study

The efficacy and safety of either STELARA or adalimumab in biologic-naïve adult patients with moderately to severely active CD was evaluated in a randomized, double-blind, parallel-group, phase 3b trial.⁴

• Patients were assigned 1:1 to receive STELARA ~6 mg/kg IV then 90 mg SC every 8 weeks or adalimumab 160 mg SC on day 0, 80 mg at week 2 then 40 mg every 2 weeks.
• Clinical remission (CDAI score <150) was assessed at week 52.
• At week 52, clinical remission (primary endpoint) was achieved in 65% (124/191) of patients treated with STELARA and 61% (119/195) of patients treated with adalimumab.
  • No statistically significant difference was found between treatment groups (4%; 95% CI, -6% to 14%; P=0.42).
  • Because there was no significant difference between treatment groups in the primary endpoint, all major secondary endpoints and other endpoint P-values were nominal and considered non-significant.
• For the odds ratio comparing the proportion of patients who achieved clinical remission at week 52 by baseline gastrointestinal involvement and by baseline ulceration location, see Table: Odds Ratio Comparing Rates of Clinical Remission at Week 52.

Prospective Study

Murate et al (2020)⁶ conducted a prospective study to identify predictors of efficacy of STELARA in patients with moderate to severe active CD.

Study Design/Methods

• STELARA (6 mg/kg) was administered q8w at a weight range-based dose (weight ≤55 kg, 260 mg; weight >55 kg and ≤85 kg, 390 mg; weight >85 kg, 520 mg).
• Clinical response was defined as a reduction from baseline in CDAI score of ≥100 or <150 points. Clinical remission was defined as a CDAI score of <150.

Results

• Twenty-two patients with moderate to severe active CD who received STELARA treatment until week 48 were included.
• At baseline, the disease location among patients according to the Montreal classification was as follows¹⁸:
  • L1 ileal disease (n=3; 13.6%)
  • L2 colonic disease (n=1; 4.5%)
  • L3 ileocolonic disease (n=18; 81.8%)
  • p perianal disease (n=11; 50.0%)
• Response to STELARA treatment based on the GI areas involved at baseline are shown in Table: Treatment Outcomes at Week 24 Based on Disease Location at Baseline.

Retrospective Studies

Arteaga et al (2023)⁷ reported the efficacy of STELARA in patients with ileum-dominant CD vs colonic CD through a retrospective, single-center study.

• The primary outcome was absence of ulcers on follow-up colonoscopy.
• Eighty-four patients with ileum-dominant CD and 27 patients with colonic CD were treated with STELARA.
• On the follow-up colonoscopy, 45% and 76% of ileum-dominant and colonic CD patients were ulcer-free, respectively, P=0.02.
  • Of the patients with ulcers on endoscopy prior to starting STELARA, 24% and 67% of ileum-dominant and colonic CD patients were ulcer-free, respectively, (P=0.01).

Narula et al (2022)⁸ conducted a pooled analysis to compare the efficacy of adalimumab, infliximab, STELARA (UNITI-1, UNITI-2, and IM-UNITI studies), and vedolizumab for achieving endoscopic healing in the ileum and colon after 1 year of therapy in patients with CD.

Study Design/Methods

• A pooled analysis of data from 4 clinical trials that included patients who had received continuous treatment with adalimumab, infliximab, STELARA, or vedolizumab throughout the trials and had ≥1 ileocolonic segment with a SES-CD of ≥3 at enrollment.
• The proportions of patients achieving 1-year endoscopic healing (defined as a SES-CD of 0) treated with each of the 4 biologics were compared.

Results

• Overall, 344 patients were included in the study, of whom 41 received treatment with STELARA.
• At baseline, the median SES-CD score in patients who received STELARA was 12.0 (interquartile range [IQR], 7.0-17.0).
• Among the patients who received STELARA, the following segments were involved at baseline:
  • Ileum: 22 (53.7%) patients
  • Ascending colon: 21 (51.2%) patients
  • Transverse colon: 15 (36.6%) patients
  • Descending colon: 23 (57.5%) patients
  • Rectum: 48 (34.0%) patients
• Endoscopic outcomes based on CD location are described in Table: Endoscopic Outcomes at 1 Year Among Patients With Ileal or Colonic CD at Baseline Who Received STELARA.

Hoffmann et al (2019)⁹ conducted a retrospective, single-center study to evaluate the efficacy and safety of STELARA in patients with moderately to severely active CD. Results on disease location are also reported.

Study Design/Methods

• Adult patients who had completed treatment with STELARA at the inflammatory bowel disease (IBD) outpatient clinic during the first 6 months and had a documented follow-up of at least 24±6 weeks from start of STELARA were included in the study.
• Patients had received a single dose of IV STELARA (weight range-based dosing of approximately 6 mg/kg), followed by administration of STELARA 90 mg SC at week 8 and q8w or q12w thereafter (based on the patient's treatment response).
• The primary endpoint was a combined endpoint of steroid-free clinical remission (defined as Harvey-Bradshaw Index [HBI] of ≤3 points without the use of any steroid preparation [budesonide, prednisone/prednisolone, or methylprednisolone]) or steroid-free clinical response (defined as an HBI reduction of ≥3 points without the use of any steroid preparation) at 24±6 weeks of STELARA therapy.

Results

• Overall, 57 patients were included in the study and 18, 9, 30, and 4 patients reported CD location (using the Montreal classification of CD) at L1, L2, L3, and L4, respectively.
• At baseline, the mean±SD HBI was 6.6±5.1 (range, 0-24) and 20 (35.1%) patients were receiving steroids, including budesonide.
• Steroid-free clinical remission/response vs no response based on disease location are as follows:
  • L1: 8 vs 10 patients (P=0.99)
  • L2: 4 vs 5 patients (P=0.99)
  • L3: 14 vs 16 patients (P=0.99)
  • L4: 1 vs 3 patients (P=0.62)

Case Reports

Ileocolonic-type CD

Murate et al (2021)¹⁰ reported the therapeutic efficacy of STELARA in the treatment of small bowel lesions in 2 patients with ileocolonic-type CD.

Case 1

• A 40-year-old female patient with ileocolonic-type CD presented with intermittent abdominal pain, fever, and diarrhea (approximately 10 times a day).
• Transoral double-balloon endoscopy (DBE) followed by gastrografin enterography revealed a longitudinal ulcer and 2 ileal stenoses with a deep ulcer, and transanal DBE with gastrografin enterography revealed a longitudinal ulcer and an ileal stenosis.
• The patient was previously treated with 5-aminosalicylic acid (5-ASA) for 3 years and was biologic-naïve, and STELARA was administered at the patient’s request.
• Within 8 weeks after STELARA therapy initiation, the patient’s symptoms were alleviated, with soft stools occurring twice a day.
• At 24 weeks after STELARA therapy initiation, the patient had no symptoms and bowel movements were normal. Transoral and transanal DBEs showed improvement in the shallow and deep longitudinal ulcers, stenosis, and colonic lesions.
• At 72 weeks after STELARA therapy initiation, the patient’s symptoms had completely disappeared, with normal stool consistency occurring once or twice a day.
  • Transoral and transanal DBE showed that the longitudinal ulcers were in the scarring stage, while the deep ulcer area had reduced and disappeared.
  • The stenosis was deemed as inconspicuous.
• From baseline to week 72 after STELARA therapy initiation, CDAI score improved from 322 to 44, serum albumin levels from 3.5 to 4.4 g/dL, and serum CRP levels from 1.76 to 0.04 mg/dL.

Case 2

• A 50-year-old male patient with ileocolonic-type CD and ileal stenosis presented with occasional abdominal pain for 1 year.
• The patient had failed response to a combination of 5-ASA, an immunomodulator, and a steroid after 25 years of treatment. Following failure, the patient was initiated on infliximab therapy 5 years ago. Endoscopic evaluation was performed each year since infliximab initiation. Due to the deterioration of the intestinal mucosa, frequency of diarrhea (3 times per day), and abdominal pain, the patient was switched to STELARA. Within 8 weeks of initiating STELARA, stool consistency improved, and its frequency was reduced.
• During the 24th week of STELARA treatment, the patient’s stool was normal and occurred twice a day.
  • Transoral and transanal DBEs showed improvement in longitudinal and circumferential ulcers and stenosis.
• During the 72nd week of treatment with STELARA, transoral and transanal DBEs revealed the following findings:
  • All longitudinal ulcers had scarred.
  • The circumferential ulcers had been covered by regenerating mucosa.
  • The endoscope could pass through the stenosis.
• From baseline to week 72 after STELARA therapy initiation, CDAI score improved from 224 to 70, serum albumin levels from 3.9 to 4.3 g/dL, and serum CRP levels from 0.40 to 0.05 mg/dL.

Murate et al (2019)¹¹ described the use of STELARA in a 20-year-old female patient with ileocolonic-type CD.

• The patient presented with severe abdominal pain, and DBE revealed severe ulcerative lesions with edema and 4 ileal stenoses, 2 of which were endoscopically nonpassable.
  • After endoscopic balloon dilation (EBD) was performed, the endoscope could pass through all 4 stenotic sites.
• STELARA was administered as a remission induction therapy.
• DBE performed after 24 weeks revealed that the endoscope could pass through all stenotic sites, including the 2 previously nonpassable sites.
  • The lumen at the 2 stenotic sites that had undergone EBD showed further dilation beyond that observed immediately after the procedure.

Upper Gastrointestinal CD

Fasoulas et al (2021)¹² reported the efficacy of STELARA in a 73-year-old female patient treated for upper GI involvement of CD.

• The patient initially presented with nausea, vomiting, epigastric pain, weight loss, malnourishment, an elevated CRP, and severe iron deficiency anemia.
• Gastroscopy revealed diffusely edematous gastric and duodenal mucosa with multiple ulcers. Only mild ileitis with sporadic aphthous ulcers were found on ileocolonoscopy. There were no strictures or jejunal involvement.
• The patient started infliximab but was discontinued due to a serious, immediate hypersensitivity reaction. The patient then was switched to STELARA, with a 260 mg IV infusion followed by 90 mg SC every 8 weeks.
• After seven months with STELARA treatment, the patient was asymptomatic with an increased body mass index and improvement upon upper endoscopy with only mild, patchy edema of the gastric antrum.
• At the time of this report, the patient was steroid-free.

Oral CD

Alrashdan et al (2021)¹³ reported the use of STELARA in a 23-year-old male patient for the treatment of severe oral CD with a past medical history of psoriasis treated with adalimumab.

• The patient presented with painful diffuse oral ulceration in the bilateral buccal mucosa and left upper vestibule opposite to molar teeth persisting over a 3-month duration. This was accompanied by diffuse asymptomatic swelling of the lower lip, recent weight loss, and frequent diarrhea.
• Intraoral examination revealed several aphthous-like ulcers, particularly on the lower labial mucosa.
• Due to his symptoms, the patient was referred to a gastroenterologist. An oral biopsy revealed diffuse granulomatous inflammation with histiocytic and chronic inflammatory infiltrate extending to the perivascular sites in the connective tissue. Immunostaining for CD68 was positive.
• The patient’s symptoms worsened with inability to swallow hard food, further wasting, and pale skin. Severe ulceration on the uvula, pillars of the fauces, and posterior pharyngeal wall was noted.
• The patient had lost 25 kg of weight and was severely anemic due to blood loss in the stool. He was admitted to the hospital due to unstable blood pressure. Colonoscopy was performed after a failed attempt due to excessive colonic bleeding. Multiple large ulcers were observed at the terminal ileum with oozing blood extending to approximately
  50 cm above the level.
• A diagnosis of CD was made and treatment with 50 mg prednisolone and 150 mg azathioprine was initiated.
• The patient’s signs and symptoms showed significant improvement with normalization of inflammatory biomarkers (CRP, 3 mg/L vs 30 mg/L [before the diagnosis of CD]; erythrocyte sedimentation rate [ESR], 10 mm/hour vs 22 mm/hour [before the diagnosis of CD]).
• Prednisolone tapering led to a relapse of bowel bleeding and oral erosions. Eight weeks later, treatment was switched to STELARA (360 mg IV induction dose followed by 90 mg SC q8w) and topical steroids for oral ulcers (as needed).
• The patient has been on this treatment regimen for 12 months and has continued to show complete remission of both CD and psoriasis.

Vulvar CD

Stoleru et al (2020)¹⁴ reported the efficacy of STELARA in the treatment of vulvar CD in a 24-year-old female patient with a history of colonic CD with perianal involvement.

• Three years ago, the patient had undergone proctocolectomy as part of the management of inflammatory colonic CD with complex perianal involvement refractory to thiopurine, infliximab, and adalimumab. Since the surgery, the patient was not on any therapy for CD.
• The patient presented with complaints of vaginal pain and swelling for 1 week and was on chronic suppressive valacyclovir treatment for recurrent genital herpes simplex virus.
• There was no evidence of small bowel CD on ileoscopy performed 1 year ago.
• Pelvic examination revealed labial edema and erythema with friable tissue and discharge. Biopsy of the vulva was consistent with vulvar CD.
• Prednisone therapy (40 mg daily and then tapered) was initiated. The patient was then transitioned to STELARA (390 mg IV infusion followed by 90 mg SC injection q8w) due to a history of treatment failure with 2 antitumor necrosis factor (TNF) alpha agents and the risk of antibody formation due to the absence of medical treatment since her surgery.
• Four months after the initiation of STELARA therapy, the patient had near-complete resolution of her symptoms.

Esophageal CD

Alli-Akintade et al (2019)¹⁵ reported the use of STELARA for the treatment of esophageal CD in a 31-year-old female patient.

• After being diagnosed with Crohn’s colitis at the age of 2 years, the patient underwent total colectomy with an end ileostomy at the age of 10 years. At the age of 29 years, upper endoscopy with histologic examination performed for symptoms of recurrent dysphagia suggested a diagnosis of esophageal CD. Multiple upper endoscopies with serial dilations of a stricture in the mid-esophagus were performed. Treatment history included azathioprine, infliximab, adalimumab, famotidine, prednisone, and budesonide slurry.
• At age 31, the patient presented with symptoms of recurring dysphagia that developed over the past 3 months after the discontinuation of budesonide slurry but was still receiving infliximab.
• Luminal narrowing (16-20 cm from the incisors) with significant friability, requiring the use of an ultrathin endoscope, was observed on upper endoscopy.
• Unlike previous use, prednisone or budesonide slurry did not lead to any improvement in the patient’s symptoms. Treatment was switched from infliximab (drug concentration [20 µg/ml] within the therapeutic range with no antibody formation) to STELARA; prednisone was continued.
• One month after STELARA initiation, upper endoscopy revealed resolution of friability; dilation of the narrowed area was performed, and prednisone was tapered. Follow-up endoscopy 3 weeks later revealed narrowing but no active inflammation; serial dilations were performed. Endoscopy 4 weeks later revealed mild narrowing with evidence of a scarred but patent esophagus. There was resolution of obstruction and inflammation at the site of the prior stricture; no further dilation was needed.
• The patient has been on treatment with STELARA q4w and experiences mild intermittent dysphagia with oral intake but has been gaining weight.

Barkin et al (2016)¹⁶ reported the efficacy of STELARA in the treatment of refractory esophageal CD in a 23-year-old male patient with a past medical history of subtotal colectomy with end-ileostomy due to structuring colonic and perianal CD.

• The patient previously failed therapy with mesalamines, steroids, thiopurines, methotrexate, anti-TNF agents, thalidomide, and other therapies. Certolizumab pegol was initiated postoperatively; however, the patient developed peristomal fistulae complicated by stomal pyoderma gangrenosum and mild ileitis with distal ileal stricture formation.
• The patient presented with symptoms of odynophagia and oral ulcers.
• Oral aphthae and multiple cratered and linear esophageal ulcers consistent with esophageal CD were observed during upper endoscopy. Ulceration and inflammation observed on biopsies were negative for herpes simplex virus and cytomegalovirus.
• Empiric treatment for herpes simplex virus with valacyclovir and prednisone led to rapid improvement in symptoms; however, weight loss due to poor oral intake recurred after prednisone was tapered. Subsequently, intermittent odynophagia and oral ulcers did not show any improvement despite the use of high-dose prednisone, oral fluticasone, aggressive acid suppression, and certolizumab pegol.
• Certolizumab pegol was replaced with STELARA (90 mg SC q8w), leading to prolonged symptom remission off steroids and acid suppression. Upper endoscopy revealed complete resolution of oral and esophageal ulceration; peri-stomal fistulae and ileitis were also improved with STELARA.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 25 November 2024.