Summary

• The company cannot recommend any practices, procedures, dosing, or usage that deviate from the approved labeling.
• STELARA was evaluated in 3 randomized, double-blind, placebo-controlled clinical trials of 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) representing 52 weeks of therapy. During the UNITI clinical trial program, the safety and efficacy of STELARA in combination with another biologic was not evaluated.¹
• STELARA was evaluated in 2 randomized, double-blind, placebo-controlled clinical studies of adult patients with moderately to severely active ulcerative colitis (UC). There was an 8-week IV induction study (UNIFI induction trial) followed by a 44-week SC randomized withdrawal maintenance study (UNIFI maintenance trial) for a total of 52 weeks of therapy. During the UNIFI clinical trial program, the safety and efficacy of STELARA in combination with a biologic was not evaluated.²
• The efficacy and safety of dual biologic therapy (DBT) of STELARA with either vedolizumab or a tumor necrosis factor (TNF) blocker in the treatment of CD was evaluated in retrospective studies and case reports.^3-13
• The efficacy of the therapy with STELARA, vedolizumab and tofacitinib in the treatment of UC was evaluated in a case report.¹⁴
• The efficacy and safety of DBT of STELARA in combination with a biologic was evaluated in a retrospective study and case series for the treatment of CD or UC.^15-17

clinical data

Phase 3 Randomized Clinical Trials in CD

• STELARA was evaluated in 3 randomized, double-blind, placebo-controlled clinical trials of adult patients with moderately to severely active CD (Crohn’s Disease Activity Index [CDAI] score of 220-450). 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
  • In UNITI-1, patients had failed or were intolerant to prior treatment with 1 or more TNF blockers.
  • In UNITI-2, patients had failed or were intolerant to conventional therapies and were either naïve to TNF blocker therapy or had received but never failed a TNF blocker.
  • IM-UNITI evaluated patients who achieved clinical response at week 8 of induction with STELARA in the UNITI-1 or UNITI-2 trials.
• During the UNITI clinical trial program, the safety and efficacy of STELARA in combination with another biologic was not evaluated.

Phase 3 Randomized Clinical Trials in UC

• STELARA was evaluated in 2 randomized, double-blind, placebo-controlled clinical trials of adult patients with moderately to severely active UC (Mayo total score of 6-12, and a subscore of 2 or 3 on the endoscopic component). There was an 8-week IV induction study (UNIFI induction trial) followed by a 44-week SC randomized withdrawal maintenance study (UNIFI maintenance trial) for a total of 52 weeks of therapy.²
  • In the UNIFI induction and maintenance trial, patients were required to have an inadequate response or unacceptable side effects from a biologic (e.g., TNF blocker and/or vedolizumab) or conventional therapy (e.g., corticosteroids or immunomodulators).
• During the UNIFI clinical trial program, the safety and efficacy of STELARA in combination with another biologic was not evaluated.

Retrospective Studies - CD

Glassner et al (2020)³ conducted a retrospective cohort study to determine the effectiveness and safety of combination therapy, vedolizumab and STELARA, in patients with CD.

• Eligible patients with data from 2015 to 2019 were included in this study.
• The primary outcomes were improvement in laboratory parameters (C-reactive protein [CRP], albumin, vitamin D and erythrocyte sedimentation rate [ESR]) as well as clinical and endoscopic scoring; the secondary outcome was safety.
• There were 30 patients with CD included in this study with a mean age of 37 years.
• The mean disease duration was 14 years; patients had failed a median of 2 (interquartile range, 2-3) previous treatments with biologics.
• Significant improvements were observed in mean ESR and albumin levels after combination therapy with STELARA and vedolizumab. Significant improvements were also observed in Harvey-Bradshaw Index (HBI) score. See Table: Outcomes in Patients with CD Treated with Combination STELARA and Vedolizumab.
• No improvements were observed in endoscopic score; however, 50% of patients did not yet have follow-up data at the time of this analysis.

• There were 5 serious adverse events (AEs) and no deaths reported.
• A multivariate analysis showed that risk factors for serious infection include the use of immunomodulators, longer disease duration, increasing age, and albumin levels.

Yang et al (2020)⁴ conducted a retrospective chart review to evaluate the efficacy and safety of DBT in a cohort of patients with refractory CD. Among the different combinations included, for STELARA, either a TNF blocker or vedolizumab was used in the DBT combination.

• The primary outcome was endoscopic improvement during maintenance therapy (>50% reduction in Simplified Endoscopic Score-Crohn’s Disease [SES-CD] or as explicitly stated by an inflammatory bowel disease specialist).
• Other outcomes were endoscopic remission (SES-CD<3 or as stated), clinical response (CD-patient-reported outcome-2 score [PRO-2] reduced by 8), clinical remission (PRO-2<8), and AEs.
• Endpoints were assessed at the time of endoscopic evaluation closest to 1 year of DBT or at the time of treatment failure.
• The median number of prior failed biologics was 4.
• There were a total of 24 therapeutic trials of DBT in this analysis among 22 patients, and prior to initiating DBT the biologic at baseline was vedolizumab (15/24), STELARA (8/24) or infliximab (1/24). No patients were in clinical remission or in endoscopic remission at baseline. The majority of patients had either a stricturing (13/22; 59%) or penetrating (8/22; 36%) phenotype and any prior history of perianal fistulas (12/22; 55%).
• In all therapeutic trials of DBT, patients were receiving a single biologic agent and the second biologic was added. Among the 24 therapeutic trials of DBT, the following combinations were evaluated: vedolizumab/STELARA (n=8; 33%), vedolizumab/infliximab (n=6; 25%), vedolizumab/adalimumab (n=4; 17%), STELARA/adalimumab (n=2; 8%), vedolizumab/certolizumab (n=2; 8%), STELARA/infliximab (n=1; 4%), and vedolizumab/golimumab (n=1; 4%).
• Endoscopic improvement, endoscopic remission, clinical response, clinical remission, and AEs occurred in 43%, 26%, 50%, 41%, and 13% of the trials, respectively. See Table: Efficacy and Safety Endpoints for Combinations of DBT.

• Patients were treated with DBT for a median of 274 days and followed for up to 1 year, which at that time, 38% of patients were remaining on DBT. The most common reasons for ending a therapeutic trial of DBT were nonresponse or worsening of disease activity requiring surgery.

Retrospective Study - CD or UC

Kwapisz et al (2021)¹⁵ conducted a retrospective study in patients with CD or UC who received infliximab, adalimumab, certolizumab pegol, golimumab, vedolizumab, or STELARA in combination for worsening luminal disease.

• Clinical response was assessed by using the CD-PRO signs and symptoms for CD and the partial Mayo score for UC.
• A total of 15 patients were treated with DBT (CD, n=14; UC, n=1) for a median duration of 6 months (range, 2-48 months). Of these 15 patients:
  • Two patients received STELARA with a TNF blocker (n=1 each for adalimumab and golimumab) and both had a clinical response and a reduction in corticosteroids. One of these patients had an infection.
  • Five patients received STELARA with vedolizumab and of these, 4 patients had a clinical response, 2 patients had a reduction in corticosteroids, 1 patient required surgery, and 1 patient required hospitalization.

Case Reports - CD

Almeida et al (2023)⁵ described 2 case reports of patients with CD treated with a combination of STELARA and adalimumab.

• A 57-year-old female with CD for 15 years including complications of transverse gastro-colon, jejuno-sigmoid, and perianal fistulas. She underwent subtotal colectomy with ileosigmoid anastomosis, segmental ileum enterectomy, segmental gastrectomy and perianal fistulotomy, which resulted in pancreatic and enterocutaneous fistulas.
  • The patient did not respond adequately with various biological therapies. To avoid surgery due to the patient’s refusal of an ostomy, combination therapy of STELARA and adalimumab was initiated.
  • However, the patient required surgery 6 months after association with definitive terminal ileostomy.
• A 50-year-old male patient who had previously undergone perianal abscess drainage and complicated appendectomy experienced postoperative complications, including perianal fistulas and enterovesical, enterocolic, and enterocutaneous fistulas.
  • Following a CD diagnosis, the patient was treated with infliximab and underwent surgery to treat multiple fistulas.
  • Surgical drainage was required for abscesses and enterocutaneous fistulas in the lumbar region.
  • Due to anaphylactic reaction to infliximab, the patient was started on combination therapy of STELARA and adalimumab.
  • The combination therapy resulted in fistula closure and avoiding the need for surgery.

Howard et al (2022)⁶ described the case report of a patient with refractory CD treated with a combination therapy of STELARA and vedolizumab.

• A 20-year-old male diagnosed at age 11 with CD (severe oral and perianal) demonstrated 3 previous biologic failures (infliximab, adalimumab, and vedolizumab). He responded well to intensified STELARA, but later had a surgery with ileo-sigmoid anastomosis.
• The patient continued having symptoms with deep rectal and sigmoid ulcers despite the addition of budesonide and cholestyramine. Budesonide was discontinued and vedolizumab 300 mg every 8 weeks (q8w) was added to STELARA 90 mg every 4 weeks (q4w). This resulted in complete clinical remission 8-10 weeks after this intervention. A follow-up ileocolonoscopy at week 20 showed complete mucosal healing and he is continuing DBT while in complete clinical remission.

Biscaglia et al (2020)⁷ described the case report of a patient with CD and dermatological comorbidities, who was treated with DBT of STELARA and vedolizumab.

• An adult patient diagnosed with CD who was in remission with initial prednisone treatment but then experienced clinical (HBI=14) and biochemical flare due to prednisone withdrawal. Treatment with infliximab was started, but it was soon discontinued due to a serious allergic reaction.
• The patient was then treated with adalimumab for 24 months with moderate benefit (HBI=7), but it was discontinued upon paradoxical appearance of palmoplantar psoriasis which did not disappear after discontinuation of adalimumab.
• Two months later, STELARA 45 mg every 12 weeks was started for the treatment of psoriasis (at the time, STELARA was not approved for the treatment of CD), and complete resolution of symptoms was observed.
• A month later, the patient experienced obstruction symptoms, which required surgery.
• Post-operatively, the patient’s CD had worsened (HBI=16), while his psoriasis had maintained remission.
• Vedolizumab was then added to STELARA, and the patient achieved clinical and ultrasonographic remission. No side effects were reported in 24 months of DBT.
• Vedolizumab was discontinued upon approval of STELARA for the treatment of CD. Sustained remission was reported for an additional 12 months.

Dimopoulos et al (2020)⁸ reported the case of a 24-year-old male diagnosed with fibrostenotic Crohn’s ileocolitis at age 9 who received DBT of STELARA and adalimumab.

• Treatment with infliximab 10 mg/kg in combination with methotrexate resulted in secondary loss of response.
• The patient was then transitioned to adalimumab and the dose was escalated to 40 mg weekly in combination with methotrexate. However, methotrexate was subsequently discontinued by the patient due to intolerance. Clinical response (without remission) was achieved with adalimumab monotherapy.
• Due to the patient’s hesitation to discontinue adalimumab, he was bridged using STELARA and continued adalimumab with a plan to discontinue adalimumab upon clinical remission.
  • He received a weight-based loading dose of STELARA IV followed by 90 mg SC q8w.
• The patient tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 5 months later but was asymptomatic and his CD symptoms remained at baseline.
• He received 1 dose of STELARA SC 1 day before SARS-CoV-2 testing and 1 dose of adalimumab 1 week before testing, which was held and resumed 2 weeks later.
• The patient remained stable without respiratory symptoms or new-onset gastrointestinal symptoms at week 2 and week 6 after testing positive for
  SARS-CoV-2 infection.

Elmoursi et al (2020)⁹ reported the case of a 35-year-old male patient with stricturing CD refractory to several TNF blockers who benefited from DBT with STELARA and vedolizumab.

• Previous treatment failures resulted in intestinal stricture requiring surgical resection multiple times. Subsequently, after further treatment failure, the patient had a proctocolectomy with ileostomy.
• The patient had a previous history with vedolizumab q8w and then subsequently switched to STELARA q8w after an ulcerated nonobstructing stricture. While on STELARA (increased to q4w) in addition to azathioprine, and budesonide, an ileoscopy revealed 2 ulcers in the neo-terminal ileum (TI).
• Vedolizumab q8w was subsequently reinitiated in combination with STELARA q4w and azathioprine. The patient's symptoms improved after 4 months, but the neo-TI ulcers continued.
• Vedolizumab dose was escalated to q4w and a dexamethasone taper was initiated. An ileoscopy 4 months later showed a normal neo-TI, and deep remission was confirmed by histologic evaluation.
• The patient continued with azathioprine with vedolizumab q4w and STELARA q4w DBT and was in corticosteroid-free deep remission with no AEs.

Fumery et al (2020)¹⁰ reported the case of a 19-year-old male with refractory luminal and perianal CD treated with the combination of STELARA and golimumab.

• This patient had 3 previous biologic failures prior to starting DBT.
• After 6 months of combination therapy, treatment was stopped due to the lack of clinical and endoscopic response; no AEs were reported.

Huff-Hardy et al (2017)¹¹ reported the case of a 22-year-old female patient with refractory CD who received a combination of vedolizumab and STELARA.

• The patient had a history that included severe colonic involvement with multiple strictures, subtotal colectomy and end ileostomy, and aggressive penetrating disease with enterocutaneous perianal fistulas.
• The patient previously received various TNF blockers, natalizumab, and vedolizumab combined with immunomodulators with poor responses, and in some cases, poorly tolerated AEs.
• The patient was then put on STELARA, but her subjective gastrointestinal complaints and vulvo-perianal disease continued to progress, which was diagnosed as moderate to severe.
• Vedolizumab was added to the patient’s STELARA and methotrexate regimen, and after 8 weeks, the vulvo-perianal disease greatly improved. After 1 year of DBT along with methotrexate, the patient achieved deep remission for the first time in 10 years.
• Except an episode of self-limited rotavirus infection, there were no other infectious complications reported with the therapy.

Kim et al (2017)¹² reported the case of a 31-year-old female patient with Crohn’s colitis and vulvar Crohn’s who received combination vedolizumab and STELARA.

• The patient was previously treated with TNF blockers, including infliximab and adalimumab, for Crohn’s colitis. She had a primary response but then lost clinical response despite dose escalation.
• She was started on vedolizumab, which resulted in mucosal healing. However, as the patient responded to vedolizumab, she had flares of vulvar lesions (which were retrospectively undiagnosed during TNF blocker treatment due to remission of vulvitis at that time).
• Concomitant STELARA was started (as part of combination biologic therapy) and the patient reported marked improvement after receiving the induction IV dose and subsequent maintenance doses. The goal afterwards was to eventually discontinue vedolizumab and use STELARA monotherapy to keep the patient's Crohn's colitis and vulvar Crohn's in remission.

Liu et al (2017)¹³ reported the case of a 27-year-old female patient with severe and refractory ileocolonic CD who received DBT of STELARA and vedolizumab.

• The patient was previously treated with various therapies including conventional treatments, biologics (including STELARA), and other agents.
• Based on her presentation, the patient was restarted on STELARA with induction dosing followed by 90 mg SC q4w in combination with azathioprine. Allopurinol was subsequently started along with 5-aminosalicylic acid and a corticosteroid.
• Symptoms and inflammation continued 5 months after STELARA initiation.
• Vedolizumab was then added to the patient's treatment and STELARA was reduced to q8w.
• Improvements in abdominal pain, nausea, and fecal calprotectin were seen 5 months after adding vedolizumab to STELARA. After 6 months of DBT, colonoscopy showed mucosal healing of the ileum and colon. No treatment AEs were noted.

Case Report - UC

Thurston et al (2023)¹⁴ described the case of a 20-year-old Caucasian male patient with UC who received STELARA, vedolizumab and tofacitinib.

• In August 2015, the patient was hospitalized for Clostridium difficile infection and received 2 infusions of infliximab 10 mg/kg, which he continued post-discharge along with mesalamine, 6-mercaptopurine (6MP), and a prednisone taper.
• A colonoscopy in November 2015 revealed severe Mayo 3 pancolitis. Vedolizumab was initiated following discontinuation of 6MP and infliximab due to insufficient response.
• Prednisone 40 mg was introduced, and the vedolizumab dose was escalated to q4w based on August 2016 colonoscopy findings of chronic colitis, with Mayo 2 inflammation of ascending, transverse, descending and rectosigmoid colon.
• The patient exhibited a positive clinical response, leading to prednisone tapering off by October 2016.
• A colonoscopy in November 2016 indicated resolution of right-sided colitis with residual proctosigmoiditis (Mayo 2), while colonoscopy on May 2017 showed persistent rectosigmoid inflammation (Mayo 2) with chronic active colitis. Due to recurring inflammation, STELARA q8w was added.
• A colonoscopy in December 2017 showed no improvement, which led to STELARA dose escalation to q4w along with increased prednisone dose and addition of budesonide and mesalamine.
• Prednisone was eventually tapered off by February 2020 following clinical improvement.
• A colonoscopy in December 2020 revealed severe (Mayo 3) recto-sigmoiditis with mild colitis in the descending to transverse colon. Tofacitinib extended release 22 mg qd was added. Budesonide was discontinued in February 2021 due to clinical improvement.
• A colonoscopy in November 2021 demonstrated complete endoscopic remission (Mayo 0), prompting de-escalation by initially discontinuing mesalamine and increasing STELARA to q8w, then adjusting vedolizumab to q8w interval.
• Subsequently, STELARA and tofacitinib were discontinued, and the patient remained in remission on vedolizumab q8w monotherapy at the time of this report.

Case Series - CD or UC

Dawoud et al (2022)¹⁶ reported the case series of 15 refractory patients with IBD treated with STELARA and vedolizumab. Patients had failed other therapies and demonstrated partial response to escalated dosing (q4w) of either STELARA or vedolizumab monotherapy.

• Of the 12 patients with CD treated with dual STELARA and vedolizumab, 11 met criteria for remission (91.6%). Six of these patients demonstrated complete endoscopic and histologic remission.
  • The average time to remission was 14.9 weeks.
  • Three patients did not have follow-up endoscopic or fecal calprotectin data, but demonstrated normalization of albumin, CRP, hemoglobin, and HBI scores.
  • Two patients in clinical remission initiated STELARA and vedolizumab due to elevations in fecal calprotectin and CRP, which normalized after initiation of combination therapy.
  • One patient did not achieve a response.
• None of the 3 patients with UC responded to the DBT.
• There were no AEs or safety concerns reported.

Privitera et al (2021)¹⁷ conducted a retrospective case series to evaluate the safety and effectiveness of DBT in adult patients with IBD due to uncontrolled active IBD or active extraintestinal manifestations (EIM), despite ongoing therapy, from a database of Italian referral centers.

• Among the 16 patients identified, 14 had a concomitant EIM. Seven patients were initiated on DBT because of continuing intestinal symptoms (cohort 1); 9 patients initiated on DBT to treat EIM (cohort 2).
• In the overall population, the median age was 38 years and the median duration of IBD was 10.8 years. The median time on DBT was 7 months (range, 3-28 months).
• Within cohort 1, 2 patients with CD received STELARA as 1 component of the DBT.
  • Both patients had a history of multiple biologic failure, as well as a history of extensive bowel resections.
  • For baseline characteristics for these 2 patients, see Table: Patient’s Baseline Characteristics.
  • For details on the specific DBT regimens, see Table: DBT Dose and Duration.
  • For clinical outcomes of these patients, see Table: Clinical Outcomes of Patients Receiving DBT (STELARA and an Additional Biologic) for Continuing Intestinal Symptoms.
• Clinical activity of intestinal symptoms was categorized according to the HBI and partial Mayo Score for CD and UC, respectively.
• A patient with a history of perianal CD who was treated with STELARA and certolizumab experienced a perianal abscess. Surgical drainage and seton placement were used to manage the abscess. No serious AEs were reported.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 02 May 2024.