SUMMARY

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• Please refer to the local labeling for relevant information on this topic.
• Safety and efficacy analyses for STELARA vs placebo based on concomitant Crohn’s disease (CD) therapy from the phase 3, randomized UNITI induction (8-week), maintenance (44-week) studies, and the open-label long-term extension (LTE) in adult patients with moderately to severely active CD are presented below.^1-3
• Additionally, analyses of pharmacokinetic and immunogenicity data from the UNITI LTE through 5 years demonstrated that the use of concomitant immunomodulators (6-mercaptopurine [6-MP], azathioprine [AZA], methotrexate [MTX]) did not impact ustekinumab serum concentrations and did not reduce anti-drug antibody incidence.⁴

CLINICAL DATA

Phase 3 Randomized Clinical Trials

UNITI Trial Program

• STELARA was evaluated in 3 randomized, double-blind, placebo-controlled clinical trials in adult patients with moderately to severely active CD (Crohn’s Disease Activity Index [CDAI] score of 220 to 450). 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.^1,2
  • In UNITI-1, patients had failed or were intolerant to prior treatment with a tumor necrosis factor (TNF) blocker.
  • In UNITI-2, patients had failed or were intolerant to prior treatment with corticosteroids, at least 1 immunomodulator, or both. Patients in UNITI-2 never failed treatment with a TNF blocker (ie, never received a TNF blocker or previously received but had not 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 studies.
• During the induction studies (UNITI-1 and UNITI-2), patients were permitted to receive oral 5-aminosalicylates (5-ASAs), immunomodulators (AZA, 6-MP, and MTX), oral corticosteroids, and/or antibiotics for the treatment of CD, provided that the patient was on a stable dose for a specified period before baseline.⁵
  • Patients receiving such medications at baseline were to maintain a stable dose throughout these studies.
• Similarly, during the phase 3 maintenance study (IM-UNITI), patients were permitted to receive oral 5-ASAs, immunomodulators (AZA, 6-MP, and MTX), oral corticosteroids, and/or antibiotics for the treatment of CD, provided that the patient was on a stable dose for a specified period before baseline.⁵
  • Patients receiving such medications at baseline were to maintain a stable dose through week 44, except for oral corticosteroids. Patients receiving corticosteroids at week 0 who were in clinical response were to initiate corticosteroid tapering at week 0 (of the maintenance study). Patients not in clinical response at week 0 were allowed to undergo tapering at the discretion of the investigator.
• For concomitant medications taken at baseline for CD in UNITI-1, UNITI-2 and IM-UNITI, please see Table: Concomitant Medications for Crohn’s Disease at Baseline.

• Results from data through 3 years in CD indicate that the use of these concomitant therapies (immunomodulators [6-MP, AZA, MTX], corticosteroids) did not appear to influence the overall safety or efficacy of STELARA.⁶

UNITI Trial Program - Analyses Through 1 Year

Hanauer et al (2018)⁷ conducted a post hoc analysis to evaluate the safety and efficacy of STELARA with and without concomitant use of immunosuppressants in adult patients with moderately to severely active CD during induction and maintenance treatment in the UNITI trial program.

• Efficacy and safety were evaluated in the induction trials (UNITI-1 and UNITI-2) and the IM-UNITI maintenance trial comparing STELARA- and placebo-treated patients who received and did not receive concomitant AZA, 6-MP, or MTX.
• During the induction trials there was no association seen between concomitant immunosuppressant use and efficacy of the STELARA ~6 mg/kg IV induction dose at any endpoint, nor was there any consistent benefit for the combined therapy.
• During maintenance, there were no significant interactions seen between concomitant immunosuppressant use and efficacy in either the STELARA 90 mg SC every 8 weeks (q8w) group or the STELARA 90 mg SC every 12 weeks (q12w) group.
• Details regarding the efficacy results of this analysis are described in Table: Role of Concomitant Immunosuppression in the Efficacy of STELARA Treatment.

• Rates of total adverse events were not clearly different between groups; however, patients receiving concomitant immunosuppressants tended to have lower rates than those receiving monotherapy. Comparing the use of immunosuppressants vs monotherapy or dose groups, no trends with rates of infections were seen.

UNITI Trial Program - Analyses Through 2 Years - From the IM-UNITI LTE

Sands et al (2018)⁸ evaluated efficacy, drug concentrations, and immunogenicity of STELARA with and without concomitant immunomodulators in patients with moderately to severely active CD through 2 years of the continuing IM-UNITI LTE.

• A total of 1281 patients entered the IM-UNITI maintenance study, which included 397 patients who responded to induction treatment with STELARA (primary population). These 397 patients were randomized to either placebo SC (n=133), STELARA 90 mg SC q12w (n=132), or STELARA 90 mg SC q8w (n=132). Patients who met loss of response criteria between weeks 8 and 32 could have a 1-time dose adjustment to STELARA 90 mg SC q8w.
• Patients who completed week 44 were eligible to enter the LTE continuing the same treatment. This subanalysis includes 82 patients on STELARA 90 mg SC q8w from the primary population who did not meet the loss of response criteria for dose adjustment and entered the LTE.
• Patients with and without concomitant immunomodulator use were evaluated for clinical remission at each study visit, serum ustekinumab concentrations from weeks 44 to 92, and immunogenicity.
• A total of 35.4% (29/82) of patients in the randomized STELARA 90 mg SC q8w LTE population had baseline use of concomitant immunomodulators while 64.6% (53/82) of patients did not receive immunomodulators at baseline and remained off immunomodulators through week 92.
• Clinical remission observed was not higher in patients with baseline immunomodulator use compared to patients without baseline immunomodulator use and were similar between the 2 groups through week 92. Additionally, concomitant immunomodulator use did not appear to have any notable or consistent effect on serum ustekinumab concentrations or immunogenicity across all timepoints examined. Details regarding all the results of this analysis are described in Table: Clinical Remission and Serum Concentration Through Week 92 Based on Immunomodulator Use at Induction Baseline: Randomized Patients Who Entered LTE in IM-UNITI.

Pooled Phase 2 and 3 Randomized Clinical Trials

Sands et al (2017)⁹ evaluated the safety of STELARA with and without concomitant use of corticosteroids or immunomodulators in patients with moderately-to-severely active CD during induction and maintenance treatment in pooled phase 2 and 3 clinical trials.

• The proportion of patients experiencing safety events (adverse events [AEs], serious adverse events [SAEs], infections, and deaths) were assessed with and without concomitant use of immunomodulators or corticosteroids after:
  • Induction treatment with IV STELARA or placebo (8 weeks)
  • Maintenance treatment with SC STELARA or placebo (up to 44 weeks).
• During the placebo-controlled induction period (week 0-8), patients who received STELARA IV which included doses of 130 mg, 1 mg/kg, 3 mg/kg, 4.5 mg/kg, and
• 6 mg/kg were pooled from 2 phase 2 (C0379T07 and CERTIFI) and 2 phase 3 (UNITI-1 and UNITI-2) clinical trials (total n=1986).
• During the maintenance period, patients who received STELARA SC (combining
• 90 mg q8w and 90 mg q12w) and placebo were pooled from the randomized responder populations (ie, responders to IV STELARA induction) from the maintenance phase of the phase 2 CERTIFI trial (week 8 to week 22) and phase 3 IM-UNITI trial (week 0 to week 44) studies (total n=541).
• Through 8 weeks of induction, the proportions of patients with AEs, SAEs, and infections were similar between STELARA and placebo groups both with and without concomitant immunomodulators or corticosteroids. During maintenance, proportions of patients experiencing AEs, SAEs, and infections were also similar between STELARA and placebo groups regardless of concomitant medication. However, compared to patients not receiving corticosteroids, proportions of patients on corticosteroids in both the STELARA and placebo groups had slightly higher rates of AEs, and patients receiving placebo on corticosteroids had slightly higher rates of SAEs and infections than the other groups.
• There were no reports of death in any groups during any treatment phase. Details regarding all the results of this analysis are described in Table: Safety Events With and Without Concomitant Immunosuppressants Through up to 52 Weeks (8 Weeks Induction and 44 Weeks Maintenance) From the Crohn’s Clinical Trial Program.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 03 June 2024.

Summarized in this response are relevant references with a focus on concomitant immunomodulators or corticosteroids from phase 3/phase 2 pivotal trials in the treatment of CD.