Summary

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• Please refer to local labeling for relevant tuberculosis (TB) infection-related information.
• A pooled analysis of long-term safety data for the treatment of STELARA up to 5 years in adults across indications (CD, UC, plaque psoriasis (PsO), and psoriatic arthritis [PsA]) was performed. The incidence of TB in patients treated with STELARA vs placebo for pooled indications was 0.01 vs 0.16 per 100 PY, respectively.¹
• In 2 phase 3 randomized, double-blind, placebo-controlled studies (PHOENIX 1 [N=753] and PHOENIX 2 [N=1212]) evaluating the long-term safety and efficacy of STELARA in adult patients with moderate to severe PsO, no cases of active TB were reported through year 5 (week 264).^2,3
• In a phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of STELARA in 110 adolescent patients, age 12 to 17 years with moderate to severe plaque PsO, there were no reports of active TB through week 60.⁴
• In a phase 3, multicenter, single-arm, open-label, study evaluating the safety and efficacy of STELARA in 44 pediatric patients, age ≥6 to <12 years with moderate to severe plaque PsO, there were no reports of TB through week 56.⁵
• No cases of active TB were reported in a pooled safety analysis of 1 phase 2 study (duration of follow-up: 36 weeks) and 2 phase 3 studies (PSUMMIT I and PSUMMIT II; duration of follow-up: 108 weeks and 60 weeks, respectively) of STELARA in adult patients with active PsA (n=1073).⁶
• In the randomized, double-blind, placebo-controlled phase 3 induction and maintenance studies (UNITI-1 [N=741], UNITI-2 [N=628] and IM-UNITI [N=397]) of adult patients with moderately to severely active CD, one case of active pulmonary TB occurred approximately 10 months after a single STELARA 130 mg intravenous (IV) induction dose, in a patient randomized to placebo maintenance treatment. During the long-term extension portion of the maintenance study (weeks 44-96), one case of TB unrelated to study drug by the investigator was reported in a 45-year-old male receiving STELARA every 8 weeks (q8w). Through 5 years (week 272), there was no evidence of increased risk for TB during the IM-UNITI maintenance and long-term extension study.^7-9
• Through week 96 of the long-term extension of the phase 3 clinical trial program (UNIFI) evaluating the safety and efficacy of STELARA therapy for the treatment of adults with moderately to severely active UC (n=516), no cases of TB were reported.¹⁰
• A pooled safety analysis through 5 years of treatment in Crohn’s disease (CD) and 4 years in ulcerative colitis (UC) reported 1 case of active TB among patients treated with STELARA (event rate: 0.02 per 100 patient-years [PY]).¹¹

POOLED SAFETY ANALYSIS ACROSS ALL APPROVED INDICATIONS

Loftus et al (2022)¹ reported OI, including active TB, from pooled long-term safety data of 13 phase 2/3 studies through 5 years of CD and PsO, 2 years of UC, and 1 year of PsA.

• OI, including active TB, was identified through sponsor clinical review guided by consensus recommendations.
• Safety outcomes were presented as events per 100 PY of follow-up. For the rate of active TB in all approved indications pooled, psoriatic diseases, and inflammatory bowel disease (IBD) through up to 5 years, see Table: Active TB in Patients Treated with STELARA vs Placebo.

• 3 active TB cases were reported in patients with IBD (additional details are also available in the CLINICAL DATA IN CROHN’S DISEASE section):
  • 1 case in the STELARA group
    • Asymptomatic 45-year-old South African patient with CD treated with STELARA q8w during the long-term extension who was positive upon QuantiFERON^®-TB Gold Test on routine screening and bronchial brushings positive for M. tuberculosis.
  • 2 cases in the placebo group
    • 32-year-old Hungarian patient with CD, 10 months after receiving last STELARA dose
    • 52-year-old Korean patient with UC with pulmonary TB who received placebo only
  • Both patients with CD completed treatment for TB and achieved full disease resolution.

CLINICAL DATA IN PLAQUE PSORIASIS

Kimball et al (2012) and Langley et al (2014) - Clinical Data in Adults

Kimball et al (2012)² and Langley et al (2014)³ evaluated the long-term safety and efficacy of STELARA in adult patients with moderate to severe plaque PsO through 5 years of follow-up in the PHOENIX 1 and PHOENIX 2 studies.

• No cases of active TB were reported through year 5 (week 264).

Leonardi et al (2008) and Papp et al (2008) - Clinical Data in Adults

Leonardi et al (2008)¹² and Papp et al (2008)¹³ evaluated the safety and efficacy of STELARA in adult patients with moderate to severe plaque PsO in 2 phase 3 randomized, double-blind, placebo-controlled plaque PsO clinical studies.

In the PHOENIX 1 trial, the patients with latent TB were distributed as follows: 8 (3.1%), 7 (2.7%), and 10 (3.9%) were in the STELARA 45 mg (n=255), STELARA 90 mg (n=256), and placebo (n=255) groups, respectively. In the PHOENIX 2 trial, the patients with latent TB were distributed as follows: 16 (3.9%), 16 (3.9%), and 11 (2.7%) were in the STELARA 45 mg (n=409), STELARA 90 mg (n=411), and placebo (n=410) groups, respectively. Latent TB was identified by a positive purified protein derivative (PPD) test without evidence of active TB.

Tsai et al (2012) – Clinical Data in Adults

Tsai et al (2012)¹⁴ evaluated the safety of isoniazid (INH) prophylaxis for newly diagnosed latent tuberculosis infection (LTBI) in STELARA-treated adult patients with moderate to severe plaque PsO.

Methods

• Safety data from moderate to severe plaque PsO patients (N=3177; 2898 patients from non-Asian trials, and 279 from Asian trials) in 5 phase 3 trials of STELARA (45 mg or 90 mg) conducted in North America, Europe, and Asia were evaluated. In addition to the PHOENIX 1 and PHOENIX 2 trials previously mentioned, this evaluation included the ACCEPT trial, which compared the safety and efficacy of STELARA and etanercept, the PEARL trial, which evaluated the therapeutic responses and safety profile of short-term use of STELARA 45 mg in Taiwanese and Korean patients, and the Japanese trial, which assessed the efficacy and safety of STELARA in Japanese patients.
• All 5 studies had a controlled period from weeks 0-12. After week 12, all studies (except ACCEPT) had a similar design through week 28. In ACCEPT, treatment was interrupted at week 12 and restarted if plaque PsO recurred; patients randomized to STELARA 45 mg or 90 mg resumed STELARA treatment at their original dose, and patients randomized to etanercept 50 mg received STELARA 90 mg.
• LTBI was diagnosed based on a positive PPD test or QuantiFERON^®-TB test (QFT) without evidence of active TB based on symptoms or chest x-ray.

Results

• At baseline, 101/2898 (3.5%) non-Asian and 66/279 (23.7%) Asian patients were newly identified with LTBI and received treatment with INH; of these 167 patients across the 5 studies, 63 (37.7%) received concurrent treatment with pyridoxine (vitamin B6).
• The majority of patients were male and the mean age ranged from about 43-49 years across the trials; mean body weight of patients in the non-Asian trials was higher than that in the Asian trials.
• The rates of adverse events (AEs) consistent with INH toxicity (gastrointestinal, hepatobiliary or neurological disorders, or hepatic laboratory AEs [including alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin]) through week 12 in the non-Asian trials (PHOENIX 1, PHOENIX 2, and ACCEPT) among those treated with INH were generally comparable between control, STELARA 45 mg, and 90 mg groups (25.7%, 20.0%, and 22.2%, respectively). The rates of INH-related AEs in the Asian trials (PEARL and Japanese trial) were 17.6%, 14.8%, and 40.0% for the control, STELARA 45 mg, and 90 mg groups, respectively. Of note, there were only 5 patients in Asian trials who received STELARA 90 mg since this dose was not used in the PEARL trial.
• Compared with non-INH-treated patients, significantly higher proportions of patients with hepatic laboratory AEs, markedly abnormal ALT values, and various levels of ALT elevations >1x the upper limit of normal (ULN) were observed among INH-treated patients through week 12.
• The proportions of patients who experienced elevations in ALT >3x ULN were comparable at week 12 between control and STELARA-treated groups in the non-Asian trials (17.9% and 12.9%, respectively).
• There was no clear association between either the 45 or 90 mg dose of STELARA and the rates of overall AEs and serious AEs in INH-treated patients across trials.
• None of the 6 serious AEs reported among INH-treated patients were related to INH toxicity.
• The rates of study agent discontinuation due to INH toxicity through week 12 were low in both the non-Asian (4⁄101, 4.0%) and Asian (1⁄66, 1.5%) trials, for an overall rate of 3.0% (5/167), which was comparable between control and STELARA groups.
• Through week 12, rates of overall AEs and serious AEs were generally comparable between the STELARA and control groups among INH-treated patients in all studies and were comparable with those in non-INH-treated patients.
• With an additional 16 weeks of follow-up in INH-treated patients who were randomized to STELARA at baseline, the cumulative rate of INH-related AEs did not increase disproportionately through week 28.
• No cases of active TB were reported in patients who received concomitant INH starting at baseline.
• One patient from the PEARL study who did not receive INH prophylaxis and had an abnormal chest x-ray but normal PPD⁄QFT at baseline developed asymptomatic pulmonary TB. This patient was successfully treated with anti-TB medications; further details of this case are summarized below.¹⁵
• There were no disproportionate increases in rates of overall AEs or serious AEs in either the INH-treated or the non-INH-treated patients across all 5 trials through week 28.

Landells et al (2015) - Clinical Data in Adolescent Patients (≥12 to <18)

Landells et al (2015)⁴ evaluated the safety and efficacy of STELARA in 110 adolescent patients, aged 12 to 17 years with moderate to severe plaque PsO, in a multicenter, phase 3, randomized, double-blind, placebo-controlled study.

• Through week 60, there were no reported cases of active TB.

Philipp et al (2020) - Clinical Data in Pediatric Patients (≥6 to <12)

Philipp et al (2020)⁵ evaluated the safety and efficacy of STELARA were evaluated in 44 pediatric patients, age ≥6 to <12 with moderate to severe plaque PsO, in a multicenter, phase 3, single-arm, open-label study.

• Through week 56, there were no reported cases of TB.

CLINICAL DATA IN PSORIATIC ARTHRITIS

McInnes et al (2013) - Clinical Data in Adults

McInnes et al (2013)¹⁶ reported results from PSUMMIT I (n=615), a phase 3, multicenter, double-blind, placebo-controlled study to assess the efficacy and safety of STELARA in reducing signs and symptoms of active PsA in adults.

Results

• The average duration of follow-up through week 52 was 29.75, 50.41, and 50.21 weeks for the placebo-to-STELARA 45 mg, STELARA 45 mg, and STELARA 90 mg groups, respectively.
• Through week 52, no cases of TB were reported.

Ritchlin et al (2014) - Clinical Data in Adults

Ritchlin et al (2014)¹⁷ evaluated the efficacy and safety of STELARA in PSUMMIT II (n=312), a phase 3, multicenter, double-blind, placebo-controlled study in adult patients with active PsA with and without previous antitumor necrosis factor (TNF) agent experience.

Results

• Through week 60, no cases of TB were reported.

Kavanaugh et al (2014) – Clinical Data in Adults

Kavanaugh et al (2014)⁶ described results of a pooled safety analysis from 1 phase 2 (duration of follow-up: 36 weeks), and 2 phase 3 studies (PSUMMIT I and PSUMMIT II; duration of follow-up: 108 weeks and 60 weeks, respectively), including adult patients exposed to STELARA for up to 2 years. No cases of active TB were reported through 2 years of follow-up.

CLINICAL DATA IN CROHN'S DISEASE

Feagan et al (2016), Sandborn et al (2018), and Sandborn et al (2021) - Clinical Data in Adults

Feagan et al (2016)⁷ evaluated the safety of STELARA in adult patients with moderately to severely active CD in 3 randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 3 studies (two 8-week IV induction studies, UNITI-1 [N=741], UNITI-2 [N=628]; one 44-week subcutaneous (SC) maintenance study, IM-UNITI [N=397]).

Sandborn et al (2018 and 2021)^8,9evaluated the safety and efficacy of STELARA in adult patients with moderately to severely active CD from the long-term extension of the IM-UNITI [N=397] study through 2 and 5 years, respectively.

• Ten months after the administration of a single IV induction dose of 130 mg STELARA, an active case of pulmonary TB was reported in a patient assigned to receive placebo during maintenance therapy.⁷
• During the long-term extension (weeks 44-96), one case of TB unrelated to the study drug by investigator was reported in a 45-year-old male from South Africa receiving STELARA q8w. The patient was asymptomatic and had tested negative for TB at screening. Upon routine annual screening, the patient had a positive QuantiFERON^®-TB Gold test with bronchial brushings that were positive for mycobacterium TB. Six months of treatment for TB was provided with complete resolution.^8,9
• There was no evidence of increased risk for TB during the IM-UNITI maintenance and long-term extension study through 5 years (week 272).⁹

CLINICAL DATA IN ULCERATIVE COLITIS

Panaccione et al (2020) - Clinical Data in Adults

Panaccione et al (2020)¹⁰ evaluated the long-term safety and efficacy of STELARA therapy for the treatment of adults with moderately to severely active UC (n=516) in the phase 3 clinical trial program (UNIFI) through 2 years.

• No cases of TB were reported in STELARA-treated patients through week 96.

POOLED SAFETY ANALYSIS OF CD AND UC STUDIES

Ghosh et al (2024)¹¹ evaluated the cumulative safety of STELARA from 6 phase 2/3 studies in CD and UC (5 CD studies and 1 UC study) through 5 years of treatment in CD and 4 years of treatment in UC.

• All patients receiving ≥1 dose of STELARA were included.
• Concomitant immunomodulators and corticosteroids were permitted.
• A total of 2575 patients received STELARA and 1389 received placebo. The total follow-up was 4826 PY for STELARA and 943 PY for placebo.
• Overall, opportunistic infections (OI) including active TB were infrequently reported in patients treated with STELARA.
  • A total of 20 patients had OI, including 15 STELARA-treated patients and 5 placebo-treated patients.
  • Active TB cases were reported in 1 patient (event rate: 0.02 per 100 PY) in the STELARA group and 2 patients (event rate: 0.21 per 100 PY) in the placebo group.
  • Details regarding these 3 cases are reported above in Loftus et al (2022) pooled safety analysis.¹

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 26 April 2024.

Summarized in this response are relevant clinical data from phase 2 and phase 3 studies, and pooled analyses of data from phase 2/3 clinical trials.