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(ustekinumab)

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STELARA® (ustekinumab)

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STELARA – Immunogenicity in Adult Patients with Crohn’s Disease or Ulcerative Colitis

Last Updated: 01/02/2025

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 regarding immunogenicity with STELARA. Summarized in this response are relevant data from pivotal clinical trial programs in adults with Crohn's disease (CD) through 5 years (UNITI/IM-UNITI Program) and ulcerative colitis (UC) through 4 years (UNIFI Program).¹^-¹²
Also summarized in this response are relevant data from 3 phase 3b studies: the SEAVUE study, which evaluated treatment with STELARA vs adalimumab; the STARDUST study, which compared a treat-to-target (T2T) maintenance strategy to a standard-of-care (SoC) approach; and the POWER study, which compared STELARA intravenous (IV) re-induction (single dose) with continued subcutaneous (SC) STELARA therapy, in adults with moderate to severe CD.¹³^-¹⁶
Additional data are available through several prospective and retrospective studies.¹⁷^-²⁵

CLINICAL DATA in CD

Phase 2b Clinical Trial

Sandborn et al (2012)¹ evaluated the serum samples of ustekinumab for antidrug antibodies (ADAs) at weeks 0, 22, and 36 among adult patients with moderate to severe CD who participated in the 36-week, randomized, double-blind, placebo-controlled phase 2b trial (CERTIFI).

Through week 36, antibodies to ustekinumab occurred in 3/427 (0.7%) patients treated with STELARA.
Circulating levels of ustekinumab did not have a marked effect on the incidence of antibodies since 81% of patients had undetectable serum ustekinumab levels at week 36.

Phase 3 Clinical Trials – UNITI and UNIFI Trial Program

UNITI-1, UNITI-2, and IM-UNITI

Feagan et al (2016)² assessed for ADAs to ustekinumab at weeks 0 and 6 during induction and at weeks 12, 24, 36, and 44 during maintenance therapy through a phase 3 development program consisting of 2 (UNITI-1 and UNITI-2) 8-week induction trials and 1 (IM-UNITI) 44-week maintenance trial in patients with CD.

Of 246 patients from UNITI-1 and 212 patients from UNITI-2, there were 2 patients who tested positive for ADAs to ustekinumab and neutralizing antibodies who received STELARA 130 mg IV.
At week 44, ADAs to ustekinumab occurred in 27/1154 (2.3%) patients who received at least 1 dose of STELARA; of these patients, 20/27 (74%) patients had titers at or below 1:800 and 17/27 (63%) patients were positive for neutralizing antibodies.³
- Many of these 27 patients were positive at 1 timepoint only, with subsequent negative antibody results.
- Induction responders who were randomized to continue receiving STELARA during maintenance had a lower incidence of ADAs (7/263 [2.7%]) compared with those who did not receive continuous STELARA maintenance therapy (7/133 [5.3%]).
- The proportion positive for ADAs was 7/375 (1.9%) for patients receiving concomitant immunomodulators vs 20/779 (2.6%) for patients who did not.

IM-UNITI Long-Term Extension (LTE) Through 2 Years

Sandborn et al (2018)⁴ evaluated patients for ADAs to ustekinumab every 6 months through 96 weeks of the IM-UNITI LTE.

There were 237 patients randomized to STELARA during the LTE with samples for ADAs to ustekinumab. Of these patients, 10/237 (4.2%) were positive for ADAs to ustekinumab.
The rate of ADAs for patients receiving STELARA 90 mg SC every 8 weeks was 2.4%, which was similar to the rate at week 44.
Rates of ADAs to ustekinumab were higher among patients randomized to placebo (5/61 [8.2%]).
The incidence of ADAs to ustekinumab in patients receiving concomitant immunomodulators was similar to those who were not (1/29 [3.4%] vs 2/53 [3.8%], respectively).⁵

IM-UNITI LTE Through 3 Years

Hanauer et al (2020)⁶ measured serum ustekinumab levels through week 156 to determine the incidence of ADAs to ustekinumab for all treated patients who received at least 1 dose of STELARA and had samples for detection.

Through week 156 of all 237 patients treated with STELARA, there were 11 (4.6%) patients positive for ADAs to ustekinumab.
In patients initially assigned to placebo, 5/61 (8.2%) patients tested positive for ADAs to ustekinumab.
Rates of ADAs to ustekinumab were lowest among patients who remained on continuous STELARA every 8 weeks without dose adjustments (2/82 [2.4%]).
ADAs were similar between patients receiving concomitant immunomodulators (4/80 [5%]) compared to those who were not (7/157 [4.5%]) at week 44.
There was no apparent relationship across the various randomized groups between ADAs and efficacy.

IM-UNITI LTE Through 5 Years

Sandborn et al (2021)⁷ assessed ADAs to ustekinumab through week 272.

Among 532 patients who received STELARA during induction and maintenance and continued into the LTE, ADAs occurred in 31/532 (5.8%) patients, testing positive at 1 or more visits through 5 years. Of these patients, 14/31 (45%) were positive at only 1 visit.
Antibodies at 1 or more visits occurred in 5% of patients who received STELARA every 8 weeks and 7% of patients who received STELARA every 12 weeks.
The occurrence of ADAs to ustekinumab at any time during the study was low regardless of concomitant immunosuppressant use at week 44:
- Patients receiving immunosuppressants: 14/181 (7.7%) developed ADAs.
- Patients not receiving immunosuppressants: 17/351 (4.8%) developed ADAs.
For patients randomized to STELARA, clinical remission at week 252 was achieved in 7/15 (46.7%) patients who had ADAs at any time during the study vs 107/222 (48.2%) patients who did not.

Phase 3b Clinical Trials – STARDUST, SEAVUE, and POWER

The STARDUST Study

Danese et al (2022)¹³ conducted a phase 3b, open-label, randomized study in adults with moderately to severely active CD to assess whether a T2T strategy was more successful than an SoC maintenance strategy. One of the assessments included in this study was immunogenicity; ADAs were measured at weeks 0, 8, and 16; at all assessment visits; and at week 48.

Antibodies to ustekinumab through week 48 were detected in 9/216 (4%) patients in the T2T group (6 patients had neutralizing antibodies) and in 17/221 (8%) patients in the SoC group (12 patients had neutralizing antibodies).

Peyrin-Biroulet et al (2024)¹⁴ conducted a phase 3b, open-label, randomized study of STELARA in patients with moderately to severely active CD to assess the efficacy in the T2T group vs SoC group. One of the assessments included in this study was immunogenicity; ADAs were assessed through week 104 of the LTE.

Antibodies to ustekinumab through week 104 in patients who entered the LTE were detected in 5/145 (3.4%) patients in the T2T group and 13/176 (7.4%) patients in the SoC group.
- Among the ADA-positive patients through week 104, 3/5 (60%) patients in the T2T group and 10/13 (76.9%) patients in the SoC group had neutralizing antibodies.
Of the patients who entered the LTE, 3/323 (0.9%) patients reported injection-site reaction as a treatment-emergent adverse event from weeks 48 to 104.
- Injection-site reactions were reported in 1/147 (0.7%) patient in the T2T group and 2/176 (1.1%) patients in the SoC group.

The SEAVUE Study

Sands et al (2022)¹⁵ conducted a phase 3b, randomized, double-blind, parallel, active-comparator study to evaluate the efficacy and safety of monotherapy with STELARA vs adalimumab in biologic-naïve adults with moderately to severely active CD. One of the outcomes evaluated in this study was ADAs, which were assessed at weeks 0, 8, 16, and 52 for both STELARA and adalimumab.

Through week 52, 4/190 (2%) of patients treated with STELARA and 145/195 (74%) of patients treated with adalimumab had ADAs at ≥1 timepoint.
The proportion of patients with anti-ustekinumab antibodies was too low to evaluate the effect of these antibodies on pharmacokinetics and efficacy.

The POWER Study

Schreiber et al (2023)¹⁶ conducted a phase 3b randomized, double-blind, multicenter study to compare the efficacy and safety of STELARA IV re-induction (single dose) with continued SC STELARA therapy in patients with CD who had a loss of response to the standard STELARA 90 mg SC every 8 weeks maintenance therapy.²⁶ One of the assessments included in this study was ADAs, which were assessed at weeks 0, 8, and 16.

Serum ustekinumab concentration data was available from 215 patients (SC group, n=107; IV group, n=108) who had ≥1 blood samples collected.
Overall, antibodies to ustekinumab through week 16 were detected in 2/215 (0.93%) patients.
- ADAs were detected in 2/107 (1.87%) patients in the SC group and none in the IV-re-induction group.

Clinical Data in UC

Phase 3 Clinical Trials – UNIFI Trial Program

UNIFI Induction and Maintenance

Sands et al (2019)⁸ reported ADAs to ustekinumab during the induction (8 weeks) and maintenance (44 weeks) phases of the UNIFI clinical trial program. Among 505 patients who received STELARA during induction and maintenance (1 year post induction), ADAs to ustekinumab developed in 23/505 (4.6%) patients.

Among these 23 patients, 5 had neutralizing antibodies and 9 had transient antibodies to ustekinumab.

Adedokun et al (2020)⁹ conducted an analysis to characterize pharmacokinetics and exposure response using data from the pivotal phase 3 induction and maintenance studies (UNIFI). Of the 680 STELARA-treated patients with appropriate testing samples, 39 (5.7%) were positive for ADA at 1 or more timepoints through 1 year.

ADA were transient (positive at a single timepoint with subsequent negative results) in 43.6% and antibodies were neutralizing in 28.2% of 39 patients with ADA.
Among IV induction responders randomized to maintenance treatment, 12/348 (3.4%) patients continuing STELARA vs 16/175 (9.1%) patients receiving placebo were positive for ADA.
When comparing those who received concomitant immunomodulators vs those who did not, ADAs occurred in 6/193 (3.1%) patients vs 33/487 (6.8%) patients.
Across multiple efficacy outcomes, ADAs did not appear to impact the response to STELARA to a notable extent. For clinical efficacy outcomes at week 44 of the UNIFI maintenance study by ADA to ustekinumab status, see Table: Clinical Efficacy at Week 44 by ADA to Ustekinumab Status.

Clinical Efficacy at Week 44 by ADA to Ustekinumab Status⁹^,²⁷

Efficacy Outcome	Achieved Efficacy Outcome, %		P-Value^a
Efficacy Outcome	ADA Positive (n=12)	ADA Negative (n=336)	P-Value^a
Clinical response^b	74.1	75.0	1.0
Clinical remission (global definition)^c	41.7	25.0	0.37
Clinical remission (US definition)^d	41.1	41.7	1.0
Endoscopic improvement^e	47.3	50.0	1.0
Histologic improvement^f	56.6	58.3	1.0
Abbreviations: ADA, antidrug antibody; US, United States. ^aDerived from Fisher’s exact test. ^bClinical response was defined as ≥30% and a >3-point decrease from induction baseline in the total Mayo score, with either a ≥1-point decrease in the rectal bleeding subscore or a score of 0 or 1. ^cClinical remission was defined as a Mayo score of ≤2 and no individual subscore of >1. ^dClinical remission was defined as an absolute stool number of ≤3, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1. ^eEndoscopic improvement was defined as a Mayo endoscopy subscore of 0 or 1. ^fHistologic improvement was defined by Geboes score (neutrophil infiltration in <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue).

No patient positive for ADAs to ustekinumab had an injection-site reaction or adverse event within 1 hour after infusion, including serum sickness-like/anaphylaxis reactions.

UNIFI LTE Through 2 Years

Panaccione et al (2020)¹⁰ reported ADAs to ustekinumab through 96 weeks of therapy.

ADAs to ustekinumab were reported in 22/400 (5.5%) patients who received STELARA in maintenance and continued to the LTE. This includes patients who were responders at week 8 to STELARA IV induction and randomized to STELARA SC maintenance and patients who were week 16 responders receiving SC treatment thereafter.
- Of these 22 patients, 4 were positive for neutralizing antibodies to ustekinumab. The proportion of randomized patients in symptomatic remission at week 92 was comparable between those who were positive and those who were negative for antibodies to ustekinumab.

UNIFI LTE Through 3 Years

Abreu et al (2022)¹¹ reported ADAs to ustekinumab through 156 weeks of therapy.

ADAs to ustekinumab were reported in 22/400 (5.5%) patients who received STELARA during the maintenance study and continued to the LTE. This includes patients who were responders at week 8 to STELARA IV induction and randomized to STELARA SC maintenance and patients who were week 16 responders receiving SC treatment thereafter.
- Of these 22 patients, 5 (22.7%) were positive for neutralizing antibodies to ustekinumab.

UNIFI LTE Through 4 Years

Afif et al (2024)¹² reported ADAs to ustekinumab through 220 weeks of therapy.

ADAs to ustekinumab were reported in 22/400 (5.5%) patients who received STELARA during the maintenance study and continued to the LTE. This includes patients who were responders at week 8 to STELARA IV induction and randomized to STELARA SC maintenance and patients who were week 16 responders receiving SC treatment thereafter.
- Of these 22 patients, 5 (22.7%) patients were positive for neutralizing antibodies to ustekinumab.

Prospective and Retrospective Studies

Additional data are available through several prospective studies and a retrospective study. Please see Table: Summary of Prospective and Retrospective Studies Evaluating Antibodies to UST in Adult Patients with CD.

Summary of Prospective and Retrospective Studies Evaluating Antibodies to UST in Adult Patients with CD¹⁷^-²⁵

Primary Author and Year	Study Design	Patient Population	Dosing Regimen	Outcomes
CD prospective studies
Afif et al (2022)¹⁷	Cross-sectional, multicenter, observational^a	110 adults	Patients had been initiated on UST either IV or SC for ≥4 weeks; the most recent dose had to be within the previous 12 weeks	No patient was positive for serum ADAs to UST
Gonczi et al (2022)¹⁸	Prospective, multicenter, observational^b	142 adults	Induction: UST weight-based IV induction (~6 mg/kg); Maintenance: 90 mg SC at week 8, then Q12W	Of 58 serum ADA measurements, 2 patients exceeded 1 AU/mL
Kwon et al (2022)¹⁹	Prospective, single center^b	10 adults with a history of LoR to IFX, adalimumab, or both	Induction: UST weight-based IV induction (~6 mg/kg); Maintenance: 90 mg SC at week 8, then Q12W^c	No patients developed ADAs to UST
Painchart et al (2020)²⁰	Prospective, single center, cohort	72 adults with refractory CD	UST 90 mg SC at weeks 0, 4, 12, then Q8W	No patients developed ADAs to UST
Verstockt et al (2019)²¹	Prospective, open-label cohort^d	86 adults refractory or intolerant to anti-TNF and/or VDZ	UST weight-based IV induction (~6 mg/kg) UST 90 mg SC Q8W	Of 57 samples available, 1 patient had detectable ADAs to UST
Biemans et al (2018)²²	Nationwide, prospective, observational, multicenter cohort (ICC registry)	125 adults (99.2% having failed ≥1 biologic)	Treated with UST for CD; dosing information not described	No ADAs were detected in the 29 (23.2%) patients in which PK was assessed
Battat et al (2017)²³	Prospective, multicenter, cohort	62 adults refractory or intolerant to anti-TNF therapy	Longitudinal cohort: UST 90 mg SC induction at weeks 0, 1, and 2 UST 90 mg SC Q8W Cross-sectional cohort: Patients who received UST for ≥26 weeks	No patients had detectable ADAs to UST
CD retrospective studies
McDonald et al (2023)²⁴	Dual-center, retrospective, observational	47 adults	Dosing not specified; UST induction (SC or IV) UST SC	No ADAs to UST were detected in patient samples
Sipponen et al (2021)²⁵	Nationwide, retrospective, multicenter, chart review (FINUSTE2)	155 adults	UST 90 mg SC Q8W or Q12W	Of 25 patients with samples, no ADAs to UST were developed
Abbreviations: ADA, antidrug antibody; CD, Crohn’s disease; ELISA, enzyme-linked immunosorbent assay; ICC, Initiative on Crohn and Colitis; IFX, infliximab; IV, intravenous; LoR, loss of response; PK, pharmacokinetics; Q8W, every 8 weeks; Q12W, every 12 weeks; SC, subcutaneous; anti-TNF, anti-tumor necrosis factor; UST, ustekinumab; VDZ, vedolizumab. ^aAntibodies to UST measured by ELISA and drug-tolerant radioimmunoassay. ^bAntibodies to UST measured by ELISA. ^cFor patients whose symptoms did not improve while receiving STELARA 90 mg Q12W, the dose could be escalated to STELARA 90 mg Q8W. ^dAntibodies to UST measured by drug-sensitive bridging assay and drug-tolerant affinity capture elution assay.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 June 2024.

References

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