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STELARA® (ustekinumab)

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Delayed Response in Adult Patients with Crohn’s Disease or Ulcerative Colitis Receiving STELARA

Last Updated: 01/29/2025

SUMMARY

Please refer to the local labeling for relevant information on STELARA.
In the pivotal clinical trials for STELARA in adult patients with Crohn’s disease (CD) or ulcerative colitis (UC), patients who did not respond to weight-based intravenous (IV) induction or 130 mg IV induction received STELARA 90 mg subcutaneous (SC) at week 8 and were re-evaluated at week 16. Results among these patients through 5 years in CD and 2 years in UC are summarized below.¹^-⁶
Additionally, post-hoc analyses were conducted to evaluate efficacy outcomes among early responders vs delayed responders using data from the STELARA pivotal clinical trial program in CD and UC.⁷^,⁸
Retrospective studies describing delayed response among adult patients with CD or UC treated with STELARA are summarized below.⁹^-¹¹

Crohn’s disease CLINICAL DATA

UNITI Clinical Trial Program

The efficacy and safety of STELARA was evaluated in 3 randomized, double-blind, placebo-controlled phase 3 studies in adult patients with moderately to severely active CD. There were two 8-week IV induction studies followed by a 44-week SC randomized withdrawal maintenance study.¹^,²

In both IV induction studies, patients were randomized in a 1:1:1 ratio to receive placebo IV, STELARA 130 mg IV, or weight-based STELARA ~6 mg/kg IV. Patients who respond to STELARA IV induction at week 8 were randomly assigned to receive STELARA 90 mg SC every 8 weeks (q8w), 90 mg every 12 weeks (q12w) or placebo through week 40.
Clinical response was defined as a decrease from baseline in the Crohn’s Disease Activity Index (CDAI) of ≥100 points or a CDAI score <150.
Patients who were not in clinical response after STELARA IV induction (either 130 mg IV or ~6 mg/kg IV) received a dose of STELARA 90 mg SC at week 8 (week 0 of the maintenance study) as part of the non-randomized population:
- At week 16 (week 8 of the maintenance study), 135/467 (28.9%) patients were in clinical remission and 236/467 (50.5%) patients were in clinical response. Patients who achieved clinical response at week 16 continued onto STELARA 90 mg q8w.
- At week 44, of the 251 patients continuing onto STELARA 90 mg SC, 126 (50.2%) were in clinical remission (CDAI<150) and 171 (68.1%) were in clinical response.

UNITI 5-Year Efficacy in Week 16 Induction Responders

Patients who were week 16 induction responders continued to receive treatment q8w throughout maintenance and the long-term extension (LTE) as part of the nonrandomized population. Remission rates in these patients at week 252 were 43.8% (88/201).⁵

UNITI Post-Hoc Analysis

Among 387 patients induced with STELARA ~6 mg/kg IV, 38.7% were week-8 responders (early responders), 23.8% were delayed responders, and 37.5% were nonresponders.
Predictors for delayed response to STELARA (patients who did not respond to STELARA after IV induction but were in response after a 90 mg SC injection at week 8) were analyzed using Pearson and Spearman correlations between drug exposure, changes in fecal calprotectin (FCP) and C-reactive protein (CRP) and the change from baseline in CDAI at weeks 6, 8, and 16.⁷
Among the delayed responders, drug levels did not correlate to CDAI changes from weeks 0-16.
A multivariate logistic regression model identified patients with younger age, non-corticosteroid use at baseline, history of extraintestinal manifestations, pure ileal disease and active fistula as more likely to have delayed response vs week 8 response.
For results on the correlations between drug exposure, changes in CRP/FCP and changes from baseline in CDAI, see Table: Serum UST, CRP and FCP Levels by Response Groups.

Serum UST, CRP and FCP Levels by Response Groups⁷

UST Levels, mcg/mL median (IQR)	Delayed Responders	Week 8 Responders
Week 8	6.83 (3.38-9.93)	6.44 (3.57-10.06)
Week 16	2.63 (1.17-4.32)	2.80 (1.19-4.43)
CRP, mean (SD)	Delayed Responders	Week 8 Responders
Week 8	10.19±13.73	8.86±10.35
Week 16	8.62±11.63	10.18±16.27
FCP, mean (SD)	Delayed Responders	Week 8 Responders
Week 6	441.11±738.63	562.25±717.87
Week 16	448.42±658.02	473.64±661.31
Pearson Correlation	Delayed Responders	Week 8 Responders
CRP vs CDAI change at week 8	0.15	0.17
CRP vs CDAI change at week 16	-0.04	0.15
Spearman Correlation	Delayed Responders	Week 8 Responders
Week 8 UST levels vs CDAI change at week 8	-0.05	-0.02
Week 16 UST levels vs CDAI change at week 16	-0.06	-0.19
FCP vs CDAI change at week 6	-0.12	0.003
FCP vs CDAI change at week 16	-0.20	0.003
Abbreviations: CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; FCP, fecal calprotectin; IQR, interquartile range; SD, standard deviation; UST, ustekinumab.

ULCERATIVE COLITIS CLINICAL DATA

UNIFI Clinical Trial Program

The efficacy and safety of STELARA was evaluated in 2 randomized, double-blind, placebo-controlled phase 3 studies in adult patients with moderately to severely active UC. There was an 8-week IV induction study followed by a 44-week SC randomized withdrawal maintenance study.³^,⁴

In the IV induction study, patients were randomized in a 1:1:1 ratio to receive placebo IV, STELARA 130 mg IV, or weight-based STELARA ~6 mg/kg IV. Patients who responded to STELARA IV induction at week 8 were assigned to receive STELARA 90 mg SC q8w, 90 mg q12w or placebo through week 40.
Clinical response was defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1.
Patients who were not in clinical response after STELARA IV induction at week 8 received a dose of STELARA 90 mg SC at week 8 (week 0 of the maintenance study) and were reevaluated at week 16. Those who achieved a clinical response entered the maintenance trial and received 90 mg SC q8w as part of the non-randomized population.
- Among patients who did not have clinical response to STELARA IV and who received STELARA 90 mg SC at week 8, 139/233 (59.7%) and 22/233 (9.4%) achieved clinical response and clinical remission, respectively, at week 16.
- At week 44, among the 157 patients continuing onto STELARA 90 mg SC, 98 (62.4%) patients maintained clinical response and 47 (29.9%) were in clinical remission.
- For additional outcomes at weeks 16 and 44 among delayed responders, see Table: Efficacy Outcomes Among Delayed Responders at Week 16 and Week 44.

Efficacy Outcomes Among Delayed Responders at Week 16 and Week 44⁴

STELARA, n (%)	Endoscopic Improvement^a,c	Histologic Improvement^a,d	HEMI^a,b,e	SFCR^a,f
Week 16 N=233	39 (16.7)	74/212 (34.9)	28 (12.1)	-
Week 44 N=157	56 (35.7)	-	50/154 (32.5)	43 (27.4)
Abbreviations: HEMI, histo-endoscopic mucosal improvement; SFCR, steroid-free clinical remission.^aPatients who had all 4 Mayo subscores missing at week 16 or week 44 were considered not to be in clinical remission or clinical response. Patients who had a missing endoscopy score at week 16 or week 44 were considered not to have endoscopic improvement. Patients who were missing any Geboes score component pertaining to histologic improvement endpoint (i.e., assessment of neutrophils in epithelium, crypt destruction, or erosions or ulcerations or granulations) at week 16 visit were considered not to have histologic improvement. Patients who had a missing endoscopy score or were missing any Geboes score component pertaining to histologic improvement endpoint were considered not to have HEMI at week 16 or week 44.^bExcludes patients whose endpoint (histologic improvement or HEMI) status cannot be determined at week 16 or week 44 due to an unevaluable biopsy (ie, a biopsy that was collected, but could not be assessed due to technical issues such as errors during sample collection and/or preparation). Note that patients who had an unevaluable biopsy at week 16 or week 44, but who did not achieve endoscopic improvement, were considered not to have HEMI.^cEndoscopic improvement was defined as an endoscopy subscore of 0 or 1.^dHistologic improvement was defined as neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue.^eHEMI is defined as having both endoscopic improvement and histologic improvement.^fPatients who had a missing value in corticosteroid use at week 44 had their last value carried forward.

UNIFI 2-Year Efficacy in Delayed Responders

There were 116 delayed responders treated in the LTE including 58 who previously failed biologics and 58 who did not fail biologic therapy (54 of which were biologic naïve). For symptomatic remission among these patients, see Table: Symptomatic Remission Among Delayed Responders through Week 92.⁶

Symptomatic Remission Among Delayed Responders through Week 92⁶^,a

	STELARA, n (%)
Symptomatic remission in delayed responders (N=116)
At maintenance baseline	74 (63.8)
Week 44	86 (74.1)
Week 92	92 (79.3)
At both week 44 and 92 among patients in symptomatic remission at maintenance baseline	61/74 (82.4)
Corticosteroid-free symptomatic remission at week 92	87 (75)
Symptomatic Remission among biologic failures (N=58)
At maintenance baseline	29 (50)
Week 44	40 (69)
Week 92	45 (77.6)
Symptomatic Remission among non-biologic failures (N=58)
At maintenance baseline	45 (77.6)
Week 44	46 (79.3)
Week 92	47 (81)
Symptomatic remission among biologic-naïve (N=54)
At maintenance baseline	42 (77.8)
Week 44	43 (79.6)
Week 92	45 (83.3)
Abbreviations: RB, rectal bleeding; SF, stool frequency; UC, ulcerative colitis.^aSymptomatic remission was defined as SF subscore of 0 or 1 and a RB subscore of 0. Patients who had both SF and RB subscores missing at a visit were considered not to be in symptomatic remission for that visit. Patients who had an ostomy or colectomy, or discontinued STELARA due to lack of therapeutic effect or due to an adverse event of worsening UC prior to the designated visit were considered not to be in symptomatic remission.

The safety profile for STELARA in the delayed responders was generally similar to that for patients randomized to STELARA. No new safety signals were observed up to week 96 of the LTE. For key safety findings, see Table: Safety through Week 96 in Randomized and Nonrandomized Patients (Delayed Responders).

Safety through Week 96 in Randomized Patients and Nonrandomized Patients (Delayed Responders)⁶

	Randomized Patients
	STELARA IV Induction Responders	Placebo SC^a	Delayed Responders
Patients treated in the LTE, N	STELARA combined^b; 284	115	STELARA 90 mg q8w; 116
Average duration of follow-up	44.3	32.4	51.7
Death	0	0	0
Patients with 1 or more, n (%)
AEs	192 (67.6)	76 (66.1)	83 (71.6)
Serious AEs	13 (4.6)	5 (4.3)	6 (5.2)
Infections^c	119 (41.9)	39 (33.9)	51 (44)
Serious infections^c	6 (2.1)	1 (0.9)	2 (1.7)
AEs leading to discontinuation from study agent	8 (2.8)	3 (2.6)	5 (4.3)
Malignancies	1 (0.4)	1 (0.9)	2 (1.7)
Excluding NMSC	0	0	0
NMSC	1 (0.4)	1 (0.9)	2 (1.7)
Abbreviations: AE, adverse event; IV, intravenous; LTE, long-term extension; NMSC, non-melanoma skin cancer; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous.^aPatients who were in clinical response to STELARA IV induction and were randomized to placebo SC on entry of the maintenance study; includes data from week 44 to week 96; or up to the time of dose adjustment to STELARA 90 mg q8w.^bSTELARA combined represents patients who received STELARA 90 mg q8w and STELARA 90 mg q12w.^cInfections as assessed by the investigator.

UNIFI Post-Hoc Analysis

A post-hoc analysis was conducted to determine differences in delayed responders (those who did not respond at week 8 but responded at week 16) vs early responders (those who responded at week 8) using data from the UNIFI program obtained through the Yale University Open Data Access (YODA) project.⁸
Sensitivity analyses were planned using an alternate definition of response, which was defined as a partial Mayo score (pMS) of ≤1.
Of the 642 STELARA-treated patients, 321 (50%) were early responders and 115 (17.9%) were delayed responders.
There were no differences between clinical outcomes among early and delayed responders. For outcomes at 1 year between these groups, see Table: Clinical Outcomes at 1 Year Among Early and Delayed Responders.

Clinical Outcomes at 1 Year Among Early and Delayed Responders⁸

	STELARA, n (%)
Outcome, n (%)	Early Responders n=321	Delayed Responders n=115	P-Value
Clinical remission^a	132 (41.1)	40 (34.8)	0.233
PRO-2 remission^b	121 (37.7)	37 (32.2)	0.291
Endoscopic improvement^c	152 (47.4)	46 (40.0)	0.174
Endoscopic remission^d	84 (26.2)	27 (23.5)	0.570
HEMI^e	142 (44.2)	43 (37.4)	0.203
Abbreviations: HEMI, histo-endoscopic mucosal improvement; MES, modified endoscopic subscore; PRO, patient-reported outcome; RB, rectal bleeding; SF, stool frequency.^aClinical remission was defined as total Mayo score ≤2 and no subscore >1.^bPRO-2 remission was defined as SF and RB subscore of 0.^cEndoscopic improvement was defined as MES ≤1.^dEndoscopic remission was defined as MES =0.^eHEMI was defined as Geboes highest grade <3.2 and MES ≤1.

When using the pMS for clinical response, there were 178 early responders and 94 delayed responders. No significant differences in clinical outcomes were observed between early and delayed responders. See Table: Clinical Outcomes in Early vs Delayed Responders (per the pMS).

Clinical Outcomes in Early vs Delayed Responders (per the pMS)¹²

	STELARA, n (%)
	Early Responders n=178	Delayed Responders n=94	P-Value
Clinical remission^a	89 (50.0)	50 (53.2)	0.617
PRO-2 remission^b	101 (56.7)	51 (54.3)	0.695
Endoscopic improvement^c	95 (53.4)	50 (53.2)	0.978
Endoscopic remission^d	59 (33.2)	34 (36.2)	0.617
HEMI^e	90 (50.6)	48 (51.1)	0.937
Abbreviations: HEMI, histo-endoscopic mucosal improvement; MES, modified endoscopic subscore; pMS, partial Mayo score; PRO, patient-reported outcome; RB, rectal bleeding; SF, stool frequency.^aClinical remission was defined as total Mayo score ≤2 and no subscore >1.^bPRO-2 remission was defined as SF and RB subscore of 0.^cEndoscopic improvement was defined as MES ≤1.^dEndoscopic remission was defined as MES =0.^eHEMI was defined as Geboes highest grade <3.2 and MES ≤1.

Retrospective studies

For additional data regarding efficacy among delayed responders to STELARA, see: Table: Summary of Retrospective Studies Evaluating Delayed Response Among Patients Treated with STELARA.

Summary of Retrospective Studies Evaluating Delayed Response Among Patients Treated with STELARA⁹^,¹⁰

Primary Author and Year	Study Design	Patient Population	Dosing Regimen	Outcomes
Crohn’s Disease
Esaki et al (2023)⁹	Retrospective study	72 adult patients	Induction: STELARA weight-based IV induction (~6 mg/kg) Maintenance: STELARA 90 mg at week 8 then q8w or q12w per physician judgement	Among 49 patients who did not achieve the primary outcome (dual remission^a) at week 8, dual remission was later achieved in 10 and 13 patients at week 26 and 52, respectively
Miyazaki et al (2020)¹⁰	Retrospective study	18 adult patients with active disease were analyzed	Induction: STELARA weight-based IV induction (~6 mg/kg) Maintenance: STELARA 90 mg SC q8w or q12w per physician judgement	Clinical remission rates at week 8 and 24 were 44.4% (8/18) and 66.7% (12/18). This indicated that there were 4 delayed responders who did not achieve clinical remission at week 8 but were later observed to be in remission at week 24.^b
Ulcerative Colitis
Tursi et al (2024)¹¹	Retrospective study	256 adult patients	Induction: STELARA weight-based IV induction (~6 mg/kg) Maintenance: STELARA 90 mg SC q8w per investigators	There were 5 patients (2%) who did not achieve clinical response at 48 weeks of follow-up. Of these patients, one was biologic-naive, two used STELARA as second line, and others were in further lines of treatment. The starting Mayo endoscopic subscore for 2 patients was 2 and for the other 3 patients, it was 3.
Abbreviations: CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; IV, intravenous; pMS, partial Mayo score; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous.^aDual remission was defined as the combination of clinical (CDAI <150) and biological (serum CRP <0.3 mg/dL) remission. ^bClinical remission was defined as CDAI <150 points.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 21 November 2024.

References

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1	Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946-1960.
2	Feagan BG, Sandborn WJ, Gasink C, et al. Supplement to: Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946-1960.
3	Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381(13):1201-1214.
4	Sands BE, Sandborn WJ, Panaccione R, et al. Supplement to: Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381(13):1201-1214.
5	Sandborn WJ, Rebuck R, Wang Y, et al. Five-year efficacy and safety of ustekinumab treatment in Crohn’s disease: the IM-UNITI trial. Clin Gastroenterol Hepatol. 2022;20(3):578-590.e4.
6	Abreu M, Sands B, Leong R, et al. Efficacy and safety of long-term treatment with ustekinumab in moderate-severe ulcerative colitis patients with delayed response to ustekinumab induction: Results from the UNIFI 2-year long-term extension [abstract]. Gastroenterology. 2020;158(6, Suppl. 1):S1201. Abstract Tu1879.
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8	Wong ECL, Dulai PS, Marshall JK, et al. Delayed ustekinumab responders in ulcerative colitis have greater inflammatory burden but similar outcomes as early responders. [Published online ahead of print June 29, 2023]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2023.06.011.
9	Esaki M, Ihara Y, Tominaga N, et al. Predictive factors of the clinical efficacy of ustekinumab in patients with refractory Crohn’s disease: tertiary centers experience in Japan. Int J Color Dis. 2023;38(1):57.
10	Miyazaki T, Watanabe K, Kojima K, et al. Efficacies and related issues of ustekinumab in Japanese patients with Crohn’s disease: a preliminary study. Digestion. 2020;101(1):53-59.
11	Tursi A, Mocci G, Scaldaferri F, et al. Ustekinumab safety and effectiveness in patients with ulcerative colitis: results from a large real-life study. Expert Opin Biol Ther. 2024;24(1-2):101-109.
12	Wong E, Duali P, Marshall J, et al. Supplement to: Delayed ustekinumab responders in ulcerative colitis have greater inflammatory burden but similar outcomes as early responders. [published online ahead of print June 29, 2023]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2023.06.011.