CLINICAL DATA

Phase 3b Study: POWER

Schreiber et al (2023)¹ conducted a phase 3b randomized, double-blind, multicenter study to compare the efficacy and safety of STELARA intravenous (IV) re-induction (single dose) with continued subcutaneous (SC) STELARA therapy in patients with Crohn’s disease (CD) who had a loss of response to the standard STELARA 90 mg SC every 8 weeks (q8w) maintenance therapy.¹⁴

Study Design/Methods

• Adult patients with moderately to severely active CD who had an initial response to STELARA IV induction therapy and later experienced a loss of response to STELARA SC maintenance therapy were included.¹⁴
  • Secondary loss of response was defined as a Crohn’s Disease Activity Index (CDAI) score of ≥220 and ≤450 with at least 1 objective sign of inflammation: elevated
    C-reactive protein (CRP; >3 mg/L) or fecal calprotectin (FCP) levels (>250 mg/kg) or evidence of active CD (≥1 ulceration site in the ileum and/or colon) on endoscopy performed ≤3 months before week 0.
• At baseline (week 0), patients were randomized to receive the following:
  • STELARA ∼6 mg/kg IV→STELARA 90 mg SC at weeks 8 and 16.
  • STELARA 90 mg SC→STELARA 90 mg SC at weeks 8 and 16.
• The primary endpoint was clinical response (defined as a reduction in the CDAI score of ≥100 points from week 0 or a CDAI score of <150) at week 16.
• Major secondary endpoints included the proportion of patients who achieved:
  • Clinical remission at weeks 8 and 16 (defined as a CDAI score of <150).
  • Clinical response at week 8.
  • Normalization of CRP levels (≤3 mg/L) and/or FCP levels (≤250 µg/g) at week 16 among patients with elevated CRP/FCP levels at baseline.
• Additional endpoints assessed at week 8 and/or week 16 included the following:
  • Patient-reported outcomes (PROs; proportion of patients with Inflammatory Bowel Disease Questionnaire response at week 16 and mean change in unweighted PRO-2 from baseline).
  • Endoscopic endpoints (proportion of patients with ≥25% improvement in simple endoscopic score for Crohn’s disease [SES-CD] from baseline, endoscopic response [defined as a reduction in SES-CD by 50% from baseline or an SES-CD of ≤3 or 0], endoscopic remission [defined as an SES-CD of ≤3 or 0], mean change from baseline in SES-CD, and endoscopic improvement [defined as a reduction in SES-CD of ≥3 points]).

Results

Patient Characteristics

• Among the 215 patients (STELARA IV, n=108; STELARA SC, n=107) included in the full analysis set at week 0, 96 (88.9%) and 99 (92.5%) patients in the STELARA IV and STELARA SC arms had a history of biologic treatment failure (characterized by primary nonresponse, secondary nonresponse, or intolerance), respectively.
• At week 16, 92.6% and 86.0% of patients in the STELARA IV and STELARA SC arms completed treatment, respectively.

Efficacy

• At week 16, a numerically greater proportion of patients in the STELARA IV arm had a clinical response (primary endpoint) compared with patients in the SC arm (49.1% vs 37.4%; P=0.089).
  • Since the primary endpoint was not met, all the P-values for other endpoints are considered nominal, and statistical significance has not been established.
• For efficacy results, see Table: Primary, Major Secondary, and Patient-Reported Outcomes at Weeks 8 and 16 and Table: Endoscopic Outcomes at Week 16.

• For efficacy outcomes in patients with or without a history of inadequate response or intolerance to a prior biologic, see Table: Primary and Major Secondary Endpoints in Patients with or Without a History of Inadequate Response or Intolerance to Prior Biologics.
• For the association of clinical response to baseline demographics and disease characteristics, see Table: Proportion of Patients Who Achieved Clinical Response at Week 16 According to Baseline Characteristics.

Safety

• At week 16, the proportion of patients who had ≥1 adverse event (AE; STELARA IV arm, 60.2%; STELARA SC arm, 61.7%) or serious adverse events (SAEs; STELARA IV, 5.6%; STELARA SC, 5.6%) was similar in the 2 treatment arms.
  • The proportion of patients with infection was similar in the 2 treatment arms (STELARA IV, 23.1%; STELARA SC, 21.5%), and 1 serious infection was reported in each treatment arm.

Pharmacokinetic Analysis of the POWER Study

Schreiber et al (2023)⁴ presented the pharmacokinetics, exposure-response relationship, and immunogenicity analysis of the POWER study at week 16.

Study Design/Methods

• Serum samples were collected at weeks 0, 8, and 16 for evaluation. Serum concentrations were evaluated using a proprietary immunoassay.
• Efficacy outcomes were analyzed according to trough concentration groups at week 0 (undetectable, 0.17 to <0.8, 0.8 to <1.3, and ≥1.3 μg/mL) and concentration quartile groups at week 16.

Results

• Serum ustekinumab concentration data was available from 215 patients (SC arm, n=107; IV arm, n=108) who had ≥1 blood samples collected.
• At week 16, 63.9% (n=69) of patients in the IV arm and 41.1% (n=44) of patients in the SC arm had trough ustekinumab concentrations of ≥1.3 μg/mL. For details on ustekinumab serum levels, see Table: Summary of Ustekinumab Serum Concentrations.
• Among patients with trough concentrations of ≥1.3 µg/mL, the proportion of patients with clinical response at week 16 was similar between treatment arms. However, there were more patients in the IV arm who achieved endoscopic remission at week 16 compared to those in the SC arm.
• For details on ustekinumab exposure-response relationships, see Table: Exposure-Response Relationships at Week 16 by Trough Serum Concentrations and QG.

• Through week 16, the incidence of antibodies to ustekinumab was low (SC, n=2; IV, n=0; 0.93% overall).

Retrospective and Prospective Cohort Study

Sedano et al (2021)⁵ assessed the efficacy of STELARA IV re-induction in patients with moderate to severe CD with partial response or secondary loss of response to STELARA every 4 weeks (q4w) SC maintenance dosing and failed prior biological therapies.

Study Design/Methods

• Response and remission after STELARA IV re-induction were assessed using the following definitions:
  • Physician Global Assessment (PGA):
    • Before re-induction:
      • Remission: no abdominal pain, ≤2 bowel movements/day, absence of blood with defecation, and stable or no weight loss; mild activity: mild to moderate abdominal pain, ≤4 bowel movements/day, occasional blood with defecation, and objective weight loss; moderate to severe activity: moderate to severe abdominal pain, >4 bowel movements/day, bloody defecation with most bowel movements, and objective weight loss.
    • After re-induction:
      • Clinical response: ≥50% reduction in CD symptoms or severity; clinical remission: complete resolution in CD symptoms or severity.
  • Harvey-Bradshaw Index (HBI):
    • Before re-induction:
      • Remission: ≤4 points; mild activity: 5-7 points; moderate to severe activity: >7 points.
    • After re-induction:
      • Response: reduction in HBI by >3 points; remission: ≤4 points.
  • Mucosal healing:
    • Endoscopic:
      • Active disease: presence of ulcers; response: improvement from previous study; remission: absence of ulcers.
    • Imaging:
      • Active disease: mucosal inflammation; response: improvement from previous study; remission: absence of mucosal inflammation.
  • CRP:
    • Active disease: >5 mg/dL; inactive disease: <5 mg/dL.

Results

Patient Characteristics

• Overall, 15 patients (12/15 have been biologic-exposed) underwent STELARA weightbased dosing IV re-induction (260 mg [weight ≤55 kg], 390 mg [>55 kg to 85 kg], and 520 mg [>85 kg]).
• Reasons for re-induction were active disease according to PGA (n=15, 100%), HBI (n=9, 60%), endoscopy and imaging (n=15, 100%), and elevated CRP levels (n=5, 33.3%).
• Mean time to IV re-induction since STELARA treatment initiation was 60.1 weeks (range, 19-138 weeks).
• Mean time to assessment after re-induction was 14.9 weeks (range, 4-29 weeks) for PGA and HBI, 30.9 weeks (range, 4-58 weeks) for endoscopy and imaging, and 28.4 weeks (range, 5-50) weeks for CRP.

Efficacy

• After re-induction, based on PGA, 10 of 15 patients (66.7%) achieved response and 8 of 15 patients (53.3%) achieved remission.
• According to HBI, 11 of 14 patients (78.6%) achieved response and 8 of 14 patients (57.1%) achieved remission.
• Two patients did not respond to re-induction, and 1 patient experienced loss of response at month 14 after initially achieving remission after re-induction.
• Eleven patients had paired CRP values before and after re-induction, with mean values of 10.1 mg/dL (range, 0.6-43.1 mg/dL) and 8.1 mg/dL (range, 0.6-31.1 mg/dL), respectively.
• Eight patients had paired endoscopy and imaging before and after re-induction, with 7 of 8 patients (87.5%) achieving response and 5 of 8 patients (62.5%) achieving remission.

Safety

• Headache was the only adverse reaction reported and was not considered to be associated with STELARA.

Retrospective Studies

Yao et al (2023)⁶ conducted a single-center, retrospective, observational, cohort study to evaluate the efficacy and safety of STELARA IV re-induction in patients with refractory CD in a real-world setting.

Study Design/Methods

• Patients included in this study were those who failed to achieve clinical remission at week 16 following STELARA treatment initiation.
• These patients were then dose optimized according to 1 of the following strategies:
  • Shortened dosing intervals: SC q8w or q4w dosing.
  • IV re-induction (weight-based dosing) followed by SC q8w or q4w dosing.
• Data specific to patients receiving IV re-induction are reported below.
• The primary outcome was clinical remission (CDAI score of <150) at 3 months after treatment optimization.
• Secondary outcomes included clinical, biochemical, and endoscopic responses and remission and safety assessments at 1 year after initiating STELARA.
  • Clinical response was defined as a decrease in the CDAI score of >70 points from the baseline value.
  • Endoscopic remission was defined as an SES-CD of ≤2.
  • Endoscopic response was defined as a decrease in the SES-CD of >50% from the baseline value.

Results

Patient Characteristics

• Overall, 128 patients who received STELARA treatment optimization (interval reduction, n=105; IV re-induction, n=23) were included.
• Reasons for treatment optimization included partial response (71.9%) and loss of response (28.1%) at week 16.
• The median interval between STELARA initiation and IV re-induction was 16.0 weeks (interquartile range [IQR], 9.0-18.0 weeks).
• The follow-up duration was 23.0 weeks (range, 13-17 weeks) for the IV re-induction cohort.

Efficacy

• For the effect of IV re-induction on CRP values and CDAI scores, see Table: Changes in CRP Value and CDAI Score Between Pre- and Post-IV Re-Induction.

• For clinical outcomes in patients who received IV re-induction, see Table: Biochemical, Clinical, and Endoscopic Outcomes After IV Re-Induction.

Safety

• There was 1 AE in the IV re-induction cohort (n=1, 4.3%). This patient experienced an allergic reaction to STELARA and discontinued treatment.

Heron et al (2022)⁷ conducted a multicenter, retrospective cohort study to assess the efficacy of STELARA IV re-induction in achieving clinical and endoscopic responses or remission in patients with active CD on STELARA maintenance therapy.

Study Design/Methods

• Adult patients with CD on STELARA treatment who received STELARA IV re-induction (standard weight-based dosing) at the physician’s discretion for a suboptimal response or loss of response were included.
• The primary outcome was the composite of clinical remission with biochemical and/or endoscopic response or remission after IV re-induction with STELARA.
  • Clinical remission was defined as an HBI score of <5 without the use of corticosteroids at the time of evaluation.
  • Biochemical remission was defined as normalization of biomarkers (FCP [<250 µg/g] and/or CRP [normal per local laboratory cut-offs]).
  • Endoscopic remission was defined as an SES-CD of <3.
  • Clinical, biochemical, and endoscopic responses were defined as a ≥50% reduction in HBI score, biomarker levels, and SES-CD, respectively.
• Secondary outcomes included clinical, biomarker, and endoscopic responses; endoscopic remission; and safety assessments.

Results

Patient Characteristics

• Among the 65 patients included, all patients had a history of treatment failure with ≥1 anti-tumor necrosis factor (TNF) agent.
• Fifty-three patients (88.3%) were on an escalated maintenance dosage of STELARA 90 mg SC q4w at the time of IV re-induction.
  • At the time of STELARA initiation, 30 patients (46.2%) had received an IV induction regimen; the remaining patients had received a high-dose SC induction regimen before IV STELARA became available.
• The reason for re-induction was partial response and loss of response in 30 (40.0%) and 35 (47.7%) patients, respectively.
• After re-induction, patients were maintained on q4w (n=55; 84.6%), every 6 weeks (q6w) (n=1; 1.5%), or q8w dosing (n=9; 13.8%).
• The median time since STELARA initiation to receiving IV re-induction was 15 months (IQR, 9-29 months).
• Clinical outcomes were assessed at a median of 14 weeks (IQR, 12-19 weeks) after reinduction.

Efficacy

• At the time of assessment of response, 58 of 65 patients (89%) remained on STELARA maintenance therapy.
  • Patients who discontinued STELARA (n=7) were considered to have failed the treatment.
• For efficacy results, see Table: Primary and Secondary Outcomes After STELARA IV ReInduction.

• Overall, 20 patients (35.7%) achieved the composite outcome of clinical remission and response/remission of all biomarkers.
• Among patients with active perianal disease at baseline (n=10), 1 was reported to experience improvement of perianal fistulas.
• Among patients who were initially on corticosteroids (prednisone or budesonide) and continued receiving STELARA maintenance therapy (n=16), 2 (12.5%) required corticosteroids at follow-up and were assessed as not achieving the primary endpoint.
• The primary outcome was achieved in 11 of 26 (42.3%), 2 of 12 (16.7%), and 5 of 22 (22.7%) patients with stricturing disease; penetrating disease; and nonstricturing, nonpenetrating disease, respectively. No patients with stricturing and penetrating disease (n=3) achieved the primary endpoint.
• No neutralizing antibodies were detected during the study period.
• No predictors of response or remission with STELARA IV re-induction were identified in univariate or logistic regression analysis (age; sex; weight; smoking status; type of reinduction [IV or SC]; concomitant immunomodulators; or HBI score, CRP levels, or ustekinumab levels before re-induction).

Safety

• No SAEs were reported after STELARA re-induction.
• A minor infusion reaction (facial erythema and dyspnea) was reported in 1 patient who was able to complete the dose at a lower infusion rate.

Lee et al (2021)⁸ conducted a retrospective analysis to evaluate AEs and clinical and endoscopic responses after IV re-induction with STELARA followed by maintenance dosing in patients with CD.

• Overall, 28 patients were included, and all were exposed to a prior biologic therapy.
• Among the 13 patients with clinical/endoscopic assessments, 53.8% achieved clinical response, 38.5% achieved clinical remission, 42.8% achieved endoscopic improvement, and 42.8% achieved endoscopic remission following re-induction with STELARA.
• Overall, 85.7% of patients reported ≥1 AE over a mean follow-up of 28.7 months during STELARA therapy prior to the IV re-induction dose, and 46.4% reported ≥1 AE following re-induction after a mean follow-up of 29.4 months. See Table: Summary of AEs and SAEs.

Ten Bokkel Huinink et al (2021)⁹ conducted a multicenter retrospective cohort study to evaluate the effectiveness and safety of re-induction with IV STELARA after secondary loss of response in patients with CD.

Study Design/Methods

• The primary outcome was drug survival at weeks 20 and 52 of STELARA maintenance therapy after the second dose of IV STELARA; patients who maintained STELARA therapy were considered to have had a response or remission to the second dose of IV STELARA.
• Secondary outcomes were the proportion of patients in clinical remission (HBI ≤4) at weeks 20 and 52, nonresponse (defined as no or insufficient response to the second IV dose of STELARA within 8 weeks from re-induction), and incidence of AEs.

Results

• Overall, 166 patients were included in this study, and 31 received a second dose of IV STELARA after a median duration of 10.4 years (IQR, 6.7-16.6 years).
• Among the 31 patients, all had received ≥1 prior anti-TNF therapy, 24 had failed ≥2 prior anti-TNF therapies, and 20 had received vedolizumab prior to initiating STELARA.
• Prior to IV re-induction, 10 patients were already optimized by shortening the dosing interval.
• The median treatment duration between initial treatment and re-induction with IV STELARA was 11.1 months (IQR, 6.9-19.5 months).
• Overall, 5 (16%), 17 (55%), and 9 (29%) patients received re-induction with STELARA at a dose of 260 mg, 390 mg, and 520 mg, respectively.
• At the time of the IV re-induction, all patients showed clinical (median HBI, 8), biochemical (median FCP level, 413 μg/g; median CRP concentration, 12.5 mg/L), or endoscopic disease activity.
• After the re-induction therapy, 17 (61%) and 10 (32%) patients started subsequent STELARA maintenance therapy with q8w and q4w dosing, respectively.
• Overall, 21 (74%) and 20 (71%) patients were still receiving STELARA maintenance therapy at weeks 20 and 52, respectively.
  • In total, 4 of 10 patients (40%) on a q4w dosing interval discontinued STELARA treatment after a median treatment duration of 3.9 months (IQR, 2.04-4.24 months), and 1 of 17 patients (6%) on a q8w dosing interval discontinued STELARA treatment after 6.9 months (P=0.047).
• Four patients did not receive maintenance therapy due to nonresponse with IV reinduction.
• At baseline, due to biochemical disease activity, 9 patients who were in clinical remission received IV re-induction.
• In the total population, 11 of 30 (37%), 15 of 27 (56%), and 13 of 29 (45%) patients were in clinical remission at weeks 8, 20, and 52, respectively.
  • Among patients without clinical remission at baseline, 23%, 44%, and 40% of patients were in clinical remission at weeks 8, 20, and 52, respectively.
• Overall, 9 patients (29%) discontinued STELARA within 1 year of receiving the second dose of IV STELARA either due to nonresponse (n=5; 56%), loss of response (n=3; 33%), or AE (n=1; 11%). Median treatment duration until cessation was 1.8 months (IQR, 1.5-4.2 months) after re-induction.
• Overall, 6 patients required hospitalization during STELARA treatment due to ileus or severe active disease.
• Three possibly related AEs were reported after IV re-induction, including a lower urinary tract infection, intestinal bacterial overgrowth, and pruritus.
• One malignancy (melanoma requiring surgical resection) was reported during follow-up.

Bennett et al (2020)¹⁰, in a single-center retrospective chart review, evaluated the efficacy of STELARA in patients with refractory moderate to severe CD. In a subset of patients, the efficacy of STELARA re-induction was also evaluated.

• Overall, 96 patients were included in the study, of whom 91 received STELARA prior to Food and Drug Administration (FDA) approval. These 91 patients received STELARA 90 mg SC at weeks 0, 4, and 12. Some patients also received STELARA 270 mg at week 8 if no clinical response was noted. Maintenance treatment was STELARA 90 mg SC q8w.
• Of the 96 patients in the study, 34 underwent re-induction with STELARA.
  • Prior to the FDA approval of STELARA for CD, patients received a modified re-induction of STELARA 270 mg SC (n=21).
  • Patients who underwent re-induction after the FDA approval of STELARA for CD received weight-based STELARA IV dosing for re-induction (n=13).
• Patients who had STELARA IV re-induction had a median follow-up of 282 days (range, 64-605 days).
• Among the 34 patients, 3 patients (9%) underwent re-induction due to a lapse in the insurance approval of STELARA (treatment interruption), 26 patients (76%) for active disease with loss of response, and 5 patients (15%) after surgery.
  • Of the 26 patients who underwent re-induction for active disease with loss of response, 6 were for partial response and 20 were for secondary loss of response.
    • Those with partial response underwent re-induction at a median of 132 days (range, 108-161 days) after the initiation of STELARA.
    • Those with a secondary loss of response underwent re-induction at a median of 535 days (range, 216-1196 days) after the initiation of STELARA.
• All 13 patients who received STELARA IV re-induction remained on STELARA by the end of the study period.
• Among the 34 patients who underwent re-induction, 13 transitioned to every 4-6-week dosing after re-induction.
• HBI and CRP values were reduced for all patients who underwent re-induction; in patients who underwent re-induction with STELARA IV, HBI significantly decreased (P<0.05), as shown in Table: Disease Activity Markers Before and After STELARA Re-Induction.

• Overall, 14 patients had endoscopic evaluation after re-induction: 5 patients who had endoscopic inflammation on prior endoscopy were in endoscopic remission, 2 patients had endoscopic improvement, and 7 patients had no change endoscopically.

Bermejo et al (2020)¹¹ conducted a retrospective, observational multicenter study evaluating the efficacy and safety of STELARA IV re-induction in patients with CD who had a loss of response to STELARA maintenance therapy.

• HBI was used to evaluate a response to IV re-induction with STELARA (at weeks 8 and 16 after re-induction or a previous time if it was decided to definitely suspend STELARA treatment due to lack of response).
• Complete remission was defined as a final score of ≤4 points, and a partial response was defined as a score of >4 but with a 3-point decrease from baseline.
• There were 31 patients included in this analysis. Previous failure to 2 and 3 biologics occurred in 48.4% and 22.6% of patients, respectively.
• At study baseline, 15 patients (48.4%) received STELARA q8w, 4 patients (12.9%) received STELARA q6w, and 12 patients (38.7%) received STELARA q4w.
• At week 8 after re-induction, remission was reported in 16 patients (51.6%) and partial response was reported in 2 patients (6.4%).
• At week 16 after re-induction, 13 patients (41.9%) were in remission and 2 patients (6.4%) had a partial response.
• Patients who achieved remission at week 16 had lower CRP levels than those who did not respond (3.0±1.7 vs 14.1±9.0 mg/L; P=0.01).
• No AEs related to re-induction were observed.
• In patients who failed re-induction, vedolizumab therapy was initiated in 5 patients, intestinal resection was performed in 2 patients, and the remainder of patients were treated with steroid therapy.

Kopylov et al (2020)¹² evaluated the efficacy and safety of dose escalation of STELARA in patients with active CD after nonresponse or loss of response to STELARA 90 mg SC q8w maintenance therapy in a multicenter retrospective cohort study. This analysis included a subset of patients who were evaluated for the efficacy of STELARA IV re-induction.

• Patients in the study received ≥2 doses of STELARA (IV induction of 6 mg/kg followed by 90 mg SC injection) and an IV re-induction (6 mg/kg) instead of a scheduled SC dose, or SC dose escalation to q4w or q6w dosing, or a combination of IV reinduction and SC dose escalation.
• The primary endpoint was clinical response, which was defined as a change in HBI ≥3 or a change in the CDAI score of ≥70 at week 16 after a dose escalation strategy.
• Overall, 142 patients were included in the study, and of those, 14 received an IV re-induction and 17 had a combination of IV re-induction and dosing interval shortening.
• At week 16, clinical response was achieved by 5 of 14 patients (35.7%) who received IV reinduction and 10 of 16 patients (62.5%) who received both IV re-induction and q4w dose escalation.
• Overall, 5 of 14 patients (35.6%) who received IV re-induction and 1 of 17 patients (5.9%) who received both IV re-induction and SC dose escalation discontinued STELARA due to clinical nonresponse.

Hudson et al (2019)¹³ conducted a retrospective cohort study of patients with CD who received a second STELARA IV loading dose after secondary loss of response.

• Patients who lost response to STELARA after initial IV standard induction followed by SC maintenance therapy and received a second STELARA IV loading dose following the standard weight-based dosing recommendations were included in the study.
• Response was defined as a resolution or improvement of clinical symptoms that led to a second IV infusion.
• Among 372 patients treated with STELARA, 18 (5%) received a second IV loading dose after experiencing secondary loss of response to their initial IV induction dose.
• The patients had all failed prior biologic therapy and received STELARA as second-line (22%), third-line (27%), fourth-line (33%), fifth-line (6%), or sixth-line (11%) therapy.
• After IV re-induction, clinical response was observed in 15 patients (83%). Three patients (17%) did not respond, and STELARA was stopped.
• Among the 15 patients remaining on STELARA, 5 (33%) continued q8w dosing, 6 (40%) were on q6w dosing, and 4 (27%) required q4w dosing.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 22 August 2024.

Summarized in this response are relevant data from a phase 3b study, a retrospective and prospective study, and retrospective studies.