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 STELARA and pharmacokinetics.
• Analysis of data from the phase 3, randomized UNIFI induction (8-week) and maintenance (44-week) studies in adults with moderately to severely active ulcerative colitis (UC) demonstrated that serum ustekinumab concentrations were doseproportional and were not affected by prior biologic use or concomitant immunomodulator therapy. The week 8 serum ustekinumab concentration threshold for induction of response was 3.7 µg/mL and a steadystate trough serum ustekinumab concentration of 1.3 µg/mL or higher was associated with a higher rate of clinical remission at maintenance week 44. There was a positive exposure-response relationship for specific clinical efficacy outcomes and normalization of specific inflammatory biomarkers during the induction and maintenance studies. It was also reported that ustekinumab serum concentrations were not associated with infections, serious infections, or serious adverse events.¹
• During the UNIFI long-term extension (LTE), serum ustekinumab concentrations were sustained through week 92. There were no clear exposureresponse relationships demonstrated between serum ustekinumab concentrations and symptomatic remission at week 92. No associations were observed between serum ustekinumab concentrations and the incidence of infections, serious infections, and serious adverse events through week 96.²

CLINICAL DATA

Pharmacokinetics and Exposure-Response Relationships: UNIFI Induction and Maintenance Phase 3 Studies

Adedokun et al (2020)¹ analyzed the pharmacokinetics and exposure-response profile of ustekinumab using data from the 52-week phase 3 UNIFI induction and maintenance studies in adults with moderately to severely active UC.

Study Design/Methods

• UNIFI was an 8-week, randomized, placebo-controlled, induction study and a 44-week, randomizedwithdrawal maintenance study.
• During the induction study, patients were randomized (1:1:1) to receive a single intravenous (IV) induction dose approximating STELARA ~6 mg/kg, STELARA 130 mg, or placebo at week 0.
• Patients enrolled in the UNIFI maintenance study were those who achieved a clinical response to a single STELARA IV induction dose from the UNIFI induction study. This included patients from the STELARA ~6 mg/kg or 130 mg groups in clinical response at week 8, or patients who had no response to placebo IV at week 8 and received a single IV dose of STELARA ~6 mg/kg at week 8 and were in clinical response 8 weeks later.
• During the maintenance study, patients were randomized (1:1:1) to receive STELARA 90 mg subcutaneously (SC) every 8 weeks (q8w), STELARA 90 mg SC every 12 weeks (q12w), or placebo SC. Dose adjustments were not permitted through maintenance week 44.
• At induction week 8 and maintenance week 44, clinical, endoscopic, and inflammatory biomarker (serum C-reactive protein [CRP], fecal calprotectin, and fecal lactoferrin) measures of efficacy and selected safety events (infections, serious infections, serious adverse events) were evaluated.
• Relationships between serum ustekinumab concentration quartiles and efficacy/safety were assessed.
• Additionally, using receiver operating characteristic (ROC) curve analyses, optimal serum concentrations of ustekinumab were identified by the authors.

Results

• Following a single IV dose of ~6 mg/kg or a 130-mg fixed dose of STELARA, median serum ustekinumab concentrations were dose-proportional (median peak concentrations 1 hour after IV induction at week 0 were 127.0 µg/mL for the ~6 mg/kg group compared to 43.2 µg/mL for the 130 mg group).
• During maintenance therapy with STELARA 90 mg SC, steady-state serum ustekinumab concentrations occurred at ~8 weeks (16 weeks after induction) with q8w dosing and at 12 weeks (20 weeks after induction) with q12w dosing. The median steady-state trough serum ustekinumab concentrations in the q8w group (2.7 to 3.1 µg/mL) were approximately 3-fold higher than those in the q12w group (0.9 to 1.2 µg/mL).
• Whether or not patients were using concomitant immunomodulator therapy (6mercaptopurine, azathioprine, methotrexate) or had previously failed or not failed biologics, serum ustekinumab concentrations were similar.
• In quartile analyses of serum ustekinumab concentrations (combined dose groups) at induction week 8 and average steady-state trough concentrations during SC maintenance, positive exposure-response relationships were observed. Please see Table: Induction: Relationship Between Serum Ustekinumab Concentration and Clinical Response, Clinical Remission, and Endoscopic Improvement at Week 8 and Table: Maintenance: Relationship Between Average Steady-State Trough Serum Ustekinumab Concentration and Clinical Remission and Endoscopic Improvement at Week 44.

• In quartile analyses of serum ustekinumab concentrations (combined dose groups) at induction week 8 and average steady-state trough concentrations during SC maintenance, positive effects were seen between serum ustekinumab concentration and normalization of inflammatory biomarker concentrations (normalized serum CRP, normalized fecal lactoferrin, and normalized fecal calprotectin). Please see Table: Induction: Relationship Between Serum Ustekinumab Concentration and Normalized CRP, Normalized Calprotectin, and Normalized Lactoferrin at Week 8 and Table: Maintenance: Relationship Between Average Steady-State Trough Serum Ustekinumab Concentration and Normalized CRP, Normalized Calprotectin, and Normalized Lactoferrin at Week 44.^{1, 3}

• ROC curves identified a target serum ustekinumab concentration ≥3.7 µg/mL at induction week 8 for achieving clinical response at that timepoint (area under the ROC curve [AUC]: 0.65; 95% confidence interval [CI], 0.61-0.69; P<0.001) and a target steadystate trough serum ustekinumab concentration threshold of 1.3 µg/mL or greater for clinical remission at maintenance week 44 (AUC: 0.64; 95% CI, 0.58-0.69; P<0.001).¹
• In multivariable logistic regression analysis, serum ustekinumab concentration at week 8 and normalized serum CRP (≤3.0 mg/L) and fecal lactoferrin (≤7.2 µg/g) status at week 8 were most closely associated with achieving clinical response at induction week 8. Average steady-state trough ustekinumab concentration and remission status at maintenance week 0 were most closely associated with achieving clinical remission at maintenance week 44.
• No associations between serum ustekinumab concentrations and selected safety events (included infections, serious infections, serious adverse events) were observed during IV induction or SC maintenance treatment.

Pharmacokinetics and Exposure-Response Relationships: UNIFI Long-Term Extension

Adedokun et al (2020)² reported the pharmacokinetics and exposure-response profile of ustekinumab through the first year of the UNIFI LTE.

Study Design/Methods

• The UNIFI LTE evaluates SC STELARA through 220 weeks of maintenance treatment; the LTE study started after the 44-week UNIFI maintenance study.
• Patients who entered the LTE continued to receive the same treatment as during the 44week maintenance study: STELARA 90 mg SC q8w (n=143), STELARA 90 mg SC q12w (n=141), or placebo SC (n=115); patients who were assigned to placebo SC during the maintenance study were discontinued after study unblinding, which occurred after the analysis of maintenance study data.
• From week 56 onward in the LTE, based on clinical judgment of the investigator, dose adjustment at any time was allowed per protocol:
  • Patients in the placebo SC arm could receive STELARA 90 mg SC q8w
  • Patients in the STELARA 90 mg SC q12w arm could receive STELARA 90 mg SC q8w
  • Patients in the STELARA 90 mg SC q8w arm could continue on STELARA
    90 mg SC q8w (sham dose adjustment)
• Patients randomized to STELARA in the maintenance study who received STELARA
  90 mg SC q12w or q8w during the LTE, did not have a dose adjustment, and had appropriate concentration data through week 92 of the LTE were included in the pharmacokinetic analyses.
• During the LTE through week 92, serum ustekinumab concentrations were assessed every 4 weeks after dosing in the q8w group and every 8 weeks after dosing in the q12w group.
• Clinical efficacy (symptomatic and partial Mayo remission, and inflammatory biomarkers) was evaluated at week 92 and safety was evaluated through week 96. These outcomes were evaluated to determine the association with serum ustekinumab concentrations.

Results

• The median non-trough serum ustekinumab concentrations ranged between 6.49 to 6.66 µg/mL at 4 weeks after dosing in the q8w group and between 2.11 to 2.56 µg/mL at 8 weeks after dosing in the q12w group during the LTE.
• In quartile analyses of serum ustekinumab concentrations at week 92, the proportion of patients in symptomatic remission was ≥80% in each quartile for each dose group (no clear exposure-response relationships were demonstrated). Please see Table: Long-Term Extension: Relationship Between Serum Ustekinumab Concentration and Symptomatic Remission in STELARA q8w and q12w Dose Groups at Week 92).
• Similar results were observed for partial Mayo remission at week 92.

• In quartile analyses of serum ustekinumab concentrations at week 92 in relation to normalized biomarkers (normalized CRP and normalized fecal calprotectin), the proportion of normalized CRP and fecal calprotectin at week 92 increased with increasing serum ustekinumab concentration. Please see Table: Long-Term Extension: Relationship Between Serum Ustekinumab Concentration and Normalized Biomarkers in STELARA q8w and q12w Dose Groups at Week 92.

• No associations between STELARA exposure and selected safety events (included infections, serious infections, serious adverse events) were observed through week 96.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 14 August 2023.

Summarized in this response are relevant data from the pivotal phase 3 UNIFI clinical trial program and the UNIFI LTE.