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 clinical use of STELARA in pediatric patients with moderate to severe plaque psoriasis.
• A phase 3, randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of STELARA in 110 pediatric patients (12 to 17 years of age) with moderate to severe plaque psoriasis (PsO) through 60 weeks.^1,2
• An additional phase 3, open-label, single-arm, multicenter study was conducted to evaluate the efficacy and safety of STELARA in 44 pediatric patients (≥6 to <12 years of age) with moderate to severe plaque PsO through 56 weeks.³

CLINICAL DATA

Landells et al (2015)^1,2 reported results from the CADMUS (A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Ustekinumab in the Treatment of ADolescent Subjects with Moderate to Severe Plaque-type psoriasis) trial.

Study Design/Methods

• Eligible patients were age 12 to 17 years with moderate to severe plaque PsO (Psoriasis Area and Severity Index [PASI] ≥12; Physician's Global Assessment [PGA] ≥3; body surface area [BSA] involvement ≥10%) for ≥6 months who were inadequately controlled on topical therapy or who were candidates for phototherapy or systemic therapy.
• Primary endpoint: PGA scores of 0 (cleared) or 1 (minimal) at week 12.
• Major secondary endpoints included: PASI 75 and 90 responses at week 12.
• Patients were randomized to 3 treatment groups.
  • STELARA standard dose
  • Half-standard dose of STELARA
  • Placebo with randomized crossover to standard or half-standard STELARA dosing at week 12 (with STELARA doses administered at weeks 12 and 16)
• Dosing was based on body weight as described in Table: STELARA Dosages in CADMUS. STELARA was administered subcutaneously at weeks 0, 4, and every 12 weeks thereafter through week 40. Final efficacy and safety evaluations occurred at weeks 52 and 60, respectively.

Results

• A total of 110 patients were randomized (placebo, n=37; half-standard, n=37; standard, n=36) with a mean age of 15.2 years. The mean baseline PASI score was 21.1 and 61.8% (68/110) of patients had a moderate (3), and 38.2% (42/110) a marked or severe (4-5) PGA score.

Efficacy

• The primary endpoint of a PGA score of 0 (cleared) or 1 (minimal) at week 12 was achieved by 67.6% (25/37) and 69.4% (25/36) of the STELARA half-standard and standard dosing groups, respectively compared with 5.4% (2/37) of placebo patients (P<0.001 for both dosing groups vs placebo).
• A PGA score of 0 (cleared) at week 12 was achieved by a significantly greater proportion of patients in the STELARA half-standard and standard dosing groups (32.4% and 47.2%, respectively) compared with 2.7% of placebo patients (P<0.001 for both dosing groups vs placebo).
• Major secondary endpoints at week 12:
  • PASI 75 was achieved by 78.4% (29/37) and 80.6% (29/36) of patients in the STELARA half-standard and standard dosing groups, respectively compared with 10.8% (4/37) in the placebo group (P<0.001 for both dosing groups vs placebo).
  • PASI 90 was achieved by 54.1% (20/37) and 61.1% (22/36) of patients in the STELARA half-standard and standard dosing groups, respectively compared with 5.4% (2/37) in the placebo group (P<0.001 for both dosing groups vs placebo).
• A PASI score of 0 (cleared) at week 12 was achieved by 21.6% and 38.9% of patients in the STELARA half-standard and standard dosing groups, respectively compared with 2.7% in the placebo group (P=0.014 and P<0.001 for STELARA dosing groups, respectively, vs placebo).
• Efficacy results through week 52 are depicted in Figures: PGA Scores of 0 (Cleared) or 1 (Minimal) through Week 52 and PASI 75 Responders through Week 52.

Safety

• Key safety findings are summarized in Tables: Summary of Key Safety Findings through Week 12 and Summary of Key Safety Findings through Week 60.

• Through week 12, infections and infestations category were the most common AEs (half-standard dose, 32.4%; standard dose, 25.0%; placebo, 40.5%); none was considered serious. Other most common AEs were nasopharyngitis (half-standard dose, 13.5%; standard dose, 2.8%; placebo, 27.0%) and headache (half-standard dose, 10.8%; standard dose, 8.3%; placebo, 5.4%). One serious AE (worsening of PsO) was reported in the STELARA half-standard dosing group.

• Through week 60, infections and infestations were the most common category of AEs, with nasopharyngitis (34.5%), upper respiratory tract infection (12.7%), and pharyngitis (8.2%) occurring most often. Five additional serious AEs were reported from week 12 through week 60 (leukopenia that was transient and coincident with recurrent herpes simplex infection, pyelonephritis, ear infection, acute contact dermatitis caused by hair dye, and death in an automobile accident). Four of the 5 serious AEs occurred in patients who received the half-standard dose of STELARA (ear infection occurred in a patient who received the standard STELARA dose).
• Through week 60, 9 (8.2%) patients tested positive for antibodies to STELARA, 6 in the half-standard dose group and 3 in the standard dose group. Six of the patients achieved a PGA 0/1 at the time of antibody detection.

Philipp et al (2020)³ reported the results from CADMUS Jr, a phase 3, open-label, single-arm, multicenter study that evaluated the efficacy and safety of STELARA in pediatric patients age ≥6 to <12 years with moderate to severe plaque PsO.

Study Design/Methods

• Eligible patients were ≥6 to <12 years of age with moderate to severe plaque PsO (PASI ≥12; PGA ≥3; BSA ≥10%) and were candidates for phototherapy or systemic therapy or were considered by the investigator to be poorly controlled with topical therapy.
• STELARA was dosed based on weight (<60 kg: 0.75 mg/kg; ≥60 kg to ≤100 kg: 45 mg; >100 kg: 90 mg) and administered by subcutaneous injection at weeks 0 and 4 followed by every 12 weeks (q12w) dosing through week 40.
• The primary endpoint was the proportion of patient with PGA scores of 0 (cleared) or 1 (minimal) at week 12.
• Major secondary endpoints included: PASI 75, PASI 90 and change from baseline Children’s Dermatology Life Quality Index (CDLQI) at week 12.
• Some other secondary endpoints were evaluated at various timepoints and included: PGA 0, PASI 100, and CDLQI 0/1 among patients with CDLQI >1 at baseline.
• PGA and PASI were assessed every 4 weeks through week 16 and every 12 weeks thereafter through week 52.
• The pharmacokinetics and immunogenicity of STELARA was evaluated at selected visits through week 52.
• Safety endpoints were evaluated at each study visit through week 56.
• Serum samples collected at baseline, week 12 and week 52 were used to evaluate biomarker studies and cytokine levels for IL-17A, IL-17F, and IL-22 before and after treatment with STELARA.
• Treatment failure was defined as patients who discontinued study treatment due to lack of efficacy or an AE of worsening PsO or those who started a prohibited medication affecting PsO outcomes.
• Baseline values were used for continuous variables and nonresponder status was assigned for binary variables for all subsequent visits once treatment failure was met.
• Patients with missing efficacy data for binary variables at week 12 were considered nonresponders.
• No imputation was performed for missing data after applying treatment failure rules at other timepoints.

Results

Patient Characteristics

• Baseline demographics and disease characteristics were typical of a pediatric population with moderate-to-severe PsO and are summarized in table: Demographics and Disease Characteristics at Baseline.

• Three patients (6.8%) discontinued treatment before week 40, (1 patient for lack of efficacy and 2 patients for protocol violations).

Efficacy

• Efficacy data at week 12 are summarized in Table: Primary, Major Secondary, and Other Secondary Endpoints at Week 12.

Pharmacokinetics

• Median trough serum ustekinumab concentrations were maintained at steady state levels from week 28 (0.34 μg/mL; interquartile range [0.184, 0.489]) through week 52 (0.38 μg/mL; interquartile range [0.207, 0.502]).
• Similar concentration levels were observed for patients weighing <60kg treated with 0.75 mg/kg dose and ≥60 kg to ≤100 kg treated with the 45 mg dose.

Immunogenicity

• Through week 52, 42 out of the 44 treated patients had at least one posttreatment serum sample that was used in the evaluation of antidrug antibody (ADA).
• Through week 52, the incidence of ADA was reported in 4 (9.5%) patients.
  • Two of the ADA positive patients had antibodies that neutralized the bioactivity of ustekinumab in vitro.
  • Two of the ADA positive patients achieved PGA 0/1 and PASI 75 responses at week 52.
  • None of the ADA positive patients reported injection site reactions after developing ADA.
  • Antibodies’ titers to ustekinumab ranged from 1:200 to 1:12,800.
  • Two ADA positive patients had titer levels ≤1:400.

Biomarkers

• Serum levels of IL-17A, IL-17F, and IL-22 were reduced significantly from baseline after treatment with STELARA at weeks 12 and 52. A summary of serum cytokine levels is summarized in table: Serum Levels of Cytokines at Baseline, Week 12, and Week 52.

Safety

• Treatment-emergent adverse events in patients who received at least 1 dose of STELARA through week 56 are summarized in table: Treatment-Emergent Adverse Events through Week 56.

• Through week 56, 16 (7.6%) injections were associated with an injection site reaction in 6 (13.6%) patients.
  • All injection site reactions were assessed as mild in intensity and resolved within 1 day.
• Three serious adverse events (infectious mononucleosis, eyelid injury, and attention deficit/hyperactivity disorder) occurred through week 56.
  • None were considered by the investigator to be related to study treatment.
• No deaths, malignancies, major adverse cardiovascular events, cases of tuberculosis, opportunistic infection or anaphylactic or serum sickness like reactions were reported through week 56.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 08 April 2024. Summarized in this response are relevant phase 3 studies.