Intravenous Golimumab in Patients with Polyarticular Juvenile Idiopathic Arthritis and Juvenile Psoriatic Arthritis and Subcutaneous Ustekinumab in Patients with Juvenile Psoriatic Arthritis: Extrapolation of Data from Studies in Adults and Adjacent Pediatric Populations

Abstract

Objectives: To describe the extrapolation approaches used to support intravenous (IV) golimumab for polyarticular juvenile idiopathic arthritis (pJIA) and juvenile psoriatic arthritis (jPsA) and subcutaneous (SC) ustekinumab for jPsA.

Methods: Pharmacokinetic, clinical response, and safety data from trials of IV golimumab and SC ustekinumab in polyarticular-course JIA (pc-JIA) (GO-VIVA) or pediatric psoriasis (PsO) (CADMUS and CADMUS Jr) and data from pivotal, phase 3 trials of these agents in adults with similar diseases were used to support extrapolation in pJIA and jPsA. In the phase 3 GO-VIVA trial, patients with pc-JIA aged 2 to < 18 years received IV golimumab 80 mg/m2 at weeks 0, 4, then every 8 weeks (Q8W). In the phase 3, randomized, placebo-controlled CADMUS trial, patients with PsO aged ≥ 12 to < 18 years received ustekinumab at weeks 0, 4, then Q12W. In the phase 3 CADMUS Jr trial, patients with PsO aged ≥ 6 to < 12 years received ustekinumab at weeks 0, 4, then Q12W. The ustekinumab analyses used data only from patients who received the standard ustekinumab dosing regimen (≤ 60 kg: 0.75 mg/kg; > 60 to ≤ 100 kg: 45 mg; > 100 kg: 90 mg).

Results: In the 127 patients with pc-JIA treated with IV golimumab (GO-VIVA), pharmacokinetic and exposure-response results were similar to those in adults with rheumatoid arthritis treated with IV golimumab. Additionally, pharmacokinetic and clinical response data from five patients with jPsA in GO-VIVA were comparable to those in adults with PsA treated with IV golimumab. No new safety signals were observed in GO-VIVA. Pharmacokinetic and clinical response data observed in the four pediatric patients with PsO and jPsA treated with ustekinumab in CADMUS and CADMUS Jr were similar to those in the 91 pediatric patients with PsO without jPsA in these trials and to those in adults with PsA treated with ustekinumab. Safety was extrapolated from CADMUS or CADMUS Jr; no new signals were observed.

Conclusions: These three sets of analyses corroborate similar exposure and efficacy of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in patients with jPsA to support extrapolation of established adult efficacy. The overall safety profiles of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in pediatric patients with PsO with or without jPsA were consistent with the safety profiles of these agents in the context of their clinical programs and cumulative use. Based on these analyses, the US Food and Drug Administration approved IV golimumab for polyarticular JIA and active PsA in patients 2 years and older and SC ustekinumab for pediatric PsA in patients 6 years and older, highlighting how use of an extrapolation approach can help streamline drug development for pediatric patient populations in whom larger clinical trials are not feasible.

Clinical trial registration: GO-VIVA (NCT02277444) was registered at clinicaltrials.gov on 29 October 2014; CADMUS (NCT01090427) was registered on 22 March 2010; and CADMUS Jr (NCT02698475) was registered on 3 March 2016.

Conflict of interest statement

Jocelyn H. Leu, Michael Clark, Karen Bensley, Kathleen G. Lomax, Katherine Berezny, and Zhenhua Xu are employees of Janssen Research & Development, LLC, a subsidiary of Johnson & Johnson, and may own stock in Johnson & Johnson. Honghui Zhou was an employee of Janssen Research & Development, LLC, a subsidiary of Johnson & Johnson, at the time the work was conducted and may own stock in Johnson & Johnson; Dr. Zhou is currently an employee at Elevar Therapeutics, Inc, Salt Lake City, UT, USA. Natalie J. Shiff is an employee of Janssen Scientific Affairs, LLC, a subsidiary of Johnson & Johnson; received salary support from the Childhood Arthritis and Rheumatology Research Alliance within the past 3 years; and owns or has owned stock in AbbVie, Gilead, Iovance, Johnson & Johnson, Novo-Nordisc, and Pfizer within the past 3 years. Robert M. Nelson is an employee of Johnson & Johnson and owns stock in Johnson & Johnson.

© 2022. The Author(s).

Figures

Fig. 1

Relationships among polyarticular JIA, adult RA, adult and juvenile PsA, and adult and pediatric PsO. Vertical purple arrows and solid lines indicate similarity of the pediatric and adult forms of each disease; blue solid and dotted boxes and arrows indicate adjacent pediatric (polyarticular JIA and jPsA) and adult (RA and PsA) diseases; green solid and dotted boxes and arrows indicate adjacent pediatric (jPsA and pediatric PsO) and adult (PsA and PsO) diseases. JIA juvenile idiopathic arthritis, jPsA, juvenile psoriatic arthritis, PsA psoriatic arthritis, PsO psoriasis, RA rheumatoid arthritis

Fig. 2

Comparisons among a adult RA, pc-JIA, adult PsA, and jPsA clinical trial populations to support extrapolation of IV golimumab data for polyarticular JIA and jPsA and b adolescent PsO, pediatric PsO, adult PsO, adult PsA, and jPsA clinical trial populations to support extrapolation of ustekinumab data for jPsA. *Data from GO-LIVE were used only for comparison of ER analyses. Filled boxes indicate clinical trial(s) dedicated to the patient population indicated. Boxes with black outline indicate clinical trial(s) where the patient population was a subset of the trial(s). The overall GO-VIVA population was used to support IV golimumab for polyarticular JIA. Solid lines and arrows indicate direct comparisons of data. ER exposure-response, IV intravenous, JIA juvenile idiopathic arthritis, jPsA juvenile psoriatic arthritis, pc-JIA polyarticular-course juvenile idiopathic arthritis, PK pharmacokinetics, PsA psoriatic arthritis, PsO psoriasis, RA rheumatoid arthritis, yrs years

Fig. 3

Exposure matching for IV golimumab for polyarticular JIA a observed Ctrough,ss golimumab concentrations in patients with pc-JIA (GO-VIVA) at week 28 and adults with RA (GO-FURTHER) at weeks 20 and 36, and b model-predicted serum golimumab AUCss over an 8-week dosing interval at week 28 in patients with pc-JIA (GO-VIVA) and adults with RA (GO-FURTHER). Horizontal line within box = median; lower edge of box = first quartile; upper edge of box = third quartile; ends of whiskers represent ± 1.5 × IQR. AUCss steady-state area under the concentration-time curve, Ctrough,ss steady-state trough concentration, IQR interquartile range, IV intravenous, JIA juvenile idiopathic arthritis, pc-JIA polyarticular-course juvenile idiopathic arthritis, RA rheumatoid arthritis

Fig. 4

Efficacy responses by golimumab steady-state trough concentration quartiles in adults with RA from GO-FURTHER (week 20) and GO-LIVE (week 24) and pediatric patients with pc-JIA from GO-VIVA (week 20) a ACR20 and JIA ACR30 response rates, and percent change from baseline in b tender joint count, c swollen joint count, d patient assessment of disease activity, e physician assessment of disease activity, and f patient assessment of physical function. Circle within box = median; lower edge of box = first quartile; upper edge of box = third quartile; ends of whiskers represent ± 1.5 × IQR. ACR20 ≥ 20% improvement from baseline in tender and swollen joint counts and ≥ 20% improvement in three of the five other core set measures. JIA ACR30 = ≥ 30% improvement from baseline in three components, without worsening of ≥ 30% in > one of the remaining JIA core measures. Patients missing data for all components of the composite endpoint were considered nonresponders. Last observation carried forward was used to impute the composite endpoint when ≥ one of the component values was missing. ACR American College of Rheumatology, Ctrough,ss steady-state trough concentration, JIA juvenile idiopathic arthritis, pc-JIA polyarticular-course juvenile idiopathic arthritis, Q quartile, RA rheumatoid arthritis

Fig. 5

Exposure matching for IV golimumab for jPsA. a Observed steady-state serum trough golimumab concentrations in patients from GO-VIVA with jPsA, pc-JIA (excluding jPsA), and pc-JIA (overall) at weeks 28 and 52, and b observed steady-state serum trough golimumab concentrations in patients with jPsA (GO-VIVA) and adults with PsA (GO-VIBRANT) at weeks 28 (jPsA), 36 (adult PsA), and 52 (both populations). *pc-JIA population excluding patients with jPsA. †Week 28 for jPsA and week 36 for adult PsA. Horizontal line within box = median; lower edge of box = first quartile; upper edge of box = third quartile; whiskers represent fifth and 95th percentiles. Ctrough,ss steady-state trough concentration, IV intravenous, jPsA juvenile psoriatic arthritis, pc-JIA polyarticular-course juvenile idiopathic arthritis, PsA psoriatic arthritis, W week

Fig. 6

Clinical response rates among patients with jPsA (GO-VIVA) and adults with PsA (GO-VIBRANT) through week 52 a JIA ACR30 versus ACR20, b JIA ACR50 versus ACR50, c JIA ACR70 versus ACR70, and d JIA ACR90 versus ACR90. Adult PsA population included only adults with baseline methotrexate use. Proportions of JIA ACR and ACR responders are based on imputed data using last observation carried forward and nonresponder imputation. ACR20/50/70/90 = ≥ 20%/50%/70%/90% improvement from baseline in ACR criteria. JIA ACR30/50/70/90 = ≥ 30%/50%/70%/90% improvement from baseline in three components, without worsening of ≥ 30%/50%/70%/90% in > one of the remaining JIA core measures. ACR American College of Rheumatology, JIA juvenile idiopathic arthritis, jPsA juvenile psoriatic arthritis, PsA psoriatic arthritis

Fig. 7

Observed serum ustekinumab Ctrough,ss through week 52 in a adults with PsO (PSTELLAR) or PsA (PSUMMIT-1) and b adults with PsA (PSUMMIT-1) and pediatric patients with PsO with or without jPsA (CADMUS and CADMUS Jr). Horizontal line within box = median; diamond = mean; lower edge of box = first quartile; upper edge of box = third quartile; ends of whiskers represent ±1.5 × IQR. Adult PsO and PsA populations included only adults who received the ustekinumab 45 mg dose regimen. Pediatric PsO with or without jPsA populations included only pediatric patients assigned to the standard dose treatment group and who received the standard dose regimen at 0.75 mg/kg or 45 mg. Ctrough,ss steady-state trough concentration, jPsA juvenile psoriatic arthritis, PsA psoriatic arthritis, PsO psoriasis, w/o without

Fig. 8

PASI75 response rates through week 52 in pediatric patients with PsO and jPsA (CADMUS and CADMUS Jr) and in adults with PsA (PSUMMIT-1). Pediatric patients with PsO and jPsA (CADMUS and CADMUS Jr) included patients in the randomized set (CADMUS) or full analysis set (CADMUS Jr) assigned to the standard dose regimen (0.75 mg/kg or 45 mg). Data for this population were imputed using last observation carried forward or nonresponder imputation after treatment failure rules were applied. Adults with PsA (PSUMMIT-1) included patients in the randomized set as per study protocol who received ustekinumab 45 mg. In this population, PASI response was evaluated only in patients with ≥ 3% of body surface area affected by PsO at baseline, and data were imputed using nonresponder imputation on PASI response parameters after treatment failure rules were applied. Treatment failure rules for all studies were initiation of therapies not allowed per protocol or discontinuation of study drugs due to inadequate efficacy or adverse event of worsening disease. PASI75 = ≥ 75% improvement from baseline in PASI score. jPsA juvenile psoriatic arthritis, NE not evaluated, PASI Psoriasis Area and Severity Index, PsA psoriatic arthritis, PsO psoriasis