Jeffrey S. Hyams

Background: Golimumab is an anti-TNFα biologic agent that has been approved for adults with moderately-to-severely active ulcerative colitis (UC). We investigated the efficacy, safety, and pharmacokinetics (PK) of golimumab in biologic-naïve children with moderately-to-severely active UC. Methods: The prospective, multicenter, open-label PURSUIT 2 study enrolled biologic-naïve children (2 to <18 years) with moderately-to-severely active UC (Mayo score 6-12; endoscopic subscore ≥2) despite conventional treatment. During the 6-week induction phase, patients received subcutaneous (SC) golimumab dosed by weight (1) at week 6. Efficacy and PK data are presented alongside a reference adult UC population who received golimumab SC 200/100 mg at weeks 0/2 and 100 mg q4w thereafter. Results: Of the 69 patients (mean age, 13.4 ± 3.3 years) enrolled, 31.9% (22/69) were in clinical remission at week 6, and of those, 54.5% (12/22) remained in clinical remission at week 54. At week 54, 31.7% (13/41) of week 6 clinical responders achieved clinical remission. Additionally, 33.3% achieved clinical remission by the Pediatric Ulcerative Colitis Activity Index (PUCAI), 56.5% clinical response by Mayo, 40.6% endoscopic improvement, and 7.2% endoscopic remission at week 6. Of those who were clinical responders at week 6, 34.1% achieved clinical remission by PUCAI, 31.7% corticosteroid-free clinical remission by Mayo, 36.6% endoscopic improvement, and 9.8% endoscopic remission at week 54. Serum golimumab concentrations through week 6 were comparable to the reference adult UC population. Through week 54, 40.6% reported serious adverse events and 13.0% serious infections. No new safety concerns were identified. Conclusions: Overall, the results of the PURSUIT 2 study support golimumab treatment for children with moderately-to-severely active UC. ClinicalTrials.gov ID: NCT03596645

Model‐informed precision dosing (MIPD) utilizes pharmacokinetic/pharmacodynamic (PK/PD) models to optimize drug therapy. However, conventional MIPD often requires manual simulation and regimen selection, which are time‐consuming and demand specialized expertise. Reinforcement learning (RL), in which an agent learns optimal decisions through iterative interactions with an environment, offers a scalable and automated alternative. In this study, we developed a model‐informed Deep Q‐Network (DQN) to personalize infliximab dosing for patients with Crohn’s disease. The DQN was trained in a simulation environment incorporating a population PK model, inter‐individual variability, and assay error. Virtual patients with randomly and independently sampled covariates from log‐normal distributions were used to explore dosing strategies at Infusions 1, 3, and 4. Doses ranged from 1 to 10 mg/kg at Infusion 1 and from 1 to 20 mg/kg thereafter, with intervals of 4–12 weeks. The reward function prioritized achieving trough concentrations of 18–26 μg/mL before Infusion 3 and 5–10 μg/mL before Infusions 4 and 5, while penalizing overtreatment and additional infusions. The DQN policy converged after 80,000 episodes, yielding target attainment probabilities (PTAs) of 92.9% and 98.4% at Infusions 4 and 5, respectively, in 1000 virtual patients. High doses (11–20 mg/kg) were selected in only 0.2% of cases. At Infusion 4, 66.8% of patients received an 8‐week interval, and 57.3% at Infusion 5. Retrospective real‐world validation showed that patients whose actual doses matched DQN recommendations had trough levels significantly closer to target ranges. These findings support the feasibility of using DQN‐based agents to enhance and automate infliximab individualized dosing in pediatric populations.

The past 25 years have witnessed remarkable advances in treating inflammatory bowel disease (IBD), from the introduction of monoclonal antibodies to the recent advances in small molecule therapy. Unfortunately, these life-altering therapies have been almost exclusively approved for adult patients and because of excessive delays in pediatric drug approval, children continue to be therapeutic orphans. Two anti-TNF biologics, infliximab, and adalimumab received pediatric approval for Crohn’s disease 8 (2006) and 6 years (2012), respectively, after adult approval. Subsequently, these 2 drugs received approval for ulcerative colitis 6 (2011) and 9 (2021) years, respectively, after adult approval. No other advanced therapies have been approved for children. It is now 10 years since the adult approval of vedolizumab and eight years since the approval of ustekinumab, and neither is close to being approved for pediatric use. Both agents are considered safe and effective in adults with ulcerative colitis. Yet, children with corticosteroid-dependent ulcerative colitis are invariably denied these medications by payers unless they have failed anti-TNF therapy. None of the recently approved or emerging biological and small molecule therapies currently used to treat adults are within a decade of approval in children. These ongoing delays significantly compromise the care of children with IBD as off-label use occurs without the benefit of adequate dosing and safety data. Pediatric gastroenterology experts configure extrapolation of efficacy and dosing based on knowledge and experience in the use of drugs. Still, it is far from optimal management or the expected standard for any adult patient, let alone a vulnerable child. Third-party payers refuse or delay the approval of effective medications. Children with poorly controlled IBD, often complicated by growth failure, have no approved therapeutic options beyond anti-TNF agents. Over the past two decades, the pediatric IBD community has repeatedly engaged with regulatory agencies as well as pharmaceutical and biotechnology companies to remedy this situation with minimal success.

Objectives: Payer mandates have resulted in children with inflammatory bowel disease (IBD) switching from originator Remicade® (O‐Rem) to an infliximab biosimilar (B‐IFX). Patients and families are fearful of switching because disease has been well controlled on O‐Rem. Real‐world data documenting clinical outcomes after such switches in pediatric patients are limited. The aim of this project was to examine 1 year of follow‐up in a large adolescent/young adult IBD cohort who changed from O‐Rem to B‐IFX.Methods: We identified patients with IBD at Connecticut Children's receiving O‐Rem for at least 1 year, who were either in clinical remission or had low disease activity, and who were subsequently switched to B‐IFX. An age, gender, IBD‐subtype, and duration since diagnosis cohort that continued on O‐Rem was then matched to the switch cohort and served as a comparator group (1: switch vs. 2: no‐switch). B‐IFX was Inflectra® in all cases.Results: Two hundred and seventy‐nine patients (mean age 18.7 years, Crohn's disease = 243, ulcerative colitis = 36) were studied (switch, n = 93, no‐switch, n = 186). Mean time since diagnosis was >6 years in both groups, and mean duration of anti‐tumor necrosis factor use was >5 years. There were no significant changes in hemoglobin, albumin, C‐reactive protein, erythrocyte sedimentation rate, or disease activity in either group over 1 year. Dosing modifications as well as the frequency of low‐level antibodies to infliximab were similar in both groups over the study period.Conclusion: Switching from O‐Rem to B‐IFX has no impact on clinical or laboratory parameters over the subsequent year. Clinicians can reliably reassure patients and families that switching is safe.

The use of electronic health records has garnered interest as an approach for conducting innovative outcome research and producing real-world evidence at a reduced cost compared to traditional clinical trials. The study aimed to evaluate the utility of deidentified EHR data from a multicenter research network to identify characteristics associated with treatment escalation (TE) in newly diagnosed pediatric ulcerative colitis patients. EHR data (01/2010-12/2021) from 13 Midwest healthcare systems (Greater Plains Collaborative) were collected for pediatric ulcerative colitis patients. We identified standard treatments, excluded missing initial therapy data, and analyzed the TE and time-to-TE outcomes. The clinical and laboratory characteristics at baseline were extracted. Logistic and Cox models were used, and the missing risk factors were imputed. Machine-learning Bayesian additive regression trees were also utilized to create partial dependence plots for assessing the associations between risk factors and clinical outcomes. A total of 502 eligible pediatric patients (aged 4–17 years) who initiated standard treatment were identified. Among them, 205 out of 502 (41%) experienced TE, with a median (P25, P75) duration of 63 (9, 237) days after the initial treatment. Additionally, 20 out of 509 (4%) patients underwent colectomy (COL) with a median (P25, P75) duration of 80 (3, 205) days. Both multivariable logistic regression and Cox proportional hazards regression demonstrated moderate discriminative power in predicting TE and time-to-TE, respectively. Common positive predictors for both TE and time-to-TE included a high monocyte proportion and elevated platelet counts. Conversely, BMI z-score, albumin, hemoglobin levels, and lymphocyte proportion were negatively associated with both TE and time-to-TE. This study demonstrates that multicenter EHR data can be used to identify a trial-comparable study sample of potentially larger size and to identify clinically meaningful endpoints for conducting outcome analysis and generating real-world evidence.

Background: Perianal fistulas and abscesses occur commonly as complications of pediatric Crohn’s disease (CD). A validated imaging assessment tool for quantification of perianal disease severity and activity is needed to evaluate treatment response. We aimed to identify magnetic resonance imaging (MRI)-based measures of perianal fistulizing disease activity and study design features appropriate for pediatric patients. Methods: Seventy-nine statements relevant to MRI-based assessment of pediatric perianal fistulizing CD activity and clinical trial design were generated from literature review and expert opinion. Statement appropriateness was rated by a panel (N = 15) of gastroenterologists, radiologists, and surgeons using modified RAND/University of California Los Angeles appropriateness methodology. Results: The modified Van Assche Index (mVAI) and the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD) were considered appropriate instruments for use in pediatric perianal fistulizing disease clinical trials. Although there was concern regarding the use of intravascular contrast material in pediatric patients, its use in clinical trials was considered appropriate. A clinically evident fistula tract and radiologic disease defined as at least 1 fistula or abscess on pelvic MRI were considered appropriate trial inclusion criteria. A coprimary clinical and radiologic end point and inclusion of a patient-reported outcome were also considered appropriate. Conclusion: Outcomes of treatment of perianal fistulizing disease in children must include MRI. Existing multi-item measures, specifically the mVAI and MAGNIFI-CD, can be adapted and used for children. Further research to assess the operating properties of the indices when used in a pediatric patient population is ongoing.