Society: AGA

Background: Tumor necrosis factor inhibitors (TNFi) are a mainstay of pediatric Crohn’s disease (PCD) therapy; yet not all patients respond, and others lose response over time. Combination therapy with methotrexate may improve response; however, this has not been rigorously evaluated.

Objective: To compare the effectiveness of TNFi in combination with low dose oral methotrexate to TNFi monotherapy in children with PCD.

Methods: We performed a multi-center, randomized, double-blind, placebo-controlled pragmatic trial. Eligible PCD patients initiating infliximab or adalimumab as standard of care were randomized in 1:1 allocation to a weight-based dose of oral methotrexate or placebo and followed for a minimum of 12 months and maximum of 36 months. The primary outcome was a composite indicator of treatment failure, including toxicity. Secondary outcomes included development of anti-drug antibodies (ADA) and patient reported outcomes (PROs) of pain interference and fatigue. Adverse events (AEs) and Serious AEs (SAEs) were collected.

Results: We recruited 297 participants at 35 centers (Table 1), including 156 in the methotrexate arm (110 infliximab and 46 adalimumab initiators) and 141 in the placebo arm (102 infliximab and 39 adalimumab initiators). Overall, 26% of participants in the combination therapy group and 44% of participants in the monotherapy group experienced treatment failure [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.45-1.05]. Among infliximab initiators, there were no differences between combination and monotherapy (HR 0.93, 95% CI 0.55-1.56, p=0.78). Among adalimumab initiators, combination therapy was associated with longer time to failure (HR 0.40, 95% CI 0.19-0.81, p=0.01, Figure 1). In the monotherapy group, adalimumab-treated patients had higher failure rates than those receiving infliximab (HR 2.19, 95% CI 1.23-3.89, p=0.008). Combination therapy patients had numerically lower rates of ADA development [(infliximab odds ratio (OR) 0.72 (0.49-1.07); adalimumab OR 0.71 (0.24-2.07)]. No differences in PROs were observed. In comparison to monotherapy, combination therapy resulted in more AEs, including nausea and vomiting and elevated liver enzymes. However, the combination group had fewer SAEs and did not require treatment discontinuation for toxicity more frequently than the monotherapy group.

Conclusions: Compared to adalimumab monotherapy, PCD patients treated with adalimumab and methotrexate experienced a 2-fold reduction in the risk of treatment failure. In contrast, no differences were observed between infliximab combination and monotherapy. A trend towards reduced immunogenicity in the combination therapy group was observed among both infliximab and adalimumab initiators. Overall, these findings suggest improved effectiveness of combination therapy in adalimumab-treated patients with a tolerable safety profile.

Background: Mirikizumab is a humanized, IgG4 monoclonal antibody directed against the p19 subunit of IL-23, a key inflammatory mediator in inflammatory bowel disease. Mirikizumab was superior to placebo in inducing clinical remission as well as other symptomatic, clinical, and endoscopic endpoints and had an acceptable safety profile in adults with moderately to severely active ulcerative colitis (UC) in the Phase (Ph)3 LUCENT-1 induction and the Ph3 LUCENT-2 maintenance studies. Here we report the first PK, efficacy, and safety data in pediatric patients with moderately to severely active UC from the Ph2 SHINE-1 study (NCT04004611), following a 12-week induction period.

Methods: Children and adolescents aged 2 to <18 years old (n=26) with active UC as defined by a Modified Mayo Score (MMS) of 4-9 points and a centrally read Mayo endoscopic subscore ≥2 and who had an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies, or those with corticosteroid-dependent colitis were enrolled in the study. Patients weighing >40 kg received an induction dose of 300 mg via intravenous (IV) infusion and patients weighing ≤40 kg received 5 or 10 mg/kg via(IV) infusion at Weeks 0, 4, and 8. The primary endpoint evaluated the pharmacokinetics (PK) of mirikizumab treatment to confirm doses for Phase 3. Patients were assessed at Week 12 for clinical response, clinical remission, and endoscopic remission and were monitored for safety throughout the trial.

Results: For pediatric patients >40kg, the observed and PK model-estimated exposures were similar to adult levels. For pediatric patients ≤40kg, the exposure at 5 mg/kg matched the adult range based on both observed and modeled concentrations. Exposure at 10 mg/kg was ~2 fold higher than the adult mean. MMS clinical response and remission, and endoscopic remission rates were consistent with those of the LUCENT adults (Figure 1); PUCAI response and remission rates were acceptable. The safety findings observed in the pediatric patients are consistent with the LUCENT-1 data (Table 1).

Conclusions: In this Ph2 pediatric UC study, mirikizumab demonstrated similar observed PK concentrations to those reported in the adult LUCENT-1 induction study, an acceptable safety profile, and clinically meaningful improvement in clinical response, clinical remission and endoscopic remission following induction treatment with mirikizumab. These results provide the first reported efficacy of a p19 inhibitor in pediatric patients with UC and provide the foundation for the pivotal Ph3 pediatric study.

<b>Figure 1. Week 12 Mirkizumab Phase 2 Peds UC Data (SHINE-1) Comparison to Mirikizumab Phase 3 Adult UC Data (LUCENT-1)</b>

Figure 1. Week 12 Mirkizumab Phase 2 Peds UC Data (SHINE-1) Comparison to Mirikizumab Phase 3 Adult UC Data (LUCENT-1)

<b>Table 1. Mirikizumab SHINE-1 Safety Summary at Interim Lock<sup>a</sup></b>

Table 1. Mirikizumab SHINE-1 Safety Summary at Interim Lock^a

Athos Bousvaros

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