Model-Based Meta-Analysis on the Efficacy of Biologics and Small Targeted Molecules for Crohn’s Disease

Abstract

Information on comparative drug efficacy is of great importance for drug development as well as clinical practice. Up to now, the relative efficacy of biologics and small targeted molecules for Crohn’s disease (CD) remains unclear. The objective of this study was to quantify the relative efficacy of investigational and approved biological treatments for CD measured in Crohn’s Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire (IBDQ), and C-reactive protein (CRP). The analysis dataset was composed of summary-level data from 46 trials, containing 12,846 patients, with treatment of 24 drugs. Six mathematical models with non-parametric placebo estimations were developed to describe the time course and dose–response of six efficacy measures. The effects of covariate were further evaluated. Time–response relationships were found in outcomes measured in CDAI. The patients’ age, disease duration, baseline CDAI, and CRP showed an impact on the efficacy. Model simulations were performed to compare the efficacies across different drugs. The most achievement in clinical remission (defined as CDAI less than 150) and clinical response (defined as the reduction in CDAI for 100 or 70) was observed in the simulation for PF-04236921 and infliximab, respectively. The most improvement in IBDQ was shown in tofacitinib. In general, tumor necrosis factor (TNF)-α inhibitors were the most effective biologics, and the highest efficacy of small targeted molecules was observed in janus kinase (JAK) inhibitors. These findings have important implications for clinical practice in CD.

Model‐based meta‐analysis using latent variable modeling to set benchmarks for new treatments of systemic lupus erythematosus

“…In MBMA, where key drivers of response (drug interventions and patient/disease variables), are not randomly distributed across multiple studies, heterogeneity in response (placebo and drug effect) across trials is also a key challenge. It should be noted that because it is not uncommon in MBMA to see heterogeneity that is highly non‐symmetric, non‐parametric approaches are often suggested to test this 39,40 . In our analysis, however, we had only explored symmetric and parametric approaches as random effects to address this heterogeneity, but other non‐symmetric and non‐parametric approaches could also be explored in future efforts.…”

“…It should be noted that because it is not uncommon in MBMA to see heterogeneity that is highly non‐symmetric, non‐parametric approaches are often suggested to test this. 39 , 40 In our analysis, however, we had only explored symmetric and parametric approaches as random effects to address this heterogeneity, but other non‐symmetric and non‐parametric approaches could also be explored in future efforts.…”

Effectiveness and Safety Profiles of Biological Therapies in Inflammatory Bowel Disease: Real Life Data from an Active Pharmacovigilance Project

“…The management of IBD has been greatly revolutionized by the availability of biologics. Although both the efficacy and safety of these drugs have been established in many clinical trials [ 65 , 66 , 67 , 68 ], the benefit/risk profile remains controversial due to the different persistence rates based on the risk of immunogenicity and SADRs, such as the onset of infections and neoplasms. Consequently, the key strength of this study is that real-world analyses increase awareness on biologic use in IBD; moreover, active pharmacovigilance plays a crucial role in detecting ADRs and SADRs [ 69 , 70 ] and post-marketing activities are essential to implement the safety profile of these new treatments, thereby reducing any under-reporting phenomena and resulting in therapy optimization in clinical practice [ 18 , 71 ].…”

Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor induced colitis

“…This is underscored by lesser chronicity in histopathology, superior biological response rate and shorter time-to-response in ICI-colitis than IBD. [6][7][8][9] ICI-colitis can be subdivided based on the specific ICI regimen, i.e., αCTLA-4 monotherapy, αPD-1 monotherapy or combined (c)ICI. Clinically, time-to-onset of αPD-1 colitis is usually longer than for αCTLA-4-based regimes, while response to steroids is better for αPD-1 colitis than for colitis after αCTLA-4 +/-αPD-1.…”