Bereswill, Mareike

AbstractBackgroundPYRAMID was an international post‐marketing registry that aimed to collect data on the long‐term safety and effectiveness of adalimumab treatment per local standard of care in patients with moderately to severely active Crohn's disease (CD). Here, we present post hoc analyses of observational data from patients who became pregnant while participating in this registry and receiving adalimumab.MethodsFrom the subpopulation of patients receiving adalimumab who became pregnant while taking part in PYRAMID, data on patient characteristics, pregnancy outcomes, and complications of pregnancy were analysed retrospectively.ResultsAcross the PYRAMID registry, 293 pregnancies occurred in patients who had gestational adalimumab exposure (average disease duration at last menstrual period: 8.6 years), resulting in 300 pregnancy outcomes. A total of 197 pregnancies (67.2%) were exposed to adalimumab in all trimesters per physician's decision. Of the known reported outcomes (96.3%), 81.7% (236/289) were live births, 10.4% (30/289) were spontaneous abortions, 4.8% (14/289) elective terminations, 2.8% (8/289) ectopic pregnancies, and 0.3% (1/289) was a stillbirth. Congenital malformations (pulmonary valve stenosis and tricuspid valve incompetence) were reported in one infant. In addition to the pregnancy outcomes described above, 23 complications of pregnancy were reported in 20 patients.ConclusionsThis analysis showed that adalimumab treatment in patients with CD, who became pregnant whilst participating in the PYRAMID registry, contributed no additional adverse effects during the pregnancy course or on pregnancy outcomes.

Abstract Background and Aims The Phase 3 study ENVISION I demonstrated efficacy and safety of adalimumab in paediatric patients with moderate to severe ulcerative colitis. The protocol-specified high-dose adalimumab regimen was numerically more efficacious than the standard-dose regimen. The objective of this work was to bridge a fixed-dosing regimen to the protocol-specified high-induction/high-maintenance, body weight-based dosing regimen studied in ENVISION I, using a pharmacometrics modelling and simulation approach. Methods A stepwise strategy was implemented, including developing an adalimumab paediatric population pharmacokinetic model; using this model to determine a fixed-dosing regimen in paediatric ulcerative colitis patients which achieves similar concentrations to those observed in ENVISION I patients; determining adalimumab exposure-response relationship using population pharmacokinetic/pharmacodynamic model and data from ENVISION I; simulating clinical remission rate in paediatric ulcerative colitis patients using the Markov exposure-response model and the dosing regimen determined to provide similar efficacy to that observed in ENVISION I. Results Both developed population pharmacokinetic and pharmacokinetic/pharmacodynamic models adequately described the observed data. Adalimumab exposure was identified as a significant predictor of clinical remission at Week 8 based on logistic regression [p <0.01]. Simulated efficacy suggested that the fixed-dosing regimen performs similarly to the more efficacious dosing regimen used in ENVISION I, by providing comparable clinical remission per Partial Mayo Score response rates over time. No relationship between adalimumab exposure and adverse events was identified. Conclusions The population pharmacokinetic/pharmacodynamic model supports the appropriateness of the use of the fixed-dosing regimen in the paediatric ulcerative colitis population.

Abstract Background PYRAMID was an international multicenter, noninterventional, postmarketing registry assessing long-term safety and effectiveness of adalimumab (Humira), as used in routine clinical practice. Methods Adult patients with moderately to severely active Crohn’s disease with or without prior adalimumab experience were enrolled in the registry and followed for up to 6 years. Effectiveness measurements included the Physician’s Global Assessment (PGA, a composite of Harvey Bradshaw Index [HBI] and rectal bleeding score), clinical remission (HBI < 5), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and Work Productivity and Activity Impairment (WPAI) questionnaire. Data were reported for adalimumab-naïve patients and analyzed by baseline immunomodulator use and disease duration. Results This study evaluated 2057 adalimumab-naïve patients. Mean PGA improved from 7.5 (baseline) to 3.9 (year 1) and 3.3 (year 6). The proportion of patients in HBI remission increased from 29% (573 of 1969; baseline) to 68% (900 of 1331; year 1) and 75% (625 of 831; year 6). Patients stratified by baseline immunomodulator use had similar HBI remission rates; patients with disease duration <2 years achieved numerically higher HBI remission rates than patients with longer disease duration. Patient-reported SIBDQ and WPAI scores improved at year 1; all WPAI subscore improvements were clinically meaningful (≥7% point change) at year 1 and maintained through year 6. Serious infections were reported in 11.1% of patients; incidence rates of malignancies, lymphoma, and demyelinating disorders were low. Conclusion Adalimumab therapy, as used in routine clinical practice, improved physician-reported and patient-reported disease outcomes and remission rates for up to 6 years. No new safety signals were observed.