White Paper AGA: Drug Development for Eosinophilic Esophagitis

Hirano, Ikuo; Spechler, Stuart J.; Furuta, Glenn T.; Dellon, Evan S.

doi:10.1016/j.cgh.2017.03.016

Cited by 37 publications

(39 citation statements)

References 97 publications

(108 reference statements)

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“…Several barriers to efficient drug development in EoE exist. 6 Importantly, there is a lack of standardized outcome measures for use in registration trials that can support labelling claims. The FDA mandates that "clinically meaningful" endpoints that measure the way patients feel, function, and survive be used.…”

Section: Discussionmentioning

confidence: 99%

“…Functional lumen imaging probe (FLIP) uses impedance planimetry to quantify esophageal distention. 6 Lower distensibility plateaus (DPs) are associated with food bolus impaction and the need for esophageal dilation. 45 In contrast, dietary and medical therapies have been demonstrated to improve DPs, and this reduction correlates with better symptomatic outcomes.…”

Section: Discussionmentioning

confidence: 99%

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Heterogeneity in Clinical, Endoscopic, and Histologic Outcome Measures and Placebo Response Rates in Clinical Trials of Eosinophilic Esophagitis: A Systematic Review

Rhijn

Jairath

et al. 2018

Clinical Gastroenterology and Hepatology

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Heterogeneity in Clinical, Endoscopic, and Histologic Outcome Measures and Placebo Response Rates in Clinical Trials of Eosinophilic Esophagitis: A Systematic Review

Rhijn

Jairath

et al. 2018

Clinical Gastroenterology and Hepatology

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“…It is not clear whether the differences in clinical presentation are related to the developmental stage of the child, the ability to cope with the underlying problem, or the lack of recognition by caregivers. These types of differences may necessitate a variety of types of validated patient‐/proxy‐reported outcome measures to assess for PD efficacy in children of different ages, thereby complicating extrapolation …”

Section: Extrapolation Of Clinical Outcomes As Pd End Pointsmentioning

confidence: 99%

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development

Conklin

Hoffman

Anker

2019

The Journal of Clinical Pharma

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Challenges in pediatric drug development include small patient numbers, limited outcomes research, ethical barriers, and sparse biosamples. Increasingly, pediatric drug development is focusing on extrapolation: leveraging knowledge about adult disease and drug responses to inform projections of drug and clinical trial performance in pediatric subpopulations. Pharmacokinetic‐pharmacodynamic (PK‐PD) modeling and extrapolation aim to reduce the numbers of patients and data points needed to establish efficacy. Planning for PK‐PD and biomarker studies should begin early in the adult drug development program. Extrapolation relies on the assumption that both the underlying disease and the mechanism of action of the drug used to treat that disease are similar in adults and pediatric subpopulations. Clearly, developmental changes in PK and PD need to be considered to enhance the quality of PK‐PD modeling and, therefore, increase the success of extrapolation. This article focuses on the influence of differences in PD between adults and pediatric subpopulations that are highly relevant for the use of extrapolation.

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“…9 Currently, there are no US Food and Drug Administration (FDA)approved pharmacologic treatments for EoE, so all pharmaceutical treatments are currently being used off-label. 10 Elimination diets are considered a first-line treatment option for EoE but can adversely affect meal-related quality of life and have demonstrated limited sustained adherence in some studies. 11,12 Common first-line treatments for EoE are swallowed topical corticosteroids, such as fluticasone propionate or budesonide.…”

Section: Introductionmentioning

confidence: 99%

Randomised clinical trial: the safety and tolerability of fluticasone propionate orally disintegrating tablets versus placebo for eosinophilic oesophagitis

Hirano

Safroneeva

Roumet

et al. 2020

Aliment Pharmacol Ther

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Summary Background APT‐1011, a fluticasone propionate orally disintegrating tablet formulation, is under investigation for the treatment of eosinophilic oesophagitis (EoE). Aims To evaluate the safety and tolerability of APT‐1011 administered to patients with EoE and to assess the effect on clinical symptoms of EoE, endoscopic appearance and oesophageal eosinophilia. Methods A randomised, double‐blind, placebo‐controlled, multicentre, phase 1b/2a study was conducted at seven medical centres in the US to evaluate the safety and tolerability of APT‐1011 over 8 weeks in adults and adolescents with EoE. Participants were randomised to placebo (n = 8), 1.5 mg APT‐1011 BID (n = 8) or 3.0 mg APT‐1011 QD (n = 8). Safety and tolerability were assessed as the primary outcome; histologic and endoscopic measures were assessed as exploratory outcomes. Results There were no deaths, serious treatment‐emergent adverse events (TEAEs), severe TEAEs or discontinuations from the study related to a TEAE. In one participant randomised to 1.5 mg APT‐1011 BID, a reduction in cortisol was observed, but without evidence of adrenal insufficiency. Compared with placebo, treatment with APT‐1011 resulted in greater reductions in oesophageal eosinophil counts, EoE Endoscopic Reference Score, patient global assessment and symptom‐based EoE activity index from baseline to end of treatment (Week 8). Conclusions APT‐1011 was safe and well tolerated in adolescents and adults with EoE. Exploratory efficacy outcomes demonstrated improvement in histologic and endoscopic findings as well evidence of symptom improvement. The results of this study support the continued development of APT‐1011 for the treatment of EoE (NCT‐01386112).

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White Paper AGA: Drug Development for Eosinophilic Esophagitis

Cited by 37 publications

References 97 publications

Heterogeneity in Clinical, Endoscopic, and Histologic Outcome Measures and Placebo Response Rates in Clinical Trials of Eosinophilic Esophagitis: A Systematic Review

Heterogeneity in Clinical, Endoscopic, and Histologic Outcome Measures and Placebo Response Rates in Clinical Trials of Eosinophilic Esophagitis: A Systematic Review

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development

Randomised clinical trial: the safety and tolerability of fluticasone propionate orally disintegrating tablets versus placebo for eosinophilic oesophagitis

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