Randomised Clinical Trial

The Safety and Tolerability of Fluticasone Propionate Orally Disintegrating Tablets Versus Placebo for Eosinophilic Oesophagitis

Ikuo Hirano; Ekaterina Safroneeva; Marie C. Roumet; Gail M. Comer; Gina Eagle; Alain Schoepfer; Gary W. Falk

Disclosures

Aliment Pharmacol Ther. 2020;51(8):750-759. 

In This Article

Abstract and Introduction

Abstract

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).

Introduction

Although currently classified as an orphan disease, eosinophilic oesophagitis (EoE) is an increasingly prevalent atopic condition characterised by symptoms of oesophageal dysfunction and infiltration of eosinophils into the oesophageal mucosa.[1–4] Untreated EoE can progress from inflammation to a mix of inflammatory and fibrostenotic disease with oesophageal remodelling that manifests by subepithelial fibrosis, oesophageal stricture formation and reduced oesophageal distensibility.[5–8] In the United States (US) and several countries in Western Europe, EoE is now recognised as a leading cause of dysphagia and food impaction in adults.[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.[1,13,14] In clinical practice in the US, the available aerosolised or nebulised corticosteroids, designed for airway delivery, are ingested by patients. Alternatively, liquid preparations of topical corticosteroids, designed for nebuliser use, have been mixed into a viscous slurry and swallowed by patients.[3,15] While the initial results of swallowed aerosolised corticosteroid treatment for EoE have demonstrated efficacy, variation in dose, administration technique and/or compliance can affect the outcomes of therapy.[3] In addition, administration of swallowed aerosolised topical corticosteroids may be suboptimal for treatment of EoE, as the aerosolised preparation is delivered to both the lungs and the oesophagus.[16] Oral drug delivery and formulation can also have an effect on relevant outcomes, such as complete histologic remission, as seen with a swallowed viscous liquid vs a swallowed, nebulised preparation of budesonide (64% vs 27%).[16]

APT-1011 is a fluticasone propionate tablet that dissolves in the mouth and is swallowed without liquids. APT-1011 was developed to specifically address the unmet therapeutic need for EoE. The objectives of this proof-of-concept study were to evaluate the safety and tolerability of two dosing regimens of APT-1011 administered orally to patients with EoE and to assess the effect of APT-1011 on clinical symptoms of EoE, endoscopic appearance and oesophageal mucosal eosinophil count.

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