FLUTICASONE PROPRIONATE ORAL DISINTEGRATING TABLET, APT-1011, IMPROVES FIBROSTENOTIC FEATURES OF STRICTURES AND GRADE 2/3 RINGS IN SUBJECTS WITH EOSINOPHILIC ESOPHAGITIS (EOE)

Background
Esophageal eosinophilic inflammation and remodeling lead to fibrostenosis in many patients with eosinophilic esophagitis (EoE). APT-1011, a novel oral disintegrating tablet of fluticasone propionate, a potent glucocorticoid with <1% bioavailability, was designed to target the esophageal mucosa for broad anti-inflammatory effects. APT-1011 has been shown to improve outcomes in patients with EoE in a phase 2b study (FLUTE). The effect on fibrostenotic features seen in FLUTE was further explored in FLUTE-2, a phase 3 study.

Aim
To evaluate the effect of APT-1011 on the resolution of strictures and improvement of grade 2/3 rings in subjects with EoE and fibrostenotic features at baseline.

Methods
The FLUTicasone in EoE (FLUTE-2) trial was a 2-Part randomized, double-blind, placebo-controlled study of APT-1011 in adults with EoE. Subjects were randomized to 3 mg APT-1011 or placebo at bedtime in Part A (to Week 12). In Part B (to Week 52) subjects received blinded treatment with APT-1011 or placebo depending on histological response (< 6 eosinophils/ high power field) in Part A. (Figure). Exploratory endpoints evaluated improvement of baseline fibrostenotic features after 12 and 52 weeks of treatment. Based on endoscopic assessment by each Investigator, strictures were categorized as present or absent, and rings were graded as 0, 1, 2, or 3 per EoE Endoscopic Reference Score. After 12 weeks of treatment (Cohort 1) pre-specified response rates were defined by absence of stricture and/or improvement of rings to less than Grade 2. Improvement after longer durations of APT-1011 treatment (Cohort 2: 38 weeks; Cohort 3: 52 weeks) and persistence of response (Cohort 4) were analyzed post-hoc (Table). Subjects with strictures not allowing passage of a 9 mm endoscope were excluded from the study.

Results
Of 143 subjects randomized (97 APT-1011; 46 placebo), 34 had strictures, 48 had grade 2/3 rings, 61 had either stricture or grade 2/3 rings and 21 had both at baseline. APT-1011 showed a higher rate of resolution of stricture or improvement of grade 2/3 rings as compared to placebo after 12 weeks of treatment (58.5% vs 25.0%; p=0.015) and higher resolution/improvement in those with both at baseline (50% vs 14.3%; p value=0.176). The improvement of grade 2/3 rings and resolution of strictures showed similar outcomes independently. Longer durations of APT-1011 (i.e., 38 and 52 weeks) showed similar results to 12 weeks of APT-1011 treatment with most subjects showing sustained improvement (Table).

Conclusions
APT-1011 treatment, as compared to placebo, effectively resolved strictures and/or improved grade 2/3 rings for 52 weeks in adult subjects with EoE. The data from this phase 3 study are consistent with outcomes shown in phase 2b. Collectively, these data suggest APT-1011 is a promising treatment for the fibrostenotic complications of EoE.