APT-1011 is an oral disintegrating tablet (ODT) formulation of fluticasone propionate developed by Ellodi/Adare Pharmaceuticals and designed to disintegrate after put on the tongue without water. Then, it is swallowed and coat the esophageal surface.

After providing proof of its efficacy in the treatment of EoE, the results of the international clinical trial FLUTE (Fluticasone in EoE) have been recently published in the Clinical Gastroenterology and Hepatology journal (1). To define the optimal dose of treatment for EoE, a total of 106 adults with active EoE recruited from 6 countries, including the U.S., Canada, Belgium, Switzerland, Spain, and Germany, were randomized 1:1:1:1:1 to 4 APT-1011 regimens or matching placebo. APT1011 regimens included 1.5 mg at bedtime (with placebo after breakfast); 1.5 mg twice daily (BID); 3 mg at bedtime (or hora somni –HS−), with placebo after breakfast; 3 mg twice daily, or placebo (taken at bedtime and after breakfast). Randomization was stratified by current esophageal stricture(s) and a positive response to prior corticosteroid therapy (Figure).

Study design

The primary efficacy outcome was histologic remission (defined as a peak count of less than 6 eosinophils/hpf) at week 12 (Part A). In addition, secondary efficacy outcomes included the proportion of patients with sustained histologic remission at Weeks 26 and 52 (Part 2). Endoscopic severity measured by the change from baseline in the EREFS (Edema / Rings / Exudates / Furrows / Strictures) score along treatment (2), and the percentage of subjects with <1 and <15 eos/hpf throughout the trial (at Weeks 12, 26 and 52) were also measured. As for symptomatic outcomes, change from baseline in the Global EoE Symptom Score at multiple time intervals, the Eosinophilic Esophagitis Activity Index (EEsAI) (3) and patient Global Impression of change, were considered.

All regimes of APT1011 resulted superior to placebo in achieving histologic remission at Week 12: Overall, 80% of patients allocated for 3 mg APT-1011 BID achieved <6 eos/hpf at week 12. This proportion was 67% for 3 mg HS, 86% for 1.5 mg BID, 48% for 1.5 mg HS, and 0% for placebo (P < .001 for all comparisons vs placebo). Histologic remission was maintained among most initial responders at Weeks 26 and 52. Endoscopic features (EREFS) showed greater improvement compared with placebo for all APT-1011 dosing groups. And for symptoms, mean dysphagia frequency showed greater improvement compared with placebo for all APT-1011 dosing groups. However, only the the 3-mg HS APT1011 dose was significantly superior to placebo in term of improvements in the Global EoE Symptom Score. When symptoms were evaluated with the validated EEsAI instrument, significantly greater improvement compared with placebo was demonstrated for the 3.0 mg BID and 3.0 mg HS doses.

Regarding to safety, oral and esophageal candidiasis was observed more frequently in the BID dosing groups, with no events in the APT-1011 1.5-mg HS and placebo groups. For the 3-mg BID group, oral and esophageal candidiasis appeared 40% of patients at Week 12, this proportion reducing at subsequent endoscopic assessments. This proportion was 18% and 16% for the 1.5 mg BID APT1011 dose, and 5% and 7% for 3 mg HS dosing group. No patient presented confirmed adrenal insufficiency throughout the trial.

In this phase 2 trial, the 3-mg at bedtime arm had the most well-balanced efficacy/safety profile for both sustained remission (balancing histologic, symptomatic, and endoscopic data), and absence of oropharyngeal/esophageal candidiasis over 52 weeks of treatment. This dosage is currently being assessed in an ongoing phase 3 study.

Following the results provided by Jorveza, the first orodispersible tablet with a corticosteroid with low bioavailability for the treatment of EoE, APT1011 confirms that orally disintegrating tablets are appropriate methods for effective drug delivery on the esophageal inner surface. The differences in the effectiveness of the various formulations of topic corticosteroids partially rely on how they are dissolved, with viscous formulas still requiring a certain volume, while the orally disintegrating tablets uses the saliva itself secreted by the effervescent stimulus of the tablet. Bearing in mind that the esophagus is a muscular organ with the function of quickly conducting boluses to the stomach and that its capacity is only virtual, a smaller volume of solution (the secreted saliva itself) could represent an additional advance therefore (4).

Author of this summary
Alfredo J Lucendo. Department of Gastroenterology. Hospital General de Tomelloso. Tomelloso, Ciudad Real. Spain.

Read full article
Dellon ES et al. Clin Gastroenterol Hepatol. 2022 Feb 16:S1542-3565(22)00139-2. doi: 10.1016/j.cgh.2022.02.013.

References

Dellon ES, Lucendo AJ, Schlag C, Schoepfer AM, Falk GW, Eagle G, Nezamis J, Comer GM, Knoop K, Hirano I. Fluticasone Propionate Orally Disintegrating Tablet (APT-1011) for Eosinophilic Esophagitis: Randomized Controlled Trial. Clin Gastroenterol Hepatol 2022 Feb 16;S1542-3565(22)00139-2. doi: 10.1016/j.cgh.2022.02.013.

Hirano I, Moy N, Heckman MG, Thomas CS, Gonsalves N, Achem SR. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. Gut 2013;62(4):489-95. doi: 10.1136/gutjnl-2011-301817.

Schoepfer AM, Straumann A, Panczak R, et al. Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis. Gastroenterology 2014 Dec;147(6):1255-66.e21.

Lucendo AJ. Drug treatment strategies for eosinophilic esophagitis in adults. Expert Opin Pharmacother. 2022 Apr 4:1-14. doi: 10.1080/14656566.2022.2060077.