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SAN ANTONIO -- More than half of patients with eosinophilic esophagitis (EoE) had objective responses to treatment with an oral formulation of a topical corticosteroid, a randomized, placebo-controlled trial showed.

After 12 weeks of treatment budesonide oral suspension (BOS), 53.1% of patients had histologic response (defined by reduced eosinophil count), and 52.6% had symptomatic response (defined by improvement in dysphagia). Only 1% of patients assigned to placebo achieved a histologic response, and significantly fewer patients met criteria for symptom response.

Analyses of secondary endpoints showed consistent, statistically significant advantages in favor of BOS, reported Ikuo Hirano, MD, of Northwestern University Feinberg School of Medicine in Chicago, at the American College of Gastroenterology meeting.

"This is the first phase III trial to demonstrate symptom efficacy using the validated DSQ (Dysphagia Symptom Questionnaire), the first completed phase III trial of a medical therapy for EoE in the United States, and the largest clinical trial for EoE conducted to date," said Hirano. "The results of this trial support the ongoing development of swallowed topical corticosteroids optimized for esophageal delivery in EoE. A 36-week, double-blind, placebo-controlled maintenance study is ongoing."

EoE and Steroids

EoE is a chronic, associated with esophageal eosinophilia and esophageal dysfunction. If left untreated for an extended period of time, EoE can progress to a fibrostenotic phenotype, which is associated with stricture formation and food impaction. Swallowing corticosteroids developed for asthma has become a common approach to EoE in the U.S., with demonstrated histologic efficacy in .

BOS is a muco-adherent liquid formation of the topical corticosteroid budesonide and was developed specifically for treatment of EoE, said Hirano. Two phase II, placebo-controlled trials, one involving and the other , demonstrated significant histologic improvement in both trials and significant symptomatic improvement in the study of adolescents and adults.

The positive phase II results led to a phase III placebo-controlled trial involving adolescents and adults with EoE. Investigators enrolled patients, ages 11 to 55 years, with peak count ≥15 eosinophils per high-powered field (eos/hpf) from at least two levels of the esophagus (proximal, mid-level, and/or distal); solid-food dysphagia on at least 4 days within the previous 2 weeks; and at least a 6-week trial of high-dose proton pump inhibitor (PPI) treatment to exclude patients with PPI-responsive EoE.

Patients were randomized 2:1 to BOS or placebo, and the trial had coprimary endpoints, both assessed after 12 weeks of randomized therapy: histologic response (≤6 eos/hpf) and symptom response (≥30% reduction in the Dysphagia Symptom Questionnaire, DSQ). The key secondary efficacy endpoint was change in DSQ score from baseline to week 12.

Data analysis included 318 patients, who had a mean age of 33 to 34 and a mean BMI of 27-28. Hirano reported that about a fourth of the patients had undergone prior dietary therapy, about 30% had received budesonide suspension, a third had received aerosolized fluticasone, about 7% had been treated with systemic corticosteroids, and about 40% had undergone endoscopy with dilation.

The study population had a peak overall eosinophil count of about 75 eos/hpf, including about 40 eos/hpf in the proximal esophagus, 56 in both the mid- and distal esophagus. Baseline DSQ score averaged about 30.

Key Results

The 12-week results showed that significantly more patients in the BOS group achieved histologic response as compared with the placebo group (P<0.001). Symptom response also occurred significantly more often with BOS (52.6% vs 39.1%, P=0.024). The absolute change in DSQ score from baseline to 6 weeks favored budesonide (-13.0 vs -9.1, P=0.015), as did the absolute change in EoE Endoscopic Reference Score (-4.0 vs -2.2, P<0.001).

Analysis of other secondary endpoints showed significantly greater improvement with budesonide for:

• Histologic response ≤1 eos/hpf: 32.4% vs 0.0% (P=0.001)
• Histologic response <15 eos/hpf: 62.0% vs 1.0% (P<0.001)
• Decline in overall peak eosinophil count: -55.2 vs - 7.6 (P<0.001)

Treatment-emergent adverse events (TEAEs) occurred in a similar proportion of patients in each group, and most of the events were mild or moderate in severity, said Hirano. No serious TEAEs or deaths occurred in either group. Infections occurred in 24.2% of the study population, 20% of the placebo group and 26.3% of the BOS group. Nasopharyngitis, sinusitis, candidiasis, and upper respiratory tract infection occurred in a similar proportion of patients in the two groups.

Adrenocorticotropic hormone testing for adrenal insufficiency showed a reduction in peak cortisol levels (≤18 µg/dL) in 8.2% of patients in the BOS arm and 3.6% of the placebo group.

The discussion that followed the presentation included a "what if" question about the study population and the observed benefits of BOS.

"Since these were patients who had been on a PPI before, do you think the response might have been amplified if they had been treated in first line?" asked Philip O. Katz, MD, of Weill Cornell Medicine in New York City. "You had a 53% response rate, which is obviously greater than placebo but still is in the middle. If people had been first line, not treated with PPIs, do you think the response might have been even better?"

Hirano said the known biology of PPI response in EoE would argue against a differential response in treated versus untreated patients.

"It's really an unknown question, but I should mention that the majority of patients in this trial continued on PPI therapy," he said.

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