Introduction
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus with increasing incidence across all age groups and limited treatment options for pediatric patients. Recently, a novel budesonide oral suspension (BOS) was shown in a phase 2/3 trial to be superior to placebo for inducing both histological remission and clinical response after 12 weeks of treatment in EoE patients ages 2 to 17 years. Here, we report endoscopic and esophageal distensibility outcomes from two sequential 12-week induction phases.
Aims & Methods
PEDEOS-1 was a phase 2/3 pivotal trial of BOS with a 12-week randomized, placebo-controlled, double-blind induction (DB) phase, followed by a 12-week open-label induction (OLI) phase for patients who did not achieve response in the DB phase, and finally a 24-week open-label extension phase. EoE patients ages of 2 to 17 were randomly assigned in a 1:1:1 ratio to an age-adapted high-dose BOS regimen, low-dose BOS regimen, or placebo in the DB phase. All patients in the OLI phase received BOS-H. Endoscopies were performed at the start and end of both phases. Histological and endoscopic endpoints included peak eosinophil (eos) counts per mm2 high-power field (hpf), EoE Endoscopic Reference Score (EREFS), EoE Histological Stage Score (EoEHSS) grade and stage scores, and esophageal diameter measured by Endoluminal Functional Lumen Imaging Probe (EndoFLIP).
Results
A total of 76 patients (ages 2-11 y: n=35; 12-17 y: n=41) enrolled in the trial, and 45 patients (2-11 y: 22; 12-17 y: 23) participated in the OLI phase. At week 12 of the DB phase, peak eos/mm2 hpf decreased by -229 with BOS-H, -170 with BOS-L, and -8 with placebo (p<0.0001 for both groups vs. placebo, Table 1). Among patients who proceeded to the OLI phase, changes in peak eos were -27 for prior BOS-H patients, -124 for prior BOS-L patients, and -221 for placebo patients. Similar dose-dependent decreases were observed in the EoEHSS stage and grade scores. Total EREFS scores improved to a similar extent with BOS-H and BOS-L during the DB phase, with further improvements over the 12-week OLI phase. In the subgroup of patients evaluated for esophageal distensibility by EndoFLIP measurement, esophageal diameter increased by 1.4 mm with BOS-H, 0.2 mm with BOS-L, and decreased by -1.2 mm with placebo during the 12-week DB phase.
1 p-values were only calculated for the change in peak eos during the DB phase
2 DB phase baseline or OLI phase baseline, respectively
|
| Double-Blind induction (DB, 12 weeks)
| Open-Label Induction (OLI, 12 weeks)
|
| BOS-H
(n=26)
| BOS-L
(n=26)
| Placebo
(n=24)
| BOS-H >
BOS-H
(n=8)
| BOS-L >
BOS-H
(n=14)
| Placebo >
BOS-H
(n=23)
|
Peak eos/mm² hpf
Mean (SD) at baseline1
Mean (SD) at week 12 (LOCF)
Mean change from baseline to week 12 (LOCF)
p-value vs. placebo1
|
238 (123.1)
10 (40.4)
-229
p<0.0001
|
246 (108.7)
76 (153.1)
-170
p<0.0001
|
239 (122.1)
228 (155.6)
-8
|
36 (74.0)
7 (20.1)
-27
|
140 (188.0)
16 (46.7)
-124
|
228 (155.6)
24 (83.9)
-221
|
EoEHSS grade score
Mean (SD) at baseline2
Mean (SD) at week 12 (LOCF)
Mean change from baseline to week 12 (LOCF)
|
0.50 (0.16)
0.10 (0.12)
-0.41 (0.19)
n=25
|
0.50 (0.14)
0.23 (0.24)
-0.27 (0.31)
|
0.55 (0.16)
0.50 (0.13)
-0.06 (0.18)
n=22
|
0.17 (0.19)
0.03 (0.05)
-0.14 (0.17)
n=7
|
0.37 (0.28)
0.12 (0.24)
-0.25 (0.29)
|
0.49 (0.13)
0.10 (0.12)
-0.41 (0.16)
n=22 |
EoEHSS stage score
Mean (SD) at baseline2
Mean (SD) at week 12 (LOCF)
Mean change from baseline to week 12 (LOCF)
|
0.50 (0.13)
0.12 (0.13)
-0.38 (0.16)
n=25
|
0.50 (0.09)
0.21 (0.25)
-0.28 (0.28)
|
0.53 (0.13)
0.49 (0.12)
-0.05 (0.14)
n=20
|
0.23 (0.17)
0.04 (0.06)
-0.18 (0.18)
n=7
|
0.36 (0.28)
0.09 (0.17)
-0.27 (0.27)
|
0.49 (0.12)
0.11 (0.16)
-0.40 (0.16)
n=22
|
EREFS total score
Mean (SD) at baseline2
Mean (SD) at week 12 (LOCF)
Mean change from baseline to week 12 (LOCF)
|
3.2 (1.0)
0.9 (1.2)
-2.2 (1.5)
n=23
|
3.6 (1.4)
1.2 (1.3)
-2.4 (1.7)
n=25 |
3.2 (1.8)
3.5 (1.6)
0.4 (2.0)
n=22
|
1.9 (1.6)
0.9 (1.0)
-1.1 (0.9)
n=7
|
1.9 (1.4)
0.8 (1.1)
-1.1 (1.7)
|
3.5 (1.6)
0.7 (0.9)
-3.0 (1.7)
n=22
|
Esophageal distensibility (mm)
Mean at baseline2
Mean at week 12 (LOCF)
Mean change from baseline to week 12 (LOCF)
|
16.2
17.6
1.4
n=5
|
15.5
15.9
0.2
n=7 |
16.3
15.1
-1.2
n=5
|
|
|
|
Conclusion
Improvement in histological and endoscopic parameters as well as esophageal distensibility was achieved in pediatric EoE patients after 12 weeks of treatment with BOS-H and BOS-L, but not with placebo. Greater decreases in histological parameters were observed with BOS-H compared to BOS-L. An additional 12 weeks of open-label BOS-H therapy further improved outcomes in BOS patients with insufficient response during the initial 12-week double-blind therapy. These results suggest that treatment outcome may be further improved beyond 12 weeks of therapy.
Disclosure
AP reports grants from Dr. Falk Pharma GmbH, United Pharmaceuticals, AbbVie and Takeda as well as consulting fees from Dr. Falk Pharma GmbH and speaking fees from Uni‐Pharma Pharmaceuticals Laboratories S.A., Cross Pharmaceuticals, Petsiavas S.A., Nestle, Touch Independent Medical Education, Sanofi-Regeneron Pharmaceuticals and SYN Innovation Laboratories. CG received funding from Dr. Falk Pharma GmbH. NZ received consulting fees from Astra Zeneca, Sanofi-Regeneron and Rafa Inc. as well as speaking fees from Sanofi-Regeneron and Rafa IncSB received speaking fees from Danone, Nutricia, FomF, HiPP, Infectopharm and Nestlé Nutrition Institute and reports advisory board participation for Danone, Dr. Falk Pharma GmbH and Infectopharm. SB and RM are employees of Dr. Falk Pharma. AJL reports consulting fees from Dr. Falk, Esocap; research support from Arena, AstraZeneca, Dr. Falk, EsoCap, Regeneron, Sanofi. JAD reports speaker fees from Capricare, Danone, Ferrer, Takeda; consulting fees from Adacyte. All other authors declare no conflicts of interest.