Introduction
Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease with substantial impact on quality of life, and increasing incidence and prevalence. Dupilumab, a fully human monoclonal antibody, blocks IL-4 and IL-13, central drivers of type 2 inflammation, and is approved in the US and EU for the treatment of EoE.
Aims & Methods
We aimed to assess the effect of dupilumab on EoE outcomes in subgroups of patients from the Phase 3 LIBERTY EoE TREET (NCT03633617) study categorized by weight or body mass index (BMI).
Data were pooled from patients in Parts A and B who received dupilumab 300 mg or placebo qw (weekly) for 24 weeks (W24). The proportion of patients achieving ≤6 or <15 eosinophils per high-power field (eos/hpf), absolute change in Dysphagia Symptom Questionnaire (DSQ) score, mean change in Endoscopic Reference Score (EREFS), and Histologic Scoring System (HSS) grade/stage scores were assessed. Outcomes were compared between pre-specified weight (<60kg and ≥60kg) and BMI groups (<25kg/m2, ≥25–<30kg/m2, and ≥30kg/m2). As this is a post hoc analysis, all p-values are nominal.
Results
122 patients received dupilumab and 118 placebo. At baseline, subgroups comprised: Weight <60kg (N=51) and ≥60kg (N=189); BMI <25kg/m2 (N=121), ≥25–<30kg/m2 (N=73), and ≥30kg/m2 (N=46). Baseline demographics and disease characteristics were generally similar across subgroups. Dupilumab was efficacious regardless of baseline weight. At W24 dupilumab treatment resulted in a greater proportion of patients achieving ≤6 eos/hpf compared with placebo (weight <60kg 47% vs 5%, p=0.0031, ≥60kg 63% vs 6%, p<0.0001), and improved DSQ score (LS mean difference [LSMD] [95% CI]: weight <60kg –8.74 [–18.77, 1.30], p=0.0878, ≥60kg –10.36 [–14.57, –6.15], p<0.0001). Dupilumab-treated patients improved at W24 vs placebo in EREFS total score (LSMD [95% CI]: –2.47 [–3.89, –1.06], p=0.0006, –3.66 [–4.50, –2.81], p<0.0001), and HSS mean grade (–0.608 [–0.837, –0.380], p<0.0001, –0.737 [–0.839, –0.636], p<0.0001) and stage scores (–0.588 [–0.811, –0.365], p<0.0001, –0.730 [–0.826, –0.633], p<0.0001). Furthermore, dupilumab treatment resulted in a greater proportion of patients achieving <15 eos/hpf compared with placebo (weight <60kg 70% vs 10%, p=0.0006, ≥60kg 78% vs 7%, p<0.0001). Similar results were observed across BMI subgroups (Table).
Table: EoE endpoints in patients categorized by weight or BMI at Week 24
| Weight <60kg | Weight ≥60kg | BMI <25kg/m2 | BMI ≥25–<30kg/m2 | BMI ≥30kg/m2 |
| Endpoint (95% CI) | PBO
N=21 | DUP
N=30 | PBO
N=97 | DUP
N=92 | PBO
N=57 | DUP
N=64 | PBO
N=37 | DUP
N=36 | PBO
N=24 | DUP
N=22 |
| % pts with peak eosinophil count ≤6 eos/hpf | 4.8
(0.1, 23.8) | 46.7
(28.3, 65.7) | 6.2
(2.3,
13.0) | 63.0
(52.3, 72.9) | 3.5
(0.4, 12.1) | 56.3
(43.3, 68.6) | 5.4
(0.7, 18.2) | 61.1
(43.5, 76.9) | 12.5
(2.7, 32.4) | 63.6
(40.7, 82.8) |
| LS mean change from baseline in DSQ score | –18.0
(–26.6, –9.4) | –26.7
(–33.6, –19.9) | –10.8
(–14.5, –7.2) | –21.2
(–24.8, –17.6) | –15.0
(–19.5, –10.4) | –22.8
(–27.0, –18.7) | –11.0
(–16.7, –5.4) | –21.1
(–27.1, –15.0) | –5.2
(–14.7, 4.4) | –19.1
(–28.8, –9.5) |
| LS mean change from baseline in EREFS total score | –1.75
(–2.95, –0.55) | –4.22
(–5.26, –3.19) | –0.25
(–1.00, 0.49) | –3.91
(–4.64, –3.18) | –0.37
(–1.18, 0.44) | –4.19
(–4.99, –3.39) | –0.56
(–1.59, 0.46) | –3.92
(–5.01, –2.84) | –0.31
(–2.78, 2.15) | –3.23
(–5.68, –0.77) |
| LS mean change from baseline in HSS mean grade score | –0.207
(–0.400, –0.013) | –0.815
(–0.976, –0.654) | –0.053
(–0.142, 0.037) | –0.790
(–0.877, –0.703) | –0.109
(–0.209, –0.010) | –0.848
(–0.946, –0.749) | –0.124
(–0.262, 0.014) | –0.771
(–0.917, –0.625) | 0.055
(–0.228, 0.337) | –0.674
(–0.950, –0.397) |
| LS mean change from baseline in HSS mean stage score | –0.192
(–0.383, –0.002) | –0.780
(–0.939, –0.622) | –0.034
(–0.120, 0.051) | –0.764
(–0.848, –0.681) | –0.100
(–0.199, –0.001) | –0.811
(–0.909, –0.714) | –0.075
(–0.203, 0.054) | –0.721
(–0.858, –0.584) | 0.061
(–0.195, 0.316) | –0.658
(–0.907, –0.410) |
| % pts with peak eosinophil count <15 eos/hpf | 9.5
(1.2, 30.4) | 70.0
(50.6, 85.3) | 7.2
(3.0, 14.3)
| 78.3
(68.4, 86.2) | 7.0
(2.0, 17.0) | 76.6
(64.3, 86.3) | 5.4
(0.7, 18.2) | 72.2
(54.8, 85.8) | 12.5
(2.7, 32.4) | 81.8
(59.7, 94.8) |
BMI, body mass index; CI, confidence interval; DSQ, Dysphagia Symptom Questionnaire; DUP, dupilumab; EREFS, Endoscopic Reference Score; eos, eosinophils; hpf, high-powered field; HSS, Histologic Scoring System; LS, least squares; PBO, placebo; pts, patients.
Conclusion
Patients with EoE improved in measures of histology, symptoms, and endoscopy, including an increased proportion achieving peak esophageal intraepithelial eosinophil count ≤6 and <15, along with reductions in DSQ score, HSS grade and stage scores, and EREFS total score at W24 with dupilumab 300 mg qw vs placebo regardless of baseline weight or BMI. Dupilumab was well tolerated, and the safety profile was similar to the overall treatment population.
Disclosure
Hirano I: Allakos, Pfizer/Arena Pharmaceuticals, Aslan, AstraZeneca, Calyx/Parexel, Ellodi/Adare Pharma Solutions, EsoCap, Gossamer Bio, Phathom, Nexstone Immunology, Receptos/BMS, Sanofi/Regeneron Pharmaceuticals Inc., Shire/Takeda – consultant; Adare Pharma Solution, Allakos, AstraZeneca, Pfizer/Arena, Meritage Pharma, Receptos/BMS, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding; Sanofi/Regeneron Pharmaceuticals Inc. – speaking.
Chehade M: Adare Pharma Solutions, Allakos, AstraZeneca, BMS, Phathom, Recludix Pharma, Regeneron Pharmaceuticals Inc., Sanofi, Shire/Takeda – consultant; Adare Pharma Solutions/Ellodi Pharmaceuticals, Allakos, AstraZeneca, Danone, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding.
Dellon ES: Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron Pharmaceuticals Inc., Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio– consultant; Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron Pharmaceuticals Inc., Revolo, Shire/Takeda – research funding; Allakos, Holoclara, Invea– educational grant.
Schoepfer AM: Adare Pharma Solutions, Aptalis, Dr. Falk – consultant; AstraZeneca, Aptalis, Dr. Falk, GSK, Nestlé, Novartis, Receptos/BMS, Regeneron Pharmaceuticals Inc. – research funding.
Xia C, Shabbir A: Regeneron Pharmaceuticals Inc. – employees and shareholders.
Glotfelty L: Sanofi – employees, may hold stock and/or stock options in the company.
