Introduction
Eosinophilic esophagitis (EoE) is a chronic, progressive, immune-mediated inflammatory disease characterized by esophageal inflammation with infiltration of eosinophils (eos) and symptoms of esophageal dysfunction. Interleukin (IL)-13, a type 2 inflammatory cytokine, plays a key role in the pathophysiology of EoE. Cendakimab (CEN) is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody targeting IL-13, inhibiting binding to both its receptors, IL-13Rα1 and IL-13Rα2. CEN reduced mean esophageal eos counts and improved symptoms and endoscopic features of EoE in a phase 2 study. We report results from a pivotal phase 3 trial (NCT04753697) of CEN in adult and adolescent patients (pts) with EoE after 24 wk of treatment.
Aims & Methods
This multicenter, multinational, randomized, double-blind, placebo (PBO)-controlled study enrolled pts aged 12–75 y with active EoE (peak esophageal eos count [PEC] ≥ 15 eos/high power field [hpf] at any 2 levels of the esophagus), ≥ 4 dysphagia days (DD) over the 14-day period prior to day 1 evaluated using the modified Daily Symptom Diary (mDSD), and lack of complete response to ≥ 8 wk proton pump inhibitor treatment. The study planned to enroll ~70% of pts who were steroid inadequate responders or intolerant (steroid IR/I). Pts were randomized 1:1:1 to receive subcutaneous CEN 360 mg weekly for 48 wk (QW/QW), CEN 360 mg QW for 24 wk followed by CEN 360 mg every other wk for 24 wk (QW/Q2W), or PBO QW for 48 wk. Coprimary endpoints were mean change from baseline (BL) to wk 24 in DD and proportion of pts with eos histologic response, defined as PEC ≤ 6/hpf at wk 24. Key secondary endpoints included eos histologic response < 15/hpf at wk 24, endoscopic response (mean change in Endoscopic Reference Score [EREFS] total score), mean change in EoE Histology Scoring System (EoEHSS) grade/stage score, and mean change in mDSD composite score, from BL to wk 24. Safety was also evaluated.
Results
Overall, 430 pts (~66% steroid IR/I) were randomized to CEN (n = 286; QW/QW, n = 143, QW/Q2W, n = 143), or PBO (n = 144). In pts treated with CEN 360 mg QW, there was a statistically significant reduction from BL to wk 24 in DD vs PBO (−6.1 vs −4.2 days; difference [95% CI] vs PBO: −1.9 [−3.0 to −0.8]; P = 0.0005) and a statistically significantly higher proportion of pts with eos histologic response at wk 24 vs PBO (28.6% vs 2.2%; difference [95% CI] vs PBO: 26.4 [20.6 to 32.2]; P < 0.0001) (Table). Statistically significant improvements in all key secondary endpoints were observed for CEN-treated vs PBO-treated pts (Table). At wk 24, adverse events (AE) related to study drug occurred in 30.3% and 18.9% of pts in the CEN and PBO arms, with AEs leading to discontinuation in 1.4% and 0.7% of pts, respectively. No deaths occurred.
Table. Efficacy results at wk 24
| | Treatment | CEN 360 mg QW (n = 286) | PBO QW (n = 144) | Difference (95% CI); P value |
| Coprimary endpoints | LS mean change from baseline in DD | −6.1 | −4.2 | −1.9 (−3.0 to −0.8); P = 0.0005 |
| Patients with eos histologic response (≤ 6/hpf), % | 28.6 | 2.2 | 26.4 (20.6 to 32.2); P < 0.0001 |
Key secondary endpoints | Patients with eos histologic response (< 15/hpf), % | 43.1 | 3.1 | 40.0 (33.3 to 46.7); P < 0.0001 |
| LS mean change in EREFSa total score | −5.2 | −1.2 | −4.0 (−4.8 to −3.2); P < 0.0001 |
| LS mean change in EoEHSS grade score | −26.2 | −3.7 | −22.5 (−25.5 to −19.5); P < 0.0001 |
| LS mean change in EoEHSS stage score | −31.7 | −6.3 | −25.4 (−28.9 to −21.9); P < 0.0001 |
| LS mean change in mDSD composite score | −12.8 | −8.7 | −4.1 (−6.4 to −1.8); P = 0.0005 |
aEREFS is a validated approach for assessing the presence and severity of the major endoscopic features of EoE. EREFS were scored on a 0-8 point scale (edema [0–1], rings [0–3], exudates [0–2], furrows [0–1], and stricture [0–1]) at 3 levels of the esophagus (proximal, mid, and distal), with total score range of 0–24. LS, least squares. |
Conclusion
Treatment with CEN demonstrated statistically significant improvement in symptoms and histologic and endoscopic features of EoE vs PBO. CEN was generally safe and well-tolerated through wk 24.
Disclosure
AS has served a consultant for Adare/Ellodi, AbbVie, AstraZeneca, Celgene/Receptos/Bristol Myers Squibb, Dr. Falk Pharma, Gossamer Bio, GSK, Janssen, MSD, Pfizer, Regeneron/Sanofi, Takeda, and Vifor; and has received grant/research support from Adare/Ellodi, Celgene/Receptos/Bristol Myers Squibb, GSK, and Regeneron/Sanofi. CMC, SZ, KL, AV, AY, and YSO are employees and shareholders of Bristol Myers Squibb. CLZ is a contractor to Bristol Myers Squibb. ESD has served as a consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Bryn, Calypso, Celgene/Receptos/Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; has received grant/research support from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Revolov, and Shire/Takeda; and has received educational grants from Allakos, Aqilion, Holoclara, and Invea. GF has served as a consultant for Adare/Ellodi, Allakos, Celgene/Receptos/Bristol Myers Squibb, LucidDx, Nexstone Immunology/Uniquity, Phathom, Regeneron/Sanofi, Shire/Takeda, and Upstream Bio; has received grant/research support from Adare/Ellodi, Allakos, Arena/Pfizer, Celldex, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Sanofi, Revolov, and Shire/Takeda. CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Ferring, Pfizer. HP has served as a consultant for Dr. Falk Pharma, Arena/Pfizer, GSK and Abbott. TV is a speaker for Dr. Falk Pharma and Bristol Myers Squibb; consultancy for Dr. Falk Pharma, Bristol Myers Squibb; research grant from Dr. Falk Pharma. SO has served a consultant for Dr. Falk Pharma, Medtronic, Regeneron/Sanofi, Celgene/Receptos/Bristol Myers Squibb; and has received grant/research support from Medtronic, Regeneron/Sanofi, Alfasigma.