P1355 - The Histological Scoring System and Endoscopic Reference Score Are Complementary Assessments for Characterizing Fibrostenotic or Inflammatory Phenotypes in Patients with Eosinophilic Esophagitis

Monday, October 25, 2021

10:30 AM – 4:15 PM PT

Location: Shoreline Exhibit Hall

Has Audio

Presenting Author(s)

MC

Margaret H. Collins, MD

Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine
Cincinnati, OH, United States

Margaret H. Collins, MD¹, Marc Rothenberg, MD, PhD¹, Albert J. Bredenoord, MD², Joshua Wechsler, MD³, Mirna Chehade, MD, MPH⁴, Zhen Chen, PhD⁵, Ledia Goga, PhD⁶, Benjamin Ortiz, MD⁵, Angela Khodzhayev, ⁵, Juby A. Jacob-Nara, MD, MPH, DHSc⁷, Yamo Deniz, MD⁵, Paul J. Rowe, MD⁷
¹Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH; ²Amsterdam University Medical Center, Amsterdam, Noord-Holland, Netherlands; ³Ann and Robert H. Lurie Children’s Hospital, Chicago, IL; ⁴Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York, NY; ⁵Regeneron Pharmaceuticals, Inc., Tarrytown, NY; ⁶Sanofi, Cambridge, MA; ⁷Sanofi, Bridgewater, NJ

Introduction: Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease of the esophagus. The Histology Scoring System (HSS) assesses severity and extent of histologic features: eosinophil density (ED), basal zone hyperplasia (BZH), eosinophil abscesses (EA), eosinophil surface layering (SL), surface epithelial alteration (SEA), dyskeratotic epithelial cells (DEC), dilated intercellular spaces (DIS), and lamina propria fibrosis (LPF). The Endoscopic Reference Score (EREFS) assesses severity of endoscopic features: edema, exudates, furrows, rings, and strictures. We analyzed if HSS components correlate with inflammatory or remodeling EREFS components in EoE patients receiving placebo in 2 trials — 12-week phase 2 proof-of-concept (POC; NCT02379052) in adults and 24-week part A of the 3-part, phase 3 TREET (P3PA; NCT03633617) in adults and adolescents.

Methods: Proximal, mid, and distal esophagus biopsies were collected at baseline (BL) and end of treatment (EOT) and scored by HSS for grade, stage, and components (higher scores=greater severity). Proximal and distal biopsies were scored by EREFS (higher scores=greater severity). EREFS scores were summed for inflammatory (edema+exudates+furrows) and remodeling (rings+stricture) subscores. Pearson correlation was performed between HSS grade and stage, total and individual components scores with EREFS total and components scores, and subscores at BL and change from BL at EOT (ΔEOT).

Results: Moderate–strong correlations were observed between total EREFS and HSS grade and stage for BL and ΔEOT in POC and BL in P3PA (Table). Moderate correlations were observed between BZH and EREFS remodeling subscore and rings at ΔEOT in P3PA. Correlations between DIS and EREFS inflammation subscore (stage) and edema (grade/stage) were moderate–strong at BL in both studies. Moderate correlations were observed between DIS grade and EREFS remodeling subscore and strictures at both timepoints in POC but not P3PA. Moderate correlations with EREFS inflammation and remodeling subscores and components were observed for both SEA and SL at BL and ΔEOT in POC.

Discussion: Specific components of HSS and EREFS, reflecting inflammatory and remodeling processes, are closely correlated and can aid identification of fibrostenotic or inflammatory phenotypes. Correlations of DIS with endoscopic inflammatory and remodeling features reflect the role of barrier dysfunction in maintaining chronic inflammation that ultimately leads to remodeling.

Table. Correlations between HSS grade and stage, total and component scores with EREFS total, subscores, and components in patients with EoE receiving placebo in the phase 2 POC study and part A of the phase 3 LIBERTY TREET study.

Pearson correlation coefficient	Timepoint	EoE phase 2 POC study (POC) (N = 24)a						EoE P3PA study (N = 39)b
Total HSS gradec x total EREFS^b,d	BL	0.4184						0.4568
Total HSS gradec x total EREFS^b,d	ΔEOT	0.4954						0.1638
Total HSS stagec x total EREFSd	BL	0.3166						0.4703
Total HSS stagec x total EREFSd	ΔEOT	0.5394						0.2905
		POC	P3PA	POC	P3PA	POC	P3PA	POC	P3PA	POC	P3PA	POC	P3PA
		DEC		BZH		DIS		SEA		EA		SL
HSS grade component x EREFS inflammation subscore^e	BL	0.0384	-0.0267	-0.0832	0.1956	0.0124	0.2300	0.1216	0.3872	-	-	-	-
HSS grade component x EREFS inflammation subscore^e	ΔEOT	0.0000	0.3629	0.3670	-0.0019	0.2643	0.1369	0.3502	0.1452	-	-	-	-
HSS stage component x EREFS inflammation subscore	BL	0.0417	-0.0707	-0.0521	0.1981	0.5075	0.3434	0.1109	0.2241	-	-	-	-
HSS stage component x EREFS inflammation subscore	ΔEOT	0.0456	0.2576	0.2833	0.2095	0.2733	0.3012	0.4387	0.1619	-	-	-	-
HSS grade component x EREFS edema score	BL	0.1300	-0.0943	0.2166	0.1402	0.3635	0.3318	0.2027	0.2239	-	-	-	-
HSS grade component x EREFS edema score	ΔEOT	-0.1478	0.1683	0.3277	-0.1837	0.3765	0.0256	0.3087	-0.1451	-	-	-	-
HSS stage component x EREFS edema score	BL	0.1410	-0.1171	0.1714	0.2143	0.6780	0.5039	0.1974	0.2544	-	-	-	-
HSS stage component x EREFS edema score	ΔEOT	-0.1276	0.0710	0.2273	0.0458	0.0000	0.3441	0.3776	0.0534	-	-	-	-
HSS grade component x EREFS exudates score	BL	0.0000	0.0217	-0.1723	0.1949	-0.1112	0.1456	0.0722	0.3992	-	-	-	-
HSS grade component x EREFS exudates score	ΔEOT	0.1372	0.4746	0.2578	0.1957	0.2417	-0.0282	0.3420	0.4098	-	-	-	-
HSS stage component x EREFS exudates score	BL	0.0000	-0.0465	-0.1203	0.2254	0.3595	0.2153	0.0616	0.1681	-	-	-	-
HSS stage component x EREFS exudates score	ΔEOT	0.1864	0.4746	0.1226	0.3208	0.2284	0.0284	0.3924	0.2221	-	-	-	-
HSS grade component x EREFS furrows score	BL	NC	-0.0117	NC	0.0625	NC	0.0442	NC	0.1535	-	-	-	-
HSS grade component x EREFS furrows score	ΔEOT	-0.1318	0.0481	0.3901	-0.0382	0.0480	0.2869	0.1914	-0.0133	-	-	-	-
HSS stage component x EREFS furrows score	BL	NC	0.0032	NC	-0.0473	NC	0.0612	NC	0.0677	-	-	-	-
HSS stage component x EREFS furrows score	ΔEOT	-0.0976	-0.0710	0.4708	0.0269	0.4385	0.2427	0.3173	0.0314	-	-	-	-
HSS grade component x EREFS remodeling subscoref	BL	0.2613	0.3172	0.2152	0.2277	0.4077	-0.0251	0.1698	-0.0555	0.2693	-0.1383	0.3493	0.0041
HSS grade component x EREFS remodeling subscoref	ΔEOT	0.0000	0.1294	0.1484	0.3042	0.3035	0.0736	0.4512	-0.0026	0.2290	-0.1962	0.4395	0.0372
HSS stage component x EREFS remodeling subscore^f	BL	0.1904	0.2372	0.1349	0.1758	0.0568	0.0515	0.0747	0.0499	0.2258	-0.1469	0.2586	-0.1288
HSS stage component x EREFS remodeling subscore^f	ΔEOT	-0.0697	0.0739	0.1241	0.3323	0.0000	0.2676	0.4488	0.0891	0.2313	-0.0757	0.4081	-0.1376
HSS grade component x EREFS rings score	BL	0.3318	0.2437	0.2697	0.1894	0.3722	-0.0516	0.2500	-0.0860	0.3321	-0.1884	0.4131	-0.0266
HSS grade component x EREFS rings score	ΔEOT	0.0000	0.1572	-0.0046	0.3703	0.0587	0.1714	0.2695	-0.0118	-0.0498	-0.2288	0.0819	-0.0382
HSS stage component x EREFS rings score	BL	0.2403	0.1791	0.2728	0.1272	-0.0329	-0.0311	0.2105	0.0169	0.2768	-0.1374	0.3937	-0.1527
HSS stage component x EREFS rings score	ΔEOT	-0.0697	0.0882	0.0628	0.3456	0.1341	0.2415	0.3410	0.0620	0.0210	-0.1272	0.1102	-0.1790
HSS grade component x EREFS stricture score	BL	0.0664	0.3674	0.0597	0.2234	0.3126	0.0613	-0.0063	0.0570	0.0824	0.0695	0.1323	0.0881
HSS grade component x EREFS stricture score	ΔEOT	0.0000	-0.0704	0.3163	-0.1671	0.5061	-0.2785	0.3757	0.0266	0.5764	0.0787	0.7392	0.2225
HSS stage component x EREFS stricture score	BL	0.0505	0.2835	-0.1117	0.2257	0.1653	0.2571	-0.1472	0.1179	0.0716	-0.1016	-0.0283	0.0134
HSS stage component x EREFS stricture score	ΔEOT	0.0000	-0.0354	0.1267	-0.0110	-0.2774	0.0981	0.2229	0.0865	0.4348	0.1437	0.6159	0.1090

Cohen’s rule of thumb denotes a correlation coefficient of 0.10 as weak relationship, 0.3 as moderate relationship, and 0.5 as strong relationship (Cohen J.,1988, Statistical Power Analysis for the Behavioral Sciences, 2nd ed. Hillsdale, NJ: Erlbaum). HSS components, ED, and LPF, were excluded from the analysis. ΔEOT was included to assess the progression of the disease.

^a24 POC patients were analyzed at baseline and 20 at Week 12.

^b39 P3PA patients were analyzed at baseline and 27 at Week 24.

^c The HSS grade and stage scores are the sum of all component scores divided by the maximum possible score.

^dThe EREFS total score is the sum of all component scores for proximal and distal regions.

^eThe EREFS inflammation subscore is the sum of edema, exudates, and furrows for proximal and distal regions.

^fThe EREFS remodeling subscore is the sum of rings and strictures for proximal and distal regions.

NC, no correlation.

Disclosures:

Margaret Collins: Allakos – Consultant. Arena Pharmaceuticals – Consultant. AstraZeneca – Consultant. BMS – Consultant. Calypso Biotech – Consultant. EsoCap – Consultant. GSK – Consultant. Receptos/BMS – Grant/Research Support. Regeneron Pharmaceuticals, Inc. – Consultant, Grant/Research Support. Shire – Consultant, Grant/Research Support.

Marc Rothenberg: Allakos – Consultant. AstraZeneca – Consultant. BMS – Consultant. Cincinnati Children’s Hospital – Other Financial or Material Support, inventor of patents owned by Cincinnati Children’s Hospital. ClostraBio – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Mapi Research Trust – Patent Holder. PulmOne – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Spoon Guru – Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds). Teva Pharmaceuticals – Patent Holder. UpToDate – Patent Holder.

Albert J. Bredenoord: Arena Pharmaceuticals – Consultant. AstraZeneca – Consultant. Bayer – Grant/Research Support. Calypso Biotech – Consultant. Dr. Falk Pharma – Consultant. EsoCap – Consultant. Gossamer Bio – Consultant. Laborie – Consultant. Medtronic – Consultant. Nutricia – Grant/Research Support. RB Pharma – Consultant. Regeneron Pharmaceuticals, Inc. – Consultant. Robarts Clinical Trials – Consultant. SST – Grant/Research Support, Stockholder/Ownership Interest (excluding diversified mutual funds).

Joshua Wechsler: Allakos – Consultant. Regeneron Pharmaceuticals, Inc. – Consultant. Sanofi – Consultant.

Mirna Chehade: Adare Pharma Solutions – Consultant. Allakos – Consultant, Grant/Research Support. AstraZeneca – Consultant, Grant/Research Support. BMS – Consultant. Danone – Grant/Research Support. Regeneron Pharmaceuticals, Inc. – Consultant, Grant/Research Support. Sanofi – Consultant, Grant/Research Support. Shire – Grant/Research Support. Shire/Takeda – Consultant.

Zhen Chen: Regeneron Pharmaceuticals, Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Ledia Goga: Sanofi – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Benjamin Ortiz: Regeneron Pharmaceuticals, Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Angela Khodzhayev: Regeneron Pharmaceuticals, Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Juby Jacob-Nara: Sanofi – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Yamo Deniz: Regeneron Pharmaceuticals, Inc. – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).

Paul J. Rowe: Sanofi – Employee, Stockholder/Ownership Interest (excluding diversified mutual funds).