D0202 - Lirentelimab (AK002) Safety and Efficacy in Patients With Higher Eosinophil Thresholds: Supplementary Analysis of Phase 2/3 EoE KRYPTOS Trial

Tuesday, October 25, 2022

10:00 AM – 12:00 PM ET

Location: Crown Ballroom

Presenting Author(s)

ED

Evan Dellon, MD, MPH

University of North Carolina School of Medicine
Chapel Hill, North Carolina

Evan Dellon, MD, MPH¹, Mirna Chehade, MD, MPH², Robert M. Genta, MD³, David A. Leiman, MD⁴, Kathryn A. Peterson, MD, MSCI⁵, Jonathan Spergel, MD, PhD⁶, Joshua Wechsler, MD, MS⁷, Enoch Bortey, PhD⁸, Alan T. Chang, BS⁸, Ikuo Hirano, MD, PhD⁹
¹University of North Carolina School of Medicine, Chapel Hill, NC; ²Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York, NY; ³Baylor College of Medicine, Houston, TX; ⁴Duke University School of Medicine, Durham, NC; ⁵University of Utah, Salt Lake City, UT; ⁶Children’s Hospital of Pennsylvania, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA; ⁷Ann & Robert H. Lurie Children’s Hospital, Chicago, IL; ⁸Allakos Inc., San Carlos, CA; ⁹Northwestern University Feinberg School of Medicine, Chicago, IL

Introduction: In the KRYPTOS phase 2/3 randomized, double-blind, placebo controlled clinical trial of lirentelimab (LIR), an IgG1 Ab against siglec-8, in EoE patients (NCT04322708), a significant histologic response was observed but the co-primary symptom endpoint was not met. However, LIR may be more effective among those with greater active inflammation. This supplementary analysis explores the effect of LIR in a subpopulation of patients with EoE and baseline esophageal eos >24/hpf, a threshold previously suggested to differentiate EoE from a cofounding condition like GERD.

Methods: Patients were randomized 1:1:1 to high dose LIR (1 mg/kg x 1 dose then 3 mg/kg x 5 doses [HD]), low dose LIR (1 mg/kg, [LD]) or placebo (PBO) for 6 monthly infusions. Co-primary endpoints were the proportion of patients who achieved an esophageal intraepithelial eos count of ≤6 eos/hpf at week 24 and the mean absolute change in daily Dysphagia Symptom Questionnaire (DSQ) score from baseline to weeks 23-24.

Results: There were 48 patients with baseline peak esophageal eos ≤24/hpf (n=14 HD, n=18 LD, and n=16 PBO) and 228 patients with eos >24/hpf (n=77 HD, n=75 LD, n=76 PBO; Table) which was related to other markers of severity including higher median levels of serum IgE (≤24/hpf: 83kU/L HD, 64kU/L LD, 65 kU/L PBO vs. >24/hpf: 105 kU/L HD, 117 kU/L LD, 98 kU/L PBO) and median levels of peripheral blood eosinophils (≤24/hpf: 310 cells/µL HD, 175 cells/µL LD, 220 cells/µL vs >24/hpf: 300 cells/µL HD and LD, 380 cells/µL PBO). Significantly more patients with eos >24/hpf met the histologic co-primary endpoint vs placebo (91% [HD], 92% [LD], 8% [PBO]; P< 0.0001). Patients with baseline eos >24/hpf also demonstrated a significant mean change and percent change in DSQ co-primary endpoint (mean change DSQ: -17.6 HD, -12.7 LD, -12.5 PBO, P=0.0222, Fig A; Percent change DSQ: -56% HD, -38% LD, -29% PBO, P=0.0019, Fig B). Safety profile was no different among patients with eos >24/hpf compared to patients with eos ≤24/hpf.

Discussion: Supplementary analysis of the KRYPTOS phase 2/3 EoE trial revealed that patients with eos >24/hpf had a significant decrease in symptoms of dysphagia with lirentelimab compared to placebo showing a difference in response when separated from other cofounding conditions like GERD. The safety profile of lirentelimab was consistent with previous reports. Further study is warranted to identify patients with EoE who may be most likely to respond to treatment with lirentelimab.

Figure: Figure. DSQ Response in Patients by Baseline Peak Eosinophil Count.
Co-primary endpoint, change in DSQ at weeks 23-24 stratified by patients with EoE baseline eos ≤24/hpf and >24/hpf; A. Mean change in DSQ. B. Percent change in DSQ. LS Means and HD lirentelimab from placebo p-values derived from MMRM model

Patient Characteristic	Peak Esophageal Eosinophils ≤24/hpf			Peak Esophageal Eosinophils >24/hpf
Patient Characteristic	HD n=14	LD n=18	PBO n=16	HD n=77	LD n=75	PBO n=76
Age, median years (range)	35.5 (15-67)	33.5 (15-67)	43.5 (20-68)	29 (12-69)	34 (12-67)	30 (12-70)
Female sex, n (%)	6 (43)	8 (44)	6 (38)	20 (26)	32 (43)	31 (41)
History of EoE, n (%)	11 (79)	15 (83)	15 (94)	70 (91)	69 (92)	71 (93)
Duration of EoE, median years (range) [mean]	4 (1-19) [6.5]	4 (0-11) [5.0]	4 (0-12) [4.9]	4 (0-38) [6.3]	5 (0-56) [7.7]	5 (0-18) [5.2]
History of atopy, n (%)	11 (79)	12 (67)	9 (56)	58 (75)	54 (72)	64 (84)
Peak esophageal eosinophil/hpf mean±SD in distal location, mean±SD in proximal/mid location, mean±SD	20±3 15±7 13±9	19±3 17±4 7±9	20±3 17±7 10±9	66±31 54±32 48±29	71±32 59±31 54±37	67±30 55±29 46±35
Peripheral blood eosinophils cells/μL, median (IQR)	310 (213-430)	175 (143-245)	220 (98-400)	300 (240-470)	300 (210-500)	380 (240-455)
Serum IgE, kU/L, median (IQR)	83 (33-348)	64 (21-168)	65 (24-140)	105 (54-349)	117 (46-314)	98 (33-255)
Baseline DSQ [0-84], mean±SD	34±10	38±11	36±10	34±12	36±12	35±13

Table: Table. Baseline Characteristics by Peak Esophageal Eosinophils
HD, high dose lirentelimab; LD, low dose lirentelimab; PBO, placebo

Disclosures:

Evan Dellon: Abbott, Abbvie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS – Consultant. Adare/Ellodi, Allakos, Arena, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda – Grant/Research Support. Allakos, Banner, Holoclara – educational grant. Celldex, Eli Lilly, EsoCap, Eupraxia, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia – Consultant. Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE – Consultant.

Mirna Chehade: Adare/Ellodi – Consultant, Grant/Research Support. Allakos – Consultant, Grant/Research Support. AstraZeneca – Consultant, Grant/Research Support. Bristol Myers Squibb – Consultant. Danone – Grant/Research Support. Phathom – Consultant. Regeneron – Consultant, Grant/Research Support. Sanofi – Consultant. Shire/Takeda – Consultant, Grant/Research Support.

Robert Genta: Adare/Ellodi – Consultant. Allakos – Consultant. Red Hill Pharmaceuticals – Consultant.

David Leiman: Allakos – Advisory Committee/Board Member, Consultant, Grant/Research Support. Arena Pharmaceuticals – Site PI. Celgene – Site PI. Medtronic – Consultant. Phathom – Site PI. Revolo Biotherapeutics – Site PI. Takeda – Grant/Research Support.

Kathryn Peterson: Adare – Grant/Research Support. AGA – Advisory Committee/Board Member, Consultant, Speakers Bureau. Alladapt – Advisory Committee/Board Member, Consultant. Allakos – Advisory Committee/Board Member, Consultant, Grant/Research Support, Speakers Bureau. AstraZeneca – Advisory Committee/Board Member, Consultant, Grant/Research Support. Bristol Myers Squibb – Advisory Committee/Board Member, Consultant. Chobani – Grant/Research Support. Ellodi – Advisory Committee/Board Member, Consultant. Ineva – Advisory Committee/Board Member, Consultant. Lucid – Advisory Committee/Board Member, Consultant. Nexeos Bio – Equity. Nexstone – Advisory Committee/Board Member, Consultant. Peerview – Advisory Committee/Board Member, Consultant, Speakers Bureau. Regeneron – Advisory Committee/Board Member, Consultant, Grant/Research Support. Regeneron-Sanofi – Grant/Research Support. Revolo – Grant/Research Support. Takeda – Advisory Committee/Board Member, Consultant, Speakers Bureau. WebMD – Advisory Committee/Board Member, Consultant, Speakers Bureau.

Jonathan Spergel: Allakos – Grant/Research Support. DBV Technologies – Consultant, Grant/Research Support. NIH – Grant/Research Support. Novartis – Consultant, Grant/Research Support. Readysetfood – Consultant. Regeneron – Grant/Research Support. Regeneron-Sanofi – Consultant. Sanofi – Grant/Research Support. Shire – Consultant. Takeda – Consultant.

Joshua Wechsler: Allakos – Grant/Research Support. Regeneron – Grant/Research Support.

Enoch Bortey: Allakos – Employee, Stock Options.

Alan Chang: Allakos – Employee, Stock Options.

Ikuo Hirano: Adare Pharma Solutions – Consultant. Allakos – Consultant. Arena Pharmaceuticals – Consultant. AstraZeneca – Consultant. Calyx/Parexel – Consultant. Esocap – Consultant. Gossamer Bio – Consultant. Lilly – Consultant. Meritage – Grant/Research Support. Nextone – Consultant. Receptos/BMS – Consultant. Receptos/BMS – Grant/Research Support. Regeneron Pharmaceuticals, Inc. – Consultant. Regeneron Pharmaceuticals, Inc. – Grant/Research Support. Shire – Consultant. Shire – Grant/Research Support.

Evan Dellon, MD, MPH¹, Mirna Chehade, MD, MPH², Robert M. Genta, MD³, David A. Leiman, MD⁴, Kathryn A. Peterson, MD, MSCI⁵, Jonathan Spergel, MD, PhD⁶, Joshua Wechsler, MD, MS⁷, Enoch Bortey, PhD⁸, Alan T. Chang, BS⁸, Ikuo Hirano, MD, PhD⁹. D0202 - Lirentelimab (AK002) Safety and Efficacy in Patients With Higher Eosinophil Thresholds: Supplementary Analysis of Phase 2/3 EoE KRYPTOS Trial, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.