Introduction
Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), an epithelial cytokine that has been implicated in the pathogenesis of EoE. CROSSING (NCT05583227) was a phase 3 study that evaluated the efficacy and safety of tezepelumab in patients with EoE.
Aims & Methods
In this multicentre, randomized, double-blind, placebo-controlled study, patients (12–80 years old) with symptomatic and histologically active EoE were randomized 1:1:1 to receive tezepelumab 210 mg, tezepelumab 420 mg or placebo subcutaneously every 4 weeks for 52 weeks. Key secondary endpoints were histologic remission (defined as a peak esophageal eosinophil count per high-power field ≤ 6), change from baseline in DSQ score at week 52, and change from baseline in Endoscopic Reference Score (EREFS) at week 52 to evaluate the long-term efficacy of tezepelumab. Adverse events (AEs) and serious AEs were assessed.
Results
Overall, 365 patients received treatment (tezepelumab 210 mg, n = 122; tezepelumab 420 mg, n = 122; placebo, n = 121). Both co-primary endpoints and all key secondary endpoints were met. At week 24, 64.8%, 68.9% and 3.5% of patients had histologic remission in the tezepelumab 210 mg, 420 mg and placebo groups, respectively; with significant differences versus placebo of 60.45 (95% confidence interval [CI]: 51.09, 69.81; p < 0.001) and 65.75 (56.81, 74.69; p < 0.001), respectively (Table). Placebo-adjusted least-squares (LS) mean differences in change from baseline in DSQ score were −4.07 (95% CI: −8.12, −0.02; p = 0.049) and −7.29 (−11.29, −3.29; p < 0.001), respectively. At week 52, 67.8%, 63.3% and 5.4% of patients had histologic remission in the tezepelumab 210 mg, 420 mg and placebo groups, respectively, with significant differences versus placebo of 63.44% (95% CI: 53.82, 73.07); p < 0.001 and 58.31% (48.58, 68.05); p < 0.001, respectively. The LS mean change from baseline in DSQ score at week 52 was −22.10 in the tezepelumab 210 mg group, −24.03 in the tezepelumab 420 mg group and −13.19 in the placebo group, with significant improvements versus placebo (LS mean difference: −8.91; [95% CI: −13.20, −4.62]; p < 0.001 and −10.84; [−15.10, −6.58]; p < 0.001, respectively). The LS mean change from baseline to week 52 in EREFS was −3.92 in the tezepelumab 210 mg group, −3.70 in the tezepelumab 420 mg group and −0.60 in the placebo group, with significant improvements versus placebo (LS mean difference: −3.32; [95% CI: −4.04, −2.60]; p < 0.001 and −3.10; [−3.81, −2.38]; p <0.001, respectively) (Table). The overall incidence of AEs and serious AEs was comparable across the tezepelumab treatment groups and placebo group.
Table. Proportion of patients with histologic remission and the change from baseline in DSQ score and EREFS at weeks 24 and 52
| Week 24 | Week 52 |
|---|
aDSQ refers to a 14-day DSQ score, comprised of daily DSQ values captured over a 14-day period; the score ranges from 0–84.
bThe scoring system was applied separately in the proximal (proximal half) and distal (distal half) endoscopy findings, and the sum for each individual component from the proximal and distal scores was added to form the total EREFS score (range 0–18).
CI, confidence interval; DSQ, Dysphagia Symptom Questionnaire; EREFS, Endoscopic Reference Score; LS, least-squares; Q4W, every 4 weeks. |
| Tezepelumab
210 mg Q4W
(n = 122)
| Tezepelumab
420 mg Q4W
(n = 122)
| Placebo
(n = 121)
|
Tezepelumab
210 mg Q4W
(n = 122) | Tezepelumab
420 mg Q4W
(n = 122)
| Placebo
(n = 121)
|
Proportion of patients with
histological remission (%)
| 64.8 | 68.9 | 3.5
| 67.8 | 63.3 | 5.4 |
Difference from placebo
(95% CI); p
| 60.45 (51.09, 69.81)
p < 0.001 | 65.75 (56.81, 74.69)
p < 0.001
| – | 63.44 (53.82, 73.07)
p < 0.001
| 58.31 (48.58, 68.05)
p < 0.001
| –
|
LS mean change from baseline
in DSQ scorea
| –18.80
| –22.02
| –14.73 | –22.10
| –24.03
|
–13.19 |
LS mean difference from placebo
(95% CI); p
| –4.07 (–8.12, –0.02)
p = 0.049
| –7.29 (–11.29, –3.29)
p < 0.001
| –
| –8.91 (−13.20, –4.62)
p < 0.001
|
–10.84 (−15.10, –6.58)
p < 0.001 | –
|
LS mean change from baseline
in EREFSb
| –3.59
| –3.65
| –0.21
| –3.92
| –3.70 | –0.60
|
LS mean difference from placebo
(95% CI); p
| –3.37 (–4.04, –2.70)
p < 0.001
| –3.43 (–4.10, –2.77)
p < 0.001
| –
| –3.32 (–4.04, –2.60)
p < 0.001
| –3.10 (–3.81, –2.38)
p < 0.001
| – |
Conclusion
In adults and adolescents with active EoE, tezepelumab demonstrated sustained improvements in histologic remission, dysphagia symptoms and endoscopic outcomes versus placebo at 24 and 52 weeks and was generally well tolerated.
Disclosure
Albert J Bredenoord has received research funding from Dr. Falk Pharma, Nutricia, Thelial Technologies and SST; and is a consultant for Alimentiv, AstraZeneca, Celgene, Calyx, Dr. Falk Pharma, Laborie Medical Technologies, Medtronic and Regeneron Pharmaceuticals.
Evan S Dellon has received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Celgene/Receptos/Bristol Myers Squibb, Celldex, Dr. Falk Pharma, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Phathom, Regeneron Pharmaceuticals, Revolo, Sanofi, Shire/Takeda and Uniquity; has received consultancy fees from Abbvie, Adare/Ellodi, Alfasigma, ALK, Amgen, Anaptysbio/First Tracks bio, Apogee, Apollo, Aqilion, Arena/Pfizer, AstraZeneca, Bethanamist, Biocryst, Bryn, Calypso, Celgene/Receptos/Bristol Myers Squibb, Celldex, Cyted, Domain, Dr. Falk Pharma, EsoCap, Eupraxia, Ferring, GI Reviewers, GSK, Holoclara, Johnson & Johnson, Knightpoint, Kymera, Lilly, LucidDx, Noa, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron Pharmaceuticals, Revolo, Robarts/Alimentiv, Roivant, Sanofi, Shire/Takeda, Target RWE and Third Harmonic Bio; and has received educational grant from Allakos, Aqilion, Holoclara and Invea.
Marc E Rothenberg is a consultant for AstraZeneca, Celldex, ClostraBio, EnZen Therapeutics, Kymera Therapeutics, Pulm One, Serpin Pharm, Spoon Guru and Uniquity Bio; has an equity interest in Celldex, ClostraBio, EnZen Therapeutics, Pulm One, Santa Ana Bio, Serpin Pharm, Spoon Guru and Uniquity Bio; has received royalties from Teva Pharmaceuticals (reslizumab), Mapi Research Trust (PEESSv2) and UpToDate; and is an inventor of patents owned by Cincinnati Children's Hospital Medical Center.
Edoardo V Savarino has served as speaker for Abbvie, Aboca, Abivax, Agave, AGPharma, Alfasigma, Apoteca, Biosline, CaDiGroup, Celltrion, Dr. Falk Pharma, EG Stada Group, Fenix Pharma, Galapagos, Giuliani, Johnson & Johnson, JB Pharmaceuticals, Innovamedica/Adacyte, Lilly, Lionhealth, Malesci, Mayoly Biohealth, Montefarco, Novartis, Omega Pharma, Pfizer, Rafa, Reckitt Benckiser, Recordati, Sandoz, Sanofi/Regeneron, SILA, Takeda, Tillots and Unifarco; has served as a consultant for Abbvie, Alfasigma, Apogee, AstraZeneca, Biogen, Bristol Myers Squibb, Celltrion, Dr. Falk Pharma, Fenix Pharma, Ferring, Giuliani, Grunenthal, Johnson & Johnson, JB Pharmaceuticals, Lilly, Merck, Nestlè, Pfizer, PRO.MED.CS Praha a.s., Reckitt Benckiser, Recordati, Sanofi/Regeneron, SILA, Takeda and Unifarco; has received research support from Bonollo, Difass, Pfizer, Reckitt Benckiser, Sanofi/Regeneron, SILA, Unifarco and Zeta Farmaceutici.
Jonathan M Spergel reports grant support from AstraZeneca, Food Allergy Research and Education, National Institutes of Health, Novartis and Regeneron Pharmaceuticals/Sanofi; and has consulted for Allakos, AstraZeneca, Bristol Myers Squibb, Lilly, Novartis, Ready.Set.Food, and Regeneron/Sanofi.
Alfredo J Lucendo has received research funding from AstraZeneca, Dr. Falk Pharma, Ellodi/Adare, EsoCap and Sanofi/Regeneron; and has served as a consultant for Dr Falk Pharma, EsoCap and Sanofi/Regeneron.
Salvatore Oliva has received speaker fees from Abbvie, Alfasigma, AstraZeneca, Bristol Myers Squibb, Dr. Falk Pharma, Medtronic, Regeneron Pharmaceuticals and Sanofi; and has received research grants from Alfasigma, Consortium of Eosinophilic Gastrointestinal Disease Researchers, European Society for Paediatric Gastroenterology Hepatology and Nutrition, Medtronic, Regeneron Pharmaceuticals and Sanofi.
Shauna Schroeder has received research support from Allakos, AstraZeneca, Bristol Myers Squibb, Celgene, Regeneron Pharmaceuticals, Sanofi, Takeda and has served as speaker and consultant for AstraZeneca, EvoEndo Inc., Regeneron Pharmaceutical, Sanofi and Takeda.
Nicola Fawcett, Joseph D Sherrill, Magnus Aurivillius, Hanna Grindebacke, Ting Li, Beata Pawlikowska, Mary Kay Margolis, Szu-Ta Chen and Sandhia S Ponnarambil are employees of AstraZeneca and may own stock or stock options in AstraZeneca.
Jyotsna Reddy and Yun Chon are employees of Amgen and own stock in Amgen.
