Introduction
Cendakimab is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody that binds to interleukin 13 (IL-13) and blocks interaction with both its receptors, IL-13Rα1 and IL-13Rα2. IL-13 is a cytokine implicated in the pathogenesis of atopic dermatitis (AD) and is thought to be a key driver of the complex pathophysiology of eosinophilic esophagitis (EoE). IL-13 signals through both IL-13Rα1 and IL-13Rα2 to regulate cellular and molecular pathways across a variety of cell types. The binding of IL-13 to IL-13Rα1 promotes a Type 2 immune response and eosinophil recruitment, whereas the binding of IL-13 to IL-13Rα2 is believed to play a role in fibrosis and epithelial tissue remodeling. Several biomarkers associated with Type 2 inflammatory diseases are known to be regulated by IL-13. Eotaxin-3, a key biomarker, plays a central role in attracting eosinophils to the site of inflammation. Periostin, an extracellular matrix protein linked to activated fibroblasts, is implicated in tissue remodeling and fibrosis. Another enzyme governed by IL-13 is matrix metalloproteinase-12 (MMP-12)—this enzyme contributes to tissue remodeling and breakdown of extracellular matrix components. Here, we evaluate the pharmacodynamic effects of IL-13 inhibition with cendakimab on the key serum biomarkers eotaxin-3, periostin, and MMP-12 in patients with AD, with a focus on exploring potential implications for EoE.
Aims & Methods
In this phase 2, multicenter, global, randomized, double-blinded, placebo-controlled, parallel-group study (NCT04800315), 220 adults with moderate-to-severe AD received cendakimab 360 mg Q2W, 720 mg QW, 720 mg Q2W, or placebo for 16 weeks. Blood samples were collected, and a panel of biomarkers were assessed. The current analysis focuses on the assessment of serum levels of eotaxin-3, periostin, and MMP-12 using Proximity Extension Assay pre- and post-treatment on day 1 (baseline), at week 1 and week 2, and then biweekly until week 16. The least square mean percent change from baseline at week 16 for each treatment group was evaluated.
Results
For all 3 doses of cendakimab, there was a significant decrease from baseline in the levels of eotaxin-3, periostin, and MMP-12 as early as week 1 post-treatment and continued through week 16 of cendakimab treatment (Table). Compared with placebo, cendakimab resulted in significantly greater reductions in these biomarker levels through week 16.
Conclusion
Cendakimab decreased levels of key inflammatory and remodeling biomarkers over 16 weeks of treatment in patients with AD. These findings suggest that cendakimab modulates pathways of inflammation, fibrosis, and tissue remodeling in AD and add to the existing clinical evidence of its modulation in other Type 2 inflammatory diseases such as EoE.
Table. Least square mean percent change from baseline in key serum biomarker levels at week 16 in patients with AD
| Treatment | Eotaxin-3
LS mean percent CFB (95%CI) | Periostin
LS mean percent CFB (95%CI) | MMP-12
LS mean percent CFB (95%CI) |
| Cendakimab 360 mg Q2W | –51.53 (–61.98 to –38.20)*,† | –47.50 (–56.45 to –36.73)*,† | –52.00 (–58.39 to –44.63)*,† |
| Cendakimab 720 mg QW | –58.20 (–67.29 to –46.59)*,† | –55.76 (–63.31 to –46.67)*,† | –54.72 (–60.83 to –47.65)*,† |
| Cendakimab 720 mg Q2W | –67.77 (–74.75 to –58.85)*,† | –60.93 (–67.57 to –52.94)*,† | –61.07 (–66.27 to –55.06)*,† |
| Placebo | –5.80 (–26.63 to 20.94) | –23.92 (–37.15 to –7.90)* | –16.69 (–28.31 to –3.19)* |
CFB, change from baseline; CI, confidence interval; LS, least square.
*
P < 0.05 versus baseline.
†P < 0.01 cendakimab versus placebo
Disclosure
ESD served as a consultant for Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/ Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GlaxoSmithKline, 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, Upstream Bio, received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/ Bristol Myers Squibb, Regeneron, Revolo, Shire/Takeda, and received educational grant from Allakos, Aqilion, Holoclara, and Invea. JL, SH, LG, CDO, and CC are employees and stockholders of Bristol Myers Squibb. JS served as consultant for Abbvie, Alamar, Aldena, Amgen, AObiome, Apollo, Arcutis, Arena, Asana, Aslan, Attovia, BioMX, Biosion, Bodewell, Boehringer-Ingelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Celgene, Connect Biopharma, Corevitas, Dermavant, Eli Lilly, FIDE, Galderma, GlaxoSmithKline, Incyte, Invea, Kiniksa, Leo Pharma, Merck, My-Or Diagnostics, Nektar, Novartis, Optum, Pfizer, RAPT, Recludix, Regeneron, Sandoz, Sanofi-Genzyme, Shaperon, TARGET-RWE, Teva, Union, UpToDate, participated on a data safety monitoring board or advisory board for Biosion and Sanofi, received grants or contracts from Galderma, Incyte, Pfizer, received honoraria from Abbvie, Eli Lilly, Leo Pharma, Pfizer, Regeneron, Sanofi-Genzyme.
