• Can an Antibody Against IL13 Be Used to Treat Eosinophilic Esophagitis?

Can an Antibody Against IL13 Be Used to Treat Eosinophilic Esophagitis?

A monoclonal antibody against IL13 reduced histologic and endoscopic features of eosinophilic esophagitis (EoE) in a placebo-controlled phase 2 trial, researchers report in the February issue of Gastroenterology. The antibody, called RPC4046, was well tolerated.

EoE is a chronic, immune-mediated disease of the esophagus characterized by eosinophil-mediated mucosal inflammation and esophageal dysfunction. The prevalence of EoE has been increasing, with estimates of 0.5 to 1 cases per 1000 persons worldwide. Complications of EoE, including strictures and food impaction, are related to esophageal remodeling and fibrostenosis, which are associated with longer duration of untreated disease. Although changes in diet and topical glucocorticosteroids can reduce eosinophilic inflammation, they do not help many patients, and the disease returns when patients stop using these treatments.

Increased serum levels of interleukin 13 (IL13) are believed to contribute to the pathogenesis of EoE. Ikuo Hirano et al evaluated the efficacy and safety of RPC4046, an antibody that blocks IL13, in 99 adults with active EoE.

In a multicenter, double-blind trial, the patients were randomly assigned to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks. Patients underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. The patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation.

At week 16, the mean changes in esophageal eosinophil count per hpf were: a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046, compared with a reduction of 4.4 ± 59.9 in patients who received placebo.

The 360-mg RPC4046 group, compared with the placebo group, had significant reductions in validated endoscopic severity score at all esophageal locations, validated histologic grade and stage scores, and clinician’s global assessment of disease severity.  They also had a mon-significant reduction in scores from the dysphagia symptom diary.

Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection.

How does the antibody work? IIL13 is overexpressed in the esophagus of patients with EoE, and overexpression of IL13 in mice results in a disease that resembles EoE in patients. The authors write that IL13 induces changes in esophageal epithelial cells that result in impaired barrier formation and production of the eosinophil chemoattractant and activating factor CCR3. IL13 induces transcription of CAPN14, which regulates esophageal barrier function and variants in this gene have been associated with EoE.

The authors state that it is notable that approximately half of the patients included in the study were refractory to steroid treatment—an increasing population that is difficult to treat. More than 50% of patients treated with topical steroids did not sustain an initial histologic response with longer administration.

The study was not powered to assess reduction in dysphagia symptoms, but Hirano et al observed a strong trend toward reduction of dysphagia in the group given 360 mg RPC4046. Important strengths of the study include the significant reduction in disease activity based on endoscopic (EREFS) and histologic outcome measures specifically designed and validated for EoE.

Hirano et al conclude that data from this trial provide evidence of the efficacy and safety of a monoclonal antibody against IL13 in adult patients with EoE, with reduction in histopathologic and endoscopic aspects of disease activity and global perception of disease severity. These findings support the contribution of IL13 to the pathogenesis of EoE. Larger studies of RPC4046 are needed in patients with EoE.

1 Comment

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    Marc Rothenberg February 26, 2019

    This is a well written blog so I thank Gastroenterology for the attention. But, i would like to clarify that increased serum levels of interleukin 13 (IL13) are NOT believed to contribute to the pathogenesis of EoE. It is not the serum or systemic levels of IL-13 that contributes to EoE; rather, it is the local overproduction of IL-13 and the subsequent IL-13-mediated signaling in the esophageal mucosa.

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