Intravenous anti–IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis

doi:10.1016/j.jaci.2014.07.049

Journal of Allergy and Clinical Immunology

Volume 135, Issue 2, February 2015, Pages 500-507

https://doi.org/10.1016/j.jaci.2014.07.049 Get rights and content

Background

Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options.

Objective

We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE.

Methods

Patients (18-50 years) with proton pump inhibitor–resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months. The primary end point was the responder rate for a greater than 75% decrease in peak eosinophil counts at week 12. Efficacy was to be declared if the lower 90% confidence limit for the proportion of responders on QAX576 was 35% or greater. Secondary end points included changes in esophageal eosinophil counts, symptoms assessed by questionnaire scores, and quantification of a series of biomarkers.

Results

Twenty-three patients completed the study up to week 12, and 18 continued to the end of the study. For the proximal and distal esophageal biopsies combined, the responder rate was 12.5% (90% confidence limit, 1% to 43%) with placebo, compared to 40.0% (90% confidence limit, 22% to 61%) with QAX576. Although the primary end point was not met, the mean esophageal eosinophil count decreased by 60% with QAX576 versus an increase of 23% with placebo (P = .004), and the decrease was sustained up to 6 months. There was a trend for improved symptoms, particularly dysphagia. QAX576 improved expression of EoE-relevant esophageal transcripts, including eotaxin-3, periostin, and markers of mast cells and barrier function, for up to 6 months after treatment. QAX576 was well tolerated.

Conclusions

QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease–related transcripts in adults with EoE in a sustained manner.

Section snippets

Study design

An overview of the study is presented in Fig 1, A. In brief, patients underwent a screening esophagogastroduodenoscopy (EGD) and baseline evaluations, followed by 2:1 randomization to the study medication or placebo. The study drug was administered at weeks 0, 4, and 8, and EGD was repeated 4 weeks after the last dose. The patients were followed up for 6 months. Responders who relapsed had the option to enter an open-label extension with 3 more monthly doses of QAX576. At the end of the study,

Study population

Twenty-five patients were randomized: 17 received QAX576, and 8 received placebo. Two patients receiving QAX576 were withdrawn after 1 dose, one because of a positive drug screen, and the other because of a non–drug-related serious adverse event (SAE). Twenty-three patients completed the day 85 assessments. Eighteen patients continued for an additional 5 months (ie, for 6 months after the last dose), with 2 receiving open-label study medication (Fig 1, B). The characteristics of the study

Discussion

We report the first study with QAX576, a fully human anti–IL-13 mAb, for the treatment of EoE. Although a preliminary phase II study, it demonstrates that (1) QAX576 reduces the intraepithelial eosinophil count in the esophagus, as measured by the mean value; (2) the effect is sustained for an additional 6 months after the third monthly infusion of the drug in the majority of subjects; (3) QAX576 improves the expression of a large set of esophageal transcripts involved in EoE, including

References (37)

G.T. Furuta et al.
Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment
Gastroenterology
(2007)
T.K. Desai et al.
Association of eosinophilic inflammation with esophageal food impaction in adults
Gastrointest Endosc
(2005)
L.M. Ingerski et al.
Health-related quality of life across pediatric chronic conditions
J Pediatr
(2010)
A. Mishra et al.
Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism
Gastroenterology
(2003)
H.S. Akei et al.
Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice
Gastroenterology
(2005)
J.M. Caldwell et al.
Glucocorticoid-regulated genes in eosinophilic esophagitis: a role for FKBP51
J Allergy Clin Immunol
(2010)
B.S. Bochner et al.
Workshop report from the National Institutes of Health Taskforce on the Research Needs of Eosinophil-Associated Diseases (TREAD)
J Allergy Clin Immunol
(2012)
C. Blanchard et al.
IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids
J Allergy Clin Immunol
(2007)
J.D. Sherrill et al.
Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis
Mucosal Immunol
(2014)
T. Wen et al.
Molecular diagnosis of eosinophilic esophagitis by gene expression profiling
Gastroenterology
(2013)

C. Blanchard et al.

Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses

Mucosal Immunol

(2008)

J.D. Sherrill et al.

Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis

J Allergy Clin Immunol

(2010)

J.P. Abonia et al.

Involvement of mast cells in eosinophilic esophagitis

J Allergy Clin Immunol

(2010)

S. Foroughi et al.

Anti-IgE treatment of eosinophil-associated gastrointestinal disorders

J Allergy Clin Immunol

(2007)

A.H. Assa'ad et al.

An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis

Gastroenterology

(2011)

R. Fiorentino et al.

Cross-sector sponsorship of research in eosinophilic esophagitis: a collaborative model for rational drug development in rare diseases

J Allergy Clin Immunol

(2012)

C.A. Liacouras et al.

Eosinophilic esophagitis: updated consensus recommendations for children and adults

J Allergy Clin Immunol

(2011)

R.J. Noel et al.

Eosinophilic esophagitis

N Engl J Med

(2004)

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: Supported by Novartis Pharma AG (ClinicalTrials.gov Identifier: NCT01022970).

: Disclosure of potential conflict of interest: M. E. Rothenberg has received consultancy fees from Immune Pharmaceuticals, Receptos, Pluristem Pharmaceuticals, Regeneron, and Novartis; has an equity interest in Immune Pharmaceuticals and Receptos and can receive royalty fees from Teva for reslizumab, which is under development; and is a coinventor on patent applications owned by Cincinnati Children's, concerning the eosinophilic esophagitis transcriptome. T. Wen is a coinventor of a patent application, owned by Cincinnati Children's Hospital, concerning the eosinophilic esophagitis transcriptome. B. Enav reports personal fees from QOL Medical outside the submitted work. I. Hirano reports personal fees from Novartis, Meritage, Aptalis, and Receptos outside the submitted work. S. Kaiser, T. Peters, I. Jones, J. P. Arm, and K. A. Gunawardena are employees of Novartis. R. Strieter is the Global Head for Translational Medicine for Respiratory disorders at Novartis Institutes of Biomedical Research and has stock equity in Novartis. R. Sabo and A. Perez are consultants for Novartis. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: Current location is West Sussex, United Kingdom.

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Food, drug, insect sting allergy, and anaphylaxisIntravenous anti–IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis

Background

Objective

Methods

Results

Conclusions

Section snippets

Study design

Study population

Discussion

Gastroenterology

Gastrointest Endosc

J Pediatr

Gastroenterology

Gastroenterology

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Mucosal Immunol

Gastroenterology

Mucosal Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Gastroenterology

J Allergy Clin Immunol

Eosinophilic esophagitis: updated consensus recommendations for children and adults

J Allergy Clin Immunol

Eosinophilic esophagitis

N Engl J Med

Food, drug, insect sting allergy, and anaphylaxis
Intravenous anti–IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis