Asthma and lower airway disease
IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers

https://doi.org/10.1016/j.jaci.2014.07.039Get rights and content

Background

Asthma with neutrophil predominance is challenging to treat with corticosteroids. Novel treatment options for asthma include those that target innate immune activity. Recent literature has indicated a significant role for IL-1β in both acute and chronic neutrophilic asthma.

Objective

This study used inhaled endotoxin (LPS) challenge as a model of innate immune activation to (1) assess the safety of the IL-1 receptor antagonist anakinra in conjunction with inhaled LPS and (2) to test the hypothesis that IL-1 blockade will suppress the acute neutrophil response to challenge with inhaled LPS.

Methods

In a phase I clinical study 17 healthy volunteers completed a double-blind, placebo-controlled crossover study in which they received 2 daily subcutaneous doses of 1 mg/kg anakinra (maximum dose, 100 mg) or saline (placebo). One hour after the second treatment dose, subjects underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 4 hours after inhaled LPS. The effect of anakinra compared with placebo on airway neutrophil counts and airway proinflammatory cytokine levels after LPS challenge was compared by using a linear mixed-model approach.

Results

Anakinra pretreatment significantly diminished airway neutrophilia compared with placebo. LPS-induced IL-1β, IL-6, and IL-8 levels were significantly reduced during the anakinra treatment period compared with those seen after placebo. Subjects tolerated the anakinra treatment well without an increased frequency of infections attributable to anakinra treatment.

Conclusions

Anakinra effectively reduced airway neutrophilic inflammation and resulted in no serious adverse events in a model of inhaled LPS challenge. Anakinra is a potential therapeutic candidate for treatment of asthma with neutrophil predominance in diseased populations.

Section snippets

Volunteer recruitment and inclusion criteria

This protocol was reviewed and approved by the University of North Carolina (UNC) Committee on the Rights of Human Subjects (Institutional Review Board) and by the Data and Safety Monitoring Board of the National Institute of Allergy and Infectious Diseases (AADCRC-UNC-03). This study was also reported to and reviewed by the US Food and Drug Administration (IND 14,669) and listed on clinicaltrials.gov as NCT01369017.

This was a double-blind, placebo-controlled crossover study comparing the

Subjects' demographics and adverse events

Twenty-three healthy volunteers were enrolled. Six subjects were excluded after failing the induced sputum screening. Seventeen subjects successfully completed period 1, and 15 subjects completed the entire study (Table I). Eight subjects received active treatment during period 1, and 9 subjects received placebo treatment during period 1.

Two subjects were withdrawn after period 1 because of study-related adverse events. Subject 10 experienced injection-site reactions 1 week after period 1

Discussion

The purpose of this early-phase human study was to determine whether in vivo treatment with anakinra could be a safe and effective intervention in an acute model of neutrophilic airway inflammation induced by LPS inhalation. In healthy volunteers we found that anakinra treatment decreased LPS-induced percentage neutrophils in sputum by 80%. Furthermore, this treatment was well tolerated by our healthy volunteer population.

Although anakinra treatment affected IL-1ra levels in the blood, it did

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    M.L.H. is supported by National Institute of Environmental Health Sciences grant K23-ES021745. K.M., M.A., H.Z., H.Z., and D.B.P. are supported by National Institute of Allergy and Infectious Diseases grant U19AI077437.

    Disclosure of potential conflict of interest: This study was funded by a grant from the National Institute of Allergy and Infectious Diseases (U19AI077437). The authors declare that they have no other relevant conflicts of interest.

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