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The Lancet

Volume 370, Issue 9596, 20–26 October 2007, Pages 1422-1431
The Lancet

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Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies

https://doi.org/10.1016/S0140-6736(07)61600-6Get rights and content

Summary

Background

Increases in T helper (Th) 2 cytokine concentrations have been seen in atopic asthma, with interleukin 4 and interleukin 13 thought to have a role in the physiological response to allergen challenge. Our aim was to assess the therapeutic effect of pitrakinra, an interleukin-4 variant that targets allergic Th2 inflammation by potently inhibiting the binding of interleukin 4 and interleukin 13 to interleukin-4Rα receptor complexes.

Methods

In two independent randomised, double-blind, placebo-controlled, parallel group phase 2a clinical trials, patients with atopic asthma were treated with pitrakinra or placebo via two routes. In study 1, patients were randomly assigned to receive either 25 mg pitrakinra (n=12) or placebo (n=12) by subcutaneous injection once daily. In study 2, patients were randomly assigned to receive either 60 mg pitrakinra (n=16) or placebo (n=16) by nebulisation twice daily. Inhaled allergen challenge was done before and after 4 weeks of treatment. The primary endpoint for study 1 was maximum percentage decrease in forced expiratory volume in 1 s (FEV1) over 4–10 h after allergen challenge, whereas that in study 2 was average percentage decrease in FEV1 over 4–10 h after allergen challenge. All patients except those with baseline data only were included in our analyses. These trials are registered with ClinicalTrials.gov, numbers NCT00535028 and NCT00535031.

Findings

No patients dropped out or were lost to follow-up in study 1; in study 2, two patients in the placebo group and one in the pitrakinra group dropped out or were lost to follow-up. These individuals had baseline data only, and were excluded from the analyses. In study 1, there was a 17·1% maximum percentage decrease in FEV1 in the pitrakinra group; by contrast, the maximum decrease was 23·1% in the placebo group (difference 6%, 95% CI −4·37 to 16·32; p=0·243). In study 2, there was a 4·4% average percentage decrease in FEV1 in the pitrakinra group; by contrast, the average percentage decrease was 15·9% in the placebo group (3·7 [95% CI 2·08–6·25] times lower in the pitrakinra group; p=0·0001). There were fewer asthma-related adverse events (p=0·069) and fewer adverse events requiring β-agonist rescue (p=0·031) after subcutaneous administration of pitrakinra than with placebo. There were too few asthma-related adverse events in study 2 to assess the effect of inhalation of pitrakinra on adverse events.

Interpretation

Local treatment, targeted at inhibition of interleukins 4 and 13 in the lung, could substantially diminish the symptoms of asthma.

Introduction

The concept that upregulation of T helper (Th) 2 cytokines is critical for the allergic inflammation associated with asthma is nearly 20 years old.1 However, confirmatory evidence that Th2 cytokines such as interleukin 4 or interleukin 13 have a critical role in the onset and development of clinical asthma has, until now, been lacking. Asthma has been reported to be characterised by infiltration of activated T lymphocytes and eosinophils into the bronchial mucosa.2 These cells, along with resident mast cells, secrete soluble growth factors and inflammatory mediators (including interleukin 4 and interleukin 13) that could directly and indirectly modify the mucosal surface. In murine models, this Th2-type immune response leads to a bronchoconstrictive and inflammatory response to allergens which enhances non-specific bronchial hyper-responsiveness.3, 4, 5, 6, 7 However, recent clinical failure of drugs targeting the Th2 process (ie, anti-interleukin 5 and interleukin-4-specific antagonists) has lessened enthusiasm for this pathway's singular importance. Despite these failures, concern has remained that targeting of interleukin 4, to the exclusion of interleukin 13, might have been too selective and that studies that inhibit both of these cytokines are needed.8, 9

One possible approach to inhibiting both interleukin 4 and interleukin 13 is through inhibition or antagonism of interleukin 4Rα, the signalling component of the heterodimeric receptor complex for both interleukin 4 and interleukin 13.10 Interleukin 4Rα forms a complex with the common γ receptor on T cells, where it specifically binds interleukin 4. Interleukin 4Rα can also dimerise with interleukin 13Rα1 on other cell types to bind both interleukin 4 and interleukin 13.11 We developed pitrakinra (Aerovant), a recombinant human interleukin-4 variant that competitively inhibits the interleukin-4Rα receptor complex to interfere with the actions of both interleukin 4 and interleukin 13. This drug, administered either subcutaneously or via nebulisation, protected allergic cynomolgus monkeys from allergen-induced airways hyper-responsiveness and lung eosiniophilia in both prophylactic and therapeutic model settings.12, 13 Subcutaneous administration in monkeys for 6 weeks or more also reduced the cutaneous wheal response and circulating concentrations of allergen-specific IgE.14 In human beings, pitrakinra decreased the eczema clinical score and circulating IgE concentrations, and normalised T-cell subsets in patients with severe atopic eczema after 4 weeks of subcutaneous administration.15 Our aim was to do two phase IIa trials of pitrakinra to investigate whether Th2 immunity was important in a clinical setting where asthmatics are experimentally challenged with aerosolised allergen.

Section snippets

Patients

For both studies, patients with atopic asthma (ages >18 years) were recruited to the Guy's Drug Research Unit, London, UK. Patients with asthma were included if they had a baseline forced expiratory volume in 1 s (FEV1) of 70% or more of predicted, needed regular or as required use of β-agonists, and showed a late phase response (≥15% drop in FEV1 between 4–10 h) to allergen challenge at screening. They must have been on a stable regimen of medications for asthma for 1 month or more, and could

Results

The trial profiles are shown in figure 2. There were no study failures or withdrawals in study 1; by contrast, two patients in the placebo group of study 2 withdrew because of adverse events, one classified as serious (both were asthma attacks precipitated by the allergen challenge protocol). These individuals provided no FEV1 data after 1 h post allergen dose, and so did not contribute to the statistical analysis of the late asthmatic response or PC20 data. Another patient in the pitrakinra

Discussion

Our data show that, compared with placebo, decreases in FEV1 after allergen challenge were significantly attenuated after 4 weeks of inhalation of pitrakinra, lending support to the hypothesis that dual inhibition of interleukin 4 and interleukin 13 can affect the course of the late asthmatic response after experimental allergen challenge. The frequency of spontaneous asthma attacks requiring rescue medication use was also diminished in the first study, suggesting improved control over asthma

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