LONDON—Investigators are disappointed with the clinical trial results of two promising allergic asthma therapies that suppress eosinophilic inflammation. Interleukin 5 (IL-5) monoclonal antibodies and recombinant human interleukin 12 (rhIL-12) did markedly reduce blood and sputum eosinophil levels in separate trials of patients with mild allergic asthma.[1,2] “However, neither drug significantly altered airway hyperresponsiveness or the late asthmatic response,” Brian J. O’Connor, MD, said in an interview with PULMONARY REVIEWS.

Despite this disappointment, the findings remain important, Dr. O’Connor emphasized, because they challenge the hypothesis that eosinophils are solely responsible for airway hyperresponsiveness and the late response in allergic asthma. “It, therefore, seems that just knocking out this one aspect of the inflammatory process is not the key to developing new asthma drugs,” he suggested. Dr. O’Connor was an investigator for both trials and is a consultant physician in the Department of Respiratory Medicine and Allergy at King’s College Hospital in London.

TRIAL METHODS

Both trials were double-blind, randomized, and placebo-controlled. IL-5 is the major hematopoietin responsible for the terminal differentiation of human eosinophils and thus promotes eosinophilic inflammation; rhIL-12 is a cytokine, which is derived from macrophages, that regulates the balance between TH1 and TH2 cells and that appears to suppress allergic eosinophilic inflammation. It has been suggested that exogenous administration of either rhIL-12 or monoclonal antibodies against IL-5 would combat human allergic asthma.

rhIL-12: To be in the rhIL-12 trial, subjects had to have mild asthma requiring only inhaled ß2-agonists. They also had to have a forced expiratory volume in one second (FEV1) of at least 70% predicted, a positive allergen skin test, early and late asthmatic responses, and a histamine provocation concentration of 8 mg/mL or less.

An early asthmatic response was defined as a drop of at least 15% in the baseline FEV1 during incremental allergen challenge; a late asthmatic response was defined as the same FEV1 decline on three or more occasions four to 10 hours after challenge. If the histamine provocation concentration (the volume required to cause a 20% drop in the FEV1) was 8 mg/mL or less, the patient was considered to have airway hyperresponsiveness.

Researchers excluded from this study people who had smoked in the past five years, used corticosteroids during the previous month, had symptoms of upper respiratory tract infection in the past two weeks, were allergic to grass pollen, or had a history of medical illness other than asthma.

Of the 119 patients screened for the trial, 39 (mean age, 26 years) were included. Once a week for four weeks, 19 of these patients were given rhIL-12 (increasing doses of 0.1, 0.25, 0.5, and 0.5 µg/kg), and 20 received placebo. Treatment and placebo were injected subcutaneously.

The investigators compared the patients’ airway reactivity to bolus inhaled histamine challenge 24 hours before the first injection and 24 hours after the fourth. Peripheral blood and sputum eosinophil levels were also measured at those points. The patients also underwent follow-up four weeks after the final injection.

IL-5 monoclonal antibodies: Of the 76 patients screened for the IL-5 antibody trial, 24 were enrolled. The patients (mean age, 27 years) were men with mild allergic asthma, a baseline histamine provocation concentration below 8 mg/mL, and early and late asthmatic responses based on the same definitions used in the rhIL-12 trial.

The enrollees were atopic, as indicated by positive skin tests for common airborne allergens, and they used short-acting inhaled ß2-agonists as needed. None had worsening asthma or a respiratory infection within the past six weeks.

They were randomized to a 30-minute infusion of 2.5 or 10 mg/kg of IL-5 monoclonal antibodies or placebo in a 2:1 ratio, which placed 16 patients in the treatment groups and eight in the placebo group. Lung function tests and blood eosinophil measurements were performed on days 2 and 3 after the infusion.

On days 8 and 29 after the infusion, airway hyperresponsiveness was assessed with histamine and inhaled allergen challenges. In both instances, sputum was induced the next day to permit sputum eosinophil measurements. Airway hyperresponsiveness and blood eosinophil levels were assessed for up to 16 weeks after the infusion.

STUDY RESULTS WERE DISAPPOINTING

rhIL-12: Four patients in the rhIL-12 group did not finish the trial because of side effects—cardiac arrhythmias in two patients and abnormal liver function and severe flu-like symptoms in one patient each. In fact, most of the rhIL-12 recipients reported a flu-like syndrome marked by headache, fever, and limb myalgia.

Those who completed the trial showed a decrease in blood eosinophil levels from a mean of 0.27 X 109/L before treatment to 0.04 X 109/L. Blood eosinophil values fell only slightly in the placebo group during that time, from a mean of 0.30 X 109/L to 0.27 X 109/L. The blood levels returned to baseline in both groups by the four-week follow-up. A similar pattern occurred with sputum eosinophil concentrations, which markedly declined in the rhIL-12 group (from 18.6% to 8.3%) but not in the placebo group (from 22% to 18.7%).

Though it reduced eosinophil levels, rhIL-12 only produced a nonsignificant trend toward improvement in airway hyperresponsiveness to histamine. It had no effect on the late asthmatic response to inhaled allergen.

IL-5 monoclonal antibodies: “The results were much the same in the IL-5 antibody trial,” reported Dr. O’Connor. Postallergen challenge blood eosinophil levels dropped substantially in both groups given the monoclonal antibody; however, the drop in blood eosinophil concentrations was greater in the 10-mg/kg group than in the 2.5-mg/kg group. Also, the decline in blood eosinophil levels persisted for up to 16 weeks in the10-mg/kg group versus 30 days in the 2.5-mg/kg group. A dose-dependent reduction in sputum eosinophil levels lasting 30 days also occurred in both treatment groups.

As in the rhIL-12 trial, however, treatment did not significantly affect airway hyperresponsiveness or the late asthmatic response. Moreover, it did not produce any clinically important side effects.

THESE TRIALS ARE ONLY THE FIRST ROUND

Given these disappointing results, the studies are a reminder that asthma treatments do not always work as well in humans as they do in animals, said asthma experts Homer A. Boushey, MD, and John V. Fahy, MD, in an accompanying editorial.[3] But, the two trials are only the first round of studies of therapies that target specific cytokines involved in allergic airway inflammation, Drs. Boushey and Fahy noted. “Long-term studies of these approaches, and the identification of new cytokine targets, may provide a different picture,” they suggested.

--Timothy Begany

References
1. Bryan SA, O’Connor BJ, Matti S, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000;356:2149-2153.

2. Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000;356:2144-2148.

3. Boushey HA, Fahy JV. Targeting cytokines in asthma therapy: round one [editorial]. Lancet. 2000;356:2114-2116.

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