| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
* From Dartmouth Medical School (Dr. Mahler), Lebanon, NH; and Abgenix, Inc. (Drs. Huang, Tabrizi, and Bell), Fremont, CA.
Correspondence to: Donald A. Mahler, MD, FCCP, Section of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756-0001; e-mail: Donald.a.mahler{at}hitchcock.org
Abstract
Study objective: To investigate the efficacy and safety of a fully human monoclonal antibody recognizing the chemokine interleukin (IL)-8 in patients with COPD.
Design: Randomized, double-blind, parallel-group, placebo-controlled trial.
Setting: Eighteen clinics/hospitals in the United States.
Patients: One hundred nine patients with stable COPD.
Interventions: Three IV infusions of either monoclonal antibody recognizing IL-8 (800-mg loading dose; 400-mg subsequent doses) or active buffer solution administered monthly over a 3-month period.
Measurements and results: The differences in the transition dyspnea index (TDI) total score, the primary outcome measure, between fully human monoclonal IgG2 antibody directed against IL-8 and placebo were 0.8, 1.0, 0.8, and 0.3 at week 2 (p = 0.046) and months 1 to 3, respectively. At all time points, the proportion of patients achieving 
1 point improvement in the TDI was greater for the monoclonal antibody group compared with the placebo group: 28% vs 11% at week 2 (p = 0.028). There were no significant differences observed for lung function, health status, 6-min walking distance, and adverse events between groups.
Conclusions: The results of this phase 2 study suggest that neutralization of IL-8 with monoclonal antibody therapy may improve dyspnea in patients with COPD. These results support the further investigation of monoclonal antibody therapy targeting IL-8 for the treatment of this disease.
Key Words: chemokine • interleukin-8 • St. George Respiratory Questionnaire • transition dyspnea index
In patients with COPD, the airflow limitation is typically progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.1 Examination of sputum, BAL fluid, and/or bronchial biopsy specimens in patients with COPD have characterized the inflammation as infiltration of neutrophils, macrophages, and CD8+ T-lymphocytes.234567 Various inflammatory mediators such as leukotriene B4 and the cytokines tumor necrosis factor-
and interleukin (IL)-8 have been implicated in the pathogenesis of COPD.8 For example, IL-8 and leukotriene B4 are elevated in sputum of patients with COPD, and both mediators are potent chemoattractants for neutrophils.234567Moreover, stimulated cultured human bronchial epithelial cells obtained by bronchoscopy biopsies produce significantly more IL-8 than unstimulated cells.9
Although maintenance bronchodilators are considered the standard of care for treating the airflow limitation associated with COPD, there is increasing interest in concomitant treatment of the airway inflammation. Various anti-inflammatory agents have been used in patients with COPD, including both oral and inhaled corticosteroids as well as phosphodiesterase inhibitors.1011121314 A novel approach to reduce the inflammatory process in COPD is to target directly the chemokines that attract and activate neutrophils. A fully human monoclonal IgG2 antibody directed against human IL-8 (ABX-IL8) has been developed. This monoclonal antibody blocks binding to IL-8 receptors on neutrophils and neutralizes IL-8–mediated neutrophil activation in vitro.15 Recently, Beeh and colleagues16 showed that pretreatment of sputum supernatant of 20 patients with COPD with an anti–IL-8 antibody led to a concentration-dependent inhibition of neutrophil chemotaxis. By binding and neutralizing IL-8, ABX-IL8 should theoretically reduce free serum and tissue levels of IL-8, and thus reduce the chemotactic gradient triggering neutrophil migration into the airways and lung tissue. Additionally, ABX-IL8 should block IL-8–induced neutrophil activation and degranulation, preventing release of a potent mucin secretagogue, neutrophil elastase.17
The purpose of this study was to examine the efficacy and safety of ABX-IL8 in symptomatic patients with COPD, all of whom had a component of chronic bronchitis. In this pilot study, we hypothesized that three infusions of ABX-IL8 administered monthly would reduce the severity of dyspnea compared with placebo treatment. Dyspnea was selected as the primary outcome measure because it is the major symptom of COPD; furthermore, the original and the updated Global Initiative for Chronic Obstructive Lung Disease guidelines118 emphasize that treatment should focus on relieving the symptoms of the disease. Secondary outcomes included health status, lung function, 6-min walking distance, and rescue use of albuterol.
Materials and Methods
Patients
Patients > 50 years of age with a diagnosis of COPD1 and a history of chronic bronchitis were recruited. Inclusion criteria were as follows: 20 pack-year smoking history; grade 1 or higher for breathlessness on the modified Medical Research Council scale19; and a baseline FEV1 30% and 
70% of predicted and < 70% of FVC. Exclusion criteria were as follows: an increase in FEV1 > 30% or > 300 mL, whichever was greater, at 30 min following two puffs (180 µg) of inhaled albuterol; postbronchodilator FEV1 > 70% of predicted; any history of asthma, bronchiectasis, cystic fibrosis, 1-antitrypsin deficiency, or congestive heart failure; any clinically significant comorbid disease; use of daytime supplemental oxygen; and any recent (within 2 months of screening) COPD exacerbation or pneumonia requiring hospitalization or emergency department treatment; or recent history of a respiratory tract infection (within 2 weeks of screening).
Concomitant use of inhaled long-acting ß-agonists and inhaled short-acting bronchodilators (ipratropium bromide and ß- agonists) were allowed, but were withheld for 12 h and 6 h, respectively, prior to each study visit. Use of systemic corticosteroids was not allowed during the study except to treat an exacerbation. Inhaled corticosteroids, oral ß-agonists, and theophylline preparations were discontinued 3 weeks prior to the first infusion.
Study Design
A randomized, double-blind, placebo-controlled, parallel-group trial was conducted at 18 centers in the United States. The Institutional Review Board at each center approved the protocol. Informed written consent was obtained. Patients were randomized 1:1 to receive ABX-IL8 (concentration of 10 mg/mL; 10 mM sodium phosphate; 138 mM sodium chloride; pH 6.0) or active buffer solution (10 mM sodium phosphate; 138 mM sodium chloride; pH 6.0) as placebo administered by IV infusion. The volume of fluid administered was the same for both active and placebo treatments. Randomization was performed centrally, and patients were stratified by bronchodilator response and by FEV1 < 40% or 40% of predicted.
There were eight visits: the screening period (one visit), the treatment period (baseline, week 2, month 1, month 2, month 3); and the follow-up period (month 4 and month 5). All treatments were administered by IV infusion over 30 min; a loading dose (800 mg) was administered at the baseline visit (month 0), followed by two doses of 400 mg administered monthly thereafter (month 1 and month 2). The dosing regimen was selected on the basis of unpublished clinical trial data supporting its safety in patients with rheumatoid arthritis and in patients with psoriasis.
Outcome Measures
Dyspnea was measured using the baseline dyspnea index (BDI) at the initial visit and the transition dyspnea index (TDI)20 at all subsequent visits. The BDI is a discriminative instrument that measures the severity of breathlessness at a baseline state; the TDI is an evaluative instrument that measures the changes in breathlessness compared to the baseline or initial visit. Both instruments include three components that affect the severity of dyspnea with activities of daily living: functional impairment, magnitude of task, and magnitude of effort.20 The primary outcome measure was the TDI total score, which represents the sum of scores for the three components (range, – 9 to + 9). The BDI and TDI have been used widely in randomized clinical trials to evaluate the efficacy of bronchodilator medications,2122232425 long-acting ß-agonist and inhaled corticosteroid combination,1226 pulmonary rehabilitation,272829 and inspiratory muscle training.3031
Secondary outcomes included change from baseline in prebronchodilator and postbronchodilator FEV1, the St. George Respiratory Questionnaire (SGRQ),32 6-min walking distance, and use of albuterol as rescue therapy. Spirometry was measured at each visit using the Koko spirometer (PDS Research; Louisville, CO). The SGRQ and 6-min walk were assessed at baseline and at each monthly visit. Lung volumes were measured by body plethysmography at baseline and again at the 3-month visit using available equipment at each testing site. Patients maintained a diary of daily use of albuterol as rescue therapy.
A COPD exacerbation was defined in the protocol as "a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD."33 All reported COPD exacerbations were reviewed prior to unblinding, and only those that met this definition were included in the analysis.
Safety was assessed at each study visit by recording of adverse events, complete blood tests, and urinalysis. Blood samples were obtained prior to and 30 min after completion of dosing at each dosing visit for measuring plasma levels of ABX-IL8. Serum was obtained at baseline and at each monthly visit for measurement of IL-8 levels and at baseline and from month 3 through month 5 for detection of human anti-human antibodies to ABX-IL8.
Concentrations of total IL-8 in serum samples collected at baseline were determined by the QuantiGlo Human IL-8 Chemiluminescent Immunoassay (R&D Systems; Minneapolis, MN), as described by the manufacturer. For determination of ABX-IL8 in serum samples, an enzyme-linked immunosorbent assay (ELISA) was developed at Abgenix, Inc. (Fremont, CA). Briefly, 96-well ELISA plates were coated with recombinant human IL-8. After blocking and washing steps, samples were diluted in 10% normal serum and added to the plates. After removal of unbound material, horseradish peroxidase-labeled mouse-anti-human IgG2 was added. Excess enzyme conjugate was removed by washing, and K-BLUE substrate (Neogen Corporation; Lexington, KY) was added to the wells. Enzyme reaction was stopped by the addition of 2 mol/L sulfuric acid, and the absorbance was measured at 450 nm. In addition, detection of human anti-human antibody response in serum samples was accomplished using a sandwich ELISA assay.
Statistical Analysis
Efficacy analyses were performed on the modified intent-to-treat populations that included all randomized patients with at least one TDI assessment. A sample size of 65 patients per group was considered sufficient based on a mean difference of 1 U in the TDI total score (considered the minimal clinically important difference)3435 at the 5% significance level with a power of 80% assuming a SD of 2.0 U in the TDI. The TDI total score was analyzed using an analysis of variance model with treatment and sites as the main factors. In addition, the proportions of patients achieving a TDI total score of 1 was compared between ABX-IL8 and placebo groups using the 
2 test.
Change from baseline in secondary end points was analyzed in patients with both baseline and posttreatment values using an analysis of covariance model with treatment and sites as main factors and the baseline value as the covariate. Other between-group comparisons used the 2 test unless the number of patients in one or more cells of the frequency table was less than five, in which case the Fisher exact test was used. If patients received disallowed concomitant medication (eg, corticosteroids, theophylline, leukotriene-receptor antagonists) to treat a COPD exacerbation, then the lowest of the pre-exacerbation or postexacerbation score was imputed during the time the patient was receiving the disallowed medication. The proportion of patients with treatment-emergent COPD exacerbation was compared between ABX-IL8 and placebo using the 2 test. Safety analyses were based on data collected from all randomized patients. Baseline characteristics of the placebo and ABX-IL8–treated groups were compared using either an unpaired t test or 2 test. Values are reported as mean ± SEM; p < 0.05 was considered statistically significant.
Results
Patient Disposition
One hundred nineteen patients were randomized to one of two treatment groups (Table 1
). Ten patients (7 patients receiving placebo, and 3 patients receiving ABX-IL8) withdrew from the study prior to the first scheduled administration of the study drug. These patients did not have a TDI assessment, and are therefore not included in the efficacy analyses. The remaining 109 patients constitute the modified intent-to-treat population. Overall, 99 patients (91%) received all three infusions of the study medication.
|
|
|
|
1 was higher in ABX-IL8–treated patients compared with placebo-treated patients at all time points (Fig 3
). However, the only statistically significant difference occurred at week 2 (28% vs 11%; p = 0.03). There were no differences in the TDI response based on baseline FEV1 percentage of predicted, bronchodilator response, or smoking status.
|
|
Health Status
At the end of the treatment period (month 3), patients treated with ABX-IL8 had a change of – 4.0 ± 2.0 U (n = 51) in the SGRQ compared with a change of – 2.1 ± 2.7 U (n = 51) for those who received placebo (
1.9; p = 0.68).
Other Outcomes
The mean change from baseline in the 6-min walking test throughout the treatment period was < 20 m (p = 0.2) for either treatment group. At baseline, the placebo and ABX-IL8 treatment groups averaged 3.9 ± 0.6 puffs per day and 3.4 ± 0.4 puffs per day of rescue albuterol, respectively. The differences between ABX-IL8–treated and placebo-treated patients in the change from baseline in the average number of puffs per day of rescue albuterol were small (– 0.1 puffs, – 0.2 puffs, – 0.4 puffs, and – 0.1 puffs per day at week 2, month 1, month 2, and month 3 visits, respectively), and were not statistically significant.
Safety and Adverse Events
ABX-IL8 and placebo infusions were well tolerated by all subjects. There were no significant infusion-related reactions reported, and no infusions were stopped because of an adverse event.
The percentage of patients experiencing adverse events was similar in the two treatment groups (Table 4 ). Five placebo-treated patients (respiratory failure, COPD exacerbation, hypersomnia, angina, and headache) and one ABX-IL8–treated patient (pneumonia) discontinued because of an adverse event (p = 0.11). The three most common adverse events considered drug related were COPD exacerbation, lower-extremity edema, and congestive heart failure.
|
Discussion
There are no current guidelines or recommendations for selection of the most appropriate primary outcome measure for evaluating biological agents for the treatment of COPD. In a study of monoclonal anti-IgE antibody therapy in patients with asthma, Milgrom and colleagues36 used the asthma symptom score for assessing efficacy. These investigators found significant improvements in this outcome, but no significant change in FEV1 at 12 weeks with either a high dose or a low dose of the monoclonal antibody. We also selected a symptom outcome, dyspnea reflected by activities of daily living as measured by the TDI, to evaluate efficacy in our study for several reasons. First, the Confronting COPD International telephone survey documented that dyspnea is the major complaint of patients with COPD.37 Second, the Global Initiative for Chronic Obstructive Lung Disease guidelines118 have emphasized that the treatment of patients with COPD should be directed toward relief of symptoms. Third, there is no rationale that a monoclonal antibody directed against a chemokine should enhance lung function, a traditional metric used to assess efficacy in trials involving bronchodilator medications.
The major findings of this pilot study were as follows: (1) ABX-IL8 reduced the severity of dyspnea as measured with the TDI compared with placebo; (2) there were no significant differences in lung function, health status, or rescue albuterol use between treatment groups; (3) the infusions of ABX-IL8 were well tolerated; and (4) adverse events were similar between the treatment and placebo groups. The TDI total score was selected to measure the changes in the severity of breathlessness in this study for two reasons: (1) it has been used widely in clinical trails, and (2) it has been shown to be responsive to a variety of interventions involving patients with COPD.2122232425262728293031 Our results showed that ABX-IL8 provided relief of dyspnea that was evident at 2 weeks after the first infusion and persisted for a 2-month period (Fig 2). However, only the difference in the TDI total score at 2 weeks between treatment groups achieved statistical significance. The early onset of the effect could be a result of the higher loading dose (800 mg) and the higher maximum serum concentration in the first dosing interval. After 2 months, there was a steady decline in the TDI total score that may be related to the lower doses of the monoclonal antibody. At the end of the follow-up period, the TDI total score for ABX-IL8–treated patients had returned to baseline, whereas the placebo-treated patients slowly improved. The loss of drug benefit during the follow-up period is consistent with the decreased drug exposure. In addition, it is possible that reduction in IL-8 could lead to a compensatory increase in proinflammatory mediators that could diminish the efficacy of ABX-IL8 over time.
This effect of ABX-IL8 raises interesting questions about the perplexing and challenging problem of breathlessness experienced by patients with COPD. Clearly, the improvements in breathlessness were not due to enhanced lung function. Whether any reduced infiltration of neutrophils as expected with ABX-IL8 could influence airway and/or tissue receptor activity that modulates the perception of dyspnea is speculative. However, vagal-mediated receptors and nerve fibers are located in the lung and transmit afferent information to the CNS. Moreover, previous studies101226 have demonstrated that inhaled corticosteroids alone and in combination with long-acting ß-agonists reduce the severity of dyspnea in patients with COPD. Thus, it is reasonable to postulate that an anti-inflammatory effect may influence breathlessness, although the exact mechanism(s) are not understood.
The improvement in the TDI total score with ABX-IL8 compared with placebo was 1-U difference at 1 month, and approached this level (differences in TDI scores of 0.8) at 2 weeks and at 2 months. The magnitude of this benefit is considered clinically meaningful,3435 and was comparable to the reported improvements in TDI total scores with individual bronchodilator therapy or with combination medications.1222232425
There were no significant changes in spirometry, lung volumes, health status, or the 6-min walking distance with either treatment or between groups. Although ABX-IL8 treatment was associated with a greater improvement in the total score of the SGRQ than with placebo, the difference ( 1.9 U) did not achieve the 4-U level considered clinically meaningful.32 However, at least 6 months of treatment may be required to demonstrate the expected benefits in health status with pharmacologic therapy.2338 Rescue albuterol use was slightly lower (range, – 0.1 to – 0.4 puffs per day) in the active-treated group, compared to placebo. It is possible that the concomitant use of long-acting ß-agonists and ipratropium bromide may have limited the utility of this end point.
Treatment with ABX-IL8 was both safe and well tolerated. Importantly, there were no infusion reactions; adverse events, including COPD exacerbations, were similar between treatment and placebo groups. Moreover, no patients had detectable antibodies to ABX-IL8.
There are two major limitations with this clinical trial. First, the dose of ABX-IL8 may have been suboptimal to demonstrate efficacy. The dose was selected based on the highest doses administered in previous phase two trials in patients with other inflammatory diseases (rheumatoid arthritis and psoriasis) in which IL-8 is elevated (unpublished data). The dosing regimen in this study resulted in trough serum concentrations of ABX-IL8 (approximately 40 µg/mL) that exceeded the concentration required to inhibit IL-8 binding to neutrophils in vitro by 90% (approximately 0.12 µg/mL).15 However, it is likely that the concentration of ABX-IL8 in the airway was substantially lower than serum and may not have been sufficient to fully inhibit IL-8 activity. Second, treatment was administered for only 3 months. Additional doses may be required over a longer time period (eg, 1 year) to more completely evaluate the benefit/safety profile of ABX-IL8.
To the best of our knowledge, this is the first report of a trial of monoclonal antibody therapy targeted against an important chemokine in patients with COPD. So far, there are two reports of using monoclonal antibodies in the treatment of asthma. As previously mentioned, Milgrom and colleagues36 demonstrated the efficacy of a monoclonal antibody directed at IgE, and this product has been approved for the treatment of asthma in the United States. More recently, Kips et al39 described a pilot study of humanized anti-human IL-5 antibody in the treatment of severe asthma. Clearly, the use of biological agents to target the inflammatory process provides a novel approach for the treatment of COPD.40
This pilot study provides preliminary support for further investigation of using monoclonal antibody therapy to treat the inflammatory component of COPD. Further work will be necessary to examine the appropriate doses, selection of outcome measures, and inclusion of biomarkers to determine the efficacy as well as mechanisms of action of biological agents in this disease. Moreover, patients with elevated levels of IL-8 as measured in serum and/or sputum, such as those experiencing an exacerbation of COPD or those with pronounced expression of systemic inflammation, may be more appropriate for targeting treatment with ABX-IL8.
Acknowledgements
The authors thank the following investigators who participated in this trial (ABX-0209): Theodore Amgott, MD, Melbourne, FL; William Beliveau, MD, Johnston, RI; Richard Casaburi, MD, Torrance, CA; James Donohue, MD, Chapel Hill, NC; Richard Fei, MD, Lafayette, LA; Charles Fogarty, MD, Spartanburg, SC; Eric Kleerup, MD, Los Angeles, CA; Bernard Levine, MD, Phoenix, AZ; Michael Littner, MD, Sepulveda, CA; Imre Noth, MD, Chicago, IL; Stephen Rennard, MD, Omaha, NE; Gerardo San Pedro, MD, Shreveport, LA; Frank Sciurba, MD, Pittsburgh, PA; David Silverstein, MD, St. Petersburg, FL; Stuart Simon, MD, Austell, GA; Raymond Tidman, MD, Blue Ridge, GA; and Sally Wenzel, MD, Denver, CO.
Footnotes
Abbreviations: ABX-IL8 = fully human monoclonal IgG2 antibody directed against interleukin-8; BDI = baseline dyspnea index; ELISA = enzyme-linked immunosorbent assay; IL = interleukin; SGRQ = St. George Respiratory Questionnaire; TDI = transition dyspnea index
Funding was provided by Abgenix, Inc.
Dr. Mahler was a consultant to Abgenix on this study.
Received for publication January 23, 2004. Accepted for publication April 21, 2004.
References
in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153,530-534[Abstract]
This article has been cited by other articles:
|
|
 |
|
  B. R. Celli Update on the Management of COPD Chest, June 1, 2008; 133(6): 1451 - 1462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Siddiqui, F. Hollins, S. Saha, and C. E. Brightling Inflammatory cell microlocalisation and airway dysfunction: cause and effect? Eur. Respir. J., December 1, 2007; 30(6): 1043 - 1056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Mahler, L. A. Waterman, J. Ward, C. McCusker, R. ZuWallack, and J. C. Baird Validity and Responsiveness of the Self-Administered Computerized Versions of the Baseline and Transition Dyspnea Indexes Chest, October 1, 2007; 132(4): 1283 - 1290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Mahler Mechanisms and Measurement of Dyspnea in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, May 1, 2006; 3(3): 234 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-i. Inoue, H. Takano, R. Yanagisawa, T. Yoshikawa, D. A. Mahler, and G. M. Bell Interleukin-8 Neutralization for COPD Chest, July 1, 2005; 128(1): 464 - 465. [Full Text] [PDF]
|
|
|
|
|
|
P. J. Barnes and R. A. Stockley COPD: current therapeutic interventions and future approaches Eur. Respir. J., June 1, 2005; 25(6): 1084 - 1106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Buhl and S. G. Farmer Future Directions in the Pharmacologic Therapy of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2005; 2(1): 83 - 93. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
