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On-Demand Inhaled Interferon-Beta 1a for the Prevention of Severa Asthma Exacerbations: Results of the INEXAS Phase 2a Study
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A6165 - On-Demand Inhaled Interferon-Beta 1a for the Prevention of Severa Asthma Exacerbations: Results of the INEXAS Phase 2a Study
Author Block: C. McCrae1, M. Olsson2, M. Aurell2, C. Lundin2, J. Paraskos3, A. Cavallin1, M. Kjerrulf1, K. Karlsson4, R. Marsden5, A. Malmgren1, P. Gustafson2, T. Harrison6; 1Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden, 2Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden, 3Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca Cambridge, Cambridge, United Kingdom, 4Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden, 5Synairgen Research Ltd., Southampton SO16 6YD, United Kingdom, 6Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
RATIONALE
Respiratory viral infections (RVI) are major triggers for asthma exacerbations potentially due to an impaired interferon-beta (IFN-β) responses, suggesting that administering IFN-β during RVI could prevent exacerbations.
METHODS
Asthma patients (n=237) on GINA steps 4-5, with a history of ≥2 severe exacerbations related to RVI in the last 24 months, were recruited and entered a waiting phase. Within 48 hours of cold or flu symptoms, subjects were randomized to a 14-day course of 6 million units of IFN-β1a or placebo (Rentschler), given once daily via nebulization (iNeb, Philips). 121 subjects were randomized (61 IFN-β1a). Primary endpoint was rate of severe exacerbations during the treatment period. Secondary and exploratory endpoints included the 6-point asthma control questionnaire (ACQ-6), forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF), serum CXCL10 protein concentrations and sputum levels of five interferon-stimulated genes (ISG). Subgroup analyses included patients with clinically confirmed cold (using the Jackson Cold Score), patients PCR-positive for a respiratory virus in nasal lavage or sputum, and patients stratified on serum CXCL10 level at randomization.
RESULTS
• Severe exacerbation rates were unexpectedly low, with no beneficial effect of IFN-β1a (7 in IFN-β1a group; 5 in placebo)
• Significant improvement in morning PEF (19.7) during days 1-7 of the treatment period (area under the curve; p=0.01)
• RVI induced changes to ACQ-6, asthma symptom score and rescue medication use were mild, with peak worsening occurring at randomization and there was no effect of IFN-β1a.
• Compared to placebo, serum CXCL10 protein and sputum ISG levels were increased by IFN-β1a throughout the treatment period, returning to baseline levels by 3 days post end-of-treatment.
• Similar results were obtained in the subgroup with clinically confirmed colds, as well as the subgroup PCR-positive for respiratory viruses.
• In a subgroup of patients with low serum CXCL10 at randomization, the difference in morning PEF between IFN-β1a and placebo was numerically larger than the overall study population, but was not statistically significant.
CONCLUSIONS
Colds led to severe exacerbations less frequently than expected for this study population. IFN-β1a did not reduce the rate of severe exacerbations, but gave rise to a statistically significant improvement in morning PEF. Pharmacodynamic effect of IFN-β1a was confirmed, with increased levels of serum CXCL10 and sputum ISG. The finding that asthma endpoints had already peaked at randomization suggests that early detection of asthma worsening is essential for an on-demand IFN-β1a therapy to be effective.
Author Block: C. McCrae1, M. Olsson2, M. Aurell2, C. Lundin2, J. Paraskos3, A. Cavallin1, M. Kjerrulf1, K. Karlsson4, R. Marsden5, A. Malmgren1, P. Gustafson2, T. Harrison6; 1Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden, 2Early Clinical Development, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden, 3Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca Cambridge, Cambridge, United Kingdom, 4Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal, Sweden, 5Synairgen Research Ltd., Southampton SO16 6YD, United Kingdom, 6Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
RATIONALE
Respiratory viral infections (RVI) are major triggers for asthma exacerbations potentially due to an impaired interferon-beta (IFN-β) responses, suggesting that administering IFN-β during RVI could prevent exacerbations.
METHODS
Asthma patients (n=237) on GINA steps 4-5, with a history of ≥2 severe exacerbations related to RVI in the last 24 months, were recruited and entered a waiting phase. Within 48 hours of cold or flu symptoms, subjects were randomized to a 14-day course of 6 million units of IFN-β1a or placebo (Rentschler), given once daily via nebulization (iNeb, Philips). 121 subjects were randomized (61 IFN-β1a). Primary endpoint was rate of severe exacerbations during the treatment period. Secondary and exploratory endpoints included the 6-point asthma control questionnaire (ACQ-6), forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF), serum CXCL10 protein concentrations and sputum levels of five interferon-stimulated genes (ISG). Subgroup analyses included patients with clinically confirmed cold (using the Jackson Cold Score), patients PCR-positive for a respiratory virus in nasal lavage or sputum, and patients stratified on serum CXCL10 level at randomization.
RESULTS
• Severe exacerbation rates were unexpectedly low, with no beneficial effect of IFN-β1a (7 in IFN-β1a group; 5 in placebo)
• Significant improvement in morning PEF (19.7) during days 1-7 of the treatment period (area under the curve; p=0.01)
• RVI induced changes to ACQ-6, asthma symptom score and rescue medication use were mild, with peak worsening occurring at randomization and there was no effect of IFN-β1a.
• Compared to placebo, serum CXCL10 protein and sputum ISG levels were increased by IFN-β1a throughout the treatment period, returning to baseline levels by 3 days post end-of-treatment.
• Similar results were obtained in the subgroup with clinically confirmed colds, as well as the subgroup PCR-positive for respiratory viruses.
• In a subgroup of patients with low serum CXCL10 at randomization, the difference in morning PEF between IFN-β1a and placebo was numerically larger than the overall study population, but was not statistically significant.
CONCLUSIONS
Colds led to severe exacerbations less frequently than expected for this study population. IFN-β1a did not reduce the rate of severe exacerbations, but gave rise to a statistically significant improvement in morning PEF. Pharmacodynamic effect of IFN-β1a was confirmed, with increased levels of serum CXCL10 and sputum ISG. The finding that asthma endpoints had already peaked at randomization suggests that early detection of asthma worsening is essential for an on-demand IFN-β1a therapy to be effective.
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