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Effect of a novel potent platelet-activating factor antagonist, modipafant, in clinical asthma
L M Kuitert1, R M Angus, N C Barnes
1Department of Thoracic Medicine, London Chest Hospital and National Heart and Lung Institute, United Kingdom.
Abstract:
Platelet-activating factor (PAF), proposed as an important inflammatory mediator in asthma, reproduces several of the features of asthma, such as microvascular leakage, mucus secretion, bronchoconstriction, and possibly increased airway responsiveness. Modipafant (UK-80,067) is the (+)-enantiomer of UK-74,505, a potent and specific PAF antagonist. We have assessed the effect of modipafant over 28 d in adult subjects with moderately severe asthma in a placebo-controlled parallel group study. A total of 218 patients with asthma were enrolled into the single-blind run-in, of whom 120 (93 males and 27 females, mean age 41.0 yr) entered the double-blind treatment phase after demonstrating symptomatic asthma in the final week of the single-blind run-in phase. Patients could take up to 1600 micrograms inhaled corticosteroid and an inhaled beta 2 agonist as rescue medication. A total of 59 patients with asthma took modipafant (one 50 mg capsule twice daily), and 61 took matched placebo. There was no significant difference between placebo and modipafant in diurnal variation in PEF, morning and evening PEF, clinic FEV1, rescue bronchodilator usage, symptom score, or airway responsiveness. We previously showed that the racemate UK-74,505 had no effect on antigen challenge, and this study shows that the active (+)-enantiomer modipafant has no effect in chronic asthma. This suggests that PAF is not an important mediator in asthma.
Insights
Modipafant, a platelet-activating factor (PAF) antagonist, did not improve asthma symptoms or lung function in adults with chronic asthma. These findings suggest PAF may not be a key mediator in this condition.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Immunology
Background:
- Platelet-activating factor (PAF) is implicated as an inflammatory mediator in asthma.
- PAF antagonists are being investigated for asthma treatment.
- Modipafant is a specific antagonist for PAF.
Purpose of the Study:
- To evaluate the efficacy of modipafant in adult patients with moderately severe chronic asthma.
- To determine if blocking PAF improves asthma control and airway responsiveness.
Main Methods:
- A 28-day, placebo-controlled, parallel-group study.
- 120 adult asthma patients received either modipafant (50 mg twice daily) or placebo.
- Standard asthma medications were permitted; outcomes included PEF, FEV1, symptom scores, and airway responsiveness.
Main Results:
- No significant differences were observed between modipafant and placebo groups in diurnal PEF variation, morning/evening PEF, clinic FEV1, rescue bronchodilator use, symptom scores, or airway responsiveness.
- Previous studies with the racemate UK-74,505 also showed no effect on antigen challenge.
Conclusions:
- Modipafant demonstrated no significant benefit in managing chronic asthma symptoms or lung function.
- The results suggest that platelet-activating factor (PAF) is not a critical mediator in the pathophysiology of chronic asthma.