Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma

The enigmatic role of the neutrophil in asthma: Friend, foe or indifferent?

“…144 Consequently, the CXCR2 antagonist AZD5069 also proved ineffective in reducing the frequency of severe exacerbations or improving asthma symptoms or lung function when tested in a phase 2b trial in patients with uncontrolled, severe asthma. 145 Similarly, various strategies that have targeted the potent neutrophil chemoattractant LTB 4 in asthmatics have yielded disappointing results, [146][147][148][149] and treatment with an anti-IL-17 receptor antibody in poorly controlled moderate-to-severe asthmatics failed to show patient benefit. 150 However, it is important to recognize that these clinical studies alone do not fully support the assertion that neutrophils are non-pathogenic in asthma as many of the trials failed to selectively enrol patients with a heightened neutrophilia and the inclusion of subjects of a non-neutrophil endotype may mask efficacy of the treatments.…”

“…Indeed the majority of the evidence is largely circumstantial, generally representing a snapshot of a complex chronic disease with variable origins and aetiologies-consequently studies clearly dissecting the contribution of neutrophils in asthma are limited and predominantly speculative. Similarly, various strategies that have targeted the potent neutrophil chemoattractant LTB 4 in asthmatics have yielded disappointing results,[146][147][148][149] and treatment with an anti-IL-17 receptor antibody in poorly controlled moderate-to-severe asthmatics failed to show patient benefit 150. In a small phase 2 study, administration of an anti-CXCR2 receptor antagonist to asthmatics reduced sputum and peripheral neutrophil counts, with some reduction in mild exacerbations but no improvement in FEV 1 , symptoms or asthma control 144.…”

The development of novel LTA4H modulators to selectively target LTB4 generation

“…There has been significant interest from pharmaceutical companies to target LTA 4 H therapeutically to alleviate LTB 4 -mediated pathologies, but despite the generation of several excellent inhibitors, these drugs have failed to demonstrate clinical efficacy or have been withdrawn from trials owing to deleterious side effects2324. It is feasible that the lack of success of these compounds may be due to their failure to distinguish between the opposing roles of LTA 4 H and thus inadvertently prevent PGP degradation.…”

“…DeCODE pharmaceuticals subsequently utilized a fragment based drug discovery program to identify inhibitors of LTA 4 H, leading to the development of the potent, orally active compound DG-051 that entered phase IIa clinical trials for myocardial infarction and stroke before further development being precluded282930. More recently, Johnson & Johnson developed potent, orally active benzothiazole derivatives as LTA 4 H inhibitors313233 leading to the assessment of JNJ-40929837 in a bronchial allergen challenge model of asthma24. Despite JNJ-40929837 demonstrating clear target engagement and reducing LTB 4 , this drug again failed to show any clinical benefit over placebo24.…”

“…More recently, Johnson & Johnson developed potent, orally active benzothiazole derivatives as LTA 4 H inhibitors313233 leading to the assessment of JNJ-40929837 in a bronchial allergen challenge model of asthma24. Despite JNJ-40929837 demonstrating clear target engagement and reducing LTB 4 , this drug again failed to show any clinical benefit over placebo24.…”