The effect of the novel phosphodiesterase-4 inhibitor MEM 1414 on the allergen induced responses in mild asthma

Abstract

Background: Inhaled allergen challenge is a standard method to study airway responses to inflammatory provocationand evaluate the therapeutic potential of novel anti-inflammatory compounds in asthma. MEM 1414 is a novel oral PDE4inhibitor with high affinity and selectivity creating the potential for an improved side effect profile vs non-selective PDEinhibitors. We evaluated the tolerability and effect of MEM 1414 on airway responses in mild asthmatics. Methods: A randomised double blind placebo controlled cross over study in two centres, in which sixteen steroidnaïve atopic asthmatics were challenged with inhaled allergen. Subjects were dosed with MEM 1414 (600 mg) orplacebo, twice daily orally for 7 days. Allergen challenge was performed on day 6 (2 hours post-dose), andmethacholine responsiveness was measured 24 hours post allergen (day 7). Biomarkers of drug effects using ex vivoLPS stimulation of whole blood production of interleukin (IL)-6 and leukotriene (LT)-B4 and fractional exhaled nitricoxide (FeNO) were measured on day 6 (0, 2 and 8 hours post-dose). Plasma pharmacokinetics were measured ondays 1, 6 and 7. The primary endpoint was the effect on late asthmatic response to allergen.Results: Treatment with MEM 1414 abrogated the late phase response with a mean difference in FEV1 (LAR 3-10hours) of 104 ml (25%) vs placebo (p < 0.005), with no effect on the early response. Biomarker responses were alsoattenuated with MEM 1414 treatment with reductions in LPS-stimulated whole blood assays for TNFa at 8 hours(p < 0.03) and LTB4 at 24 hours (p = 0.0808) with no change in the IL-6 response. The MEM 1414 treatment phase wasassociated with higher incidence of nausea (6/16 MEM 1414 vs 2/16 placebo) and vomiting (3/16 vs 0/16 placebo). Conclusions: Oral MEM 1414, a novel PDE4 inhibitor, significantly reduces the late response following inhaled allergenchallenge. MEM 1414 also inhibited whole blood assays of cytokine production from inflammatory cells. MEM 1414 wasassociated with a typical adverse event profile of PDE4 inhibitors, namely nausea and vomiting although these weremild side effects.Trial registration number: Current controlled trials ISRCTN48047493.