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 provocation and evaluate the therapeutic potential of novel anti-inflammatory compounds in asthma. MEM 1414 is a novel oral PDE4 inhibitor with high affinity and selectivity creating the potential for an improved side effect profile vs non-selective PDE inhibitors. 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 steroid naïve atopic asthmatics were challenged with inhaled allergen. Subjects were dosed with MEM 1414 (600 mg) or placebo, twice daily orally for 7 days. Allergen challenge was performed on day 6 (2 hours post-dose), and methacholine responsiveness was measured 24 hours post allergen (day 7). Biomarkers of drug effects using ex vivo LPS stimulation of whole blood production of interleukin (IL)-6 and leukotriene (LT)-B4 and fractional exhaled nitric oxide (FeNO) were measured on day 6 (0, 2 and 8 hours post-dose). Plasma pharmacokinetics were measured on days 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 3-10 hours) of 104 ml (25%) vs placebo (p < 0.005), with no effect on the early response. Biomarker responses were also attenuated with MEM 1414 treatment with reductions in LPS-stimulated whole blood assays for TNFα 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 was associated 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 allergen challenge. MEM 1414 also inhibited whole blood assays of cytokine production from inflammatory cells. MEM 1414 was associated with a typical adverse event profile of PDE4 inhibitors, namely nausea and vomiting although these were mild side effects.

TRIAL REGISTRATION NUMBER:

Current controlled trials ISRCTN48047493.

• Authors: Brian R Leaker, Dave Singh, Ferhana Y Ali, Peter J Barnes, Brian O'Connor
• Journal: BMC pulmonary medicine (BMC Pulm Med) Vol. 14 Pg. 166 (Oct 28 2014) ISSN: 1471-2466 [Electronic] England
• PMID: 25351474 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Interleukin-6
• Lipopolysaccharides
• Phosphodiesterase 4 Inhibitors
• Tumor Necrosis Factor-alpha
• Leukotriene B4
• Nitric Oxide

Topics

• Administration, Oral
• Adolescent
• Adult
• Allergens
• Asthma (drug therapy, physiopathology)
• Breath Tests
• Bronchial Provocation Tests
• Cells, Cultured
• Female
• Forced Expiratory Volume
• Humans
• Interleukin-6 (metabolism)
• Leukotriene B4 (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Middle Aged
• Nausea (chemically induced)
• Nitric Oxide (analysis)
• Phosphodiesterase 4 Inhibitors (pharmacology, therapeutic use)
• Time Factors
• Tumor Necrosis Factor-alpha (metabolism)
• Vomiting (chemically induced)
• Young Adult