RATIONALE: IL-4 and IL-13 are key cytokines in the pathogenesis of allergic diseases. AER 003 is a PEGylated recombinant protein derived from human IL-4. Three point mutations (T13D, R121D, Y124D) result in a protein that binds with high affinity to the IL-4 receptorα chain and acts as an antagonist of IL-4 and IL-13, while site-specific PEGylation (40kDa at N38C) extends circulating half life. METHODS: A double-blind, randomized, two-period cross-over study investigated the effect of a single subcutaneous dose of AER 003 or placebo administered on Day 1, on allergen-induced AHR and airway eosinophilia in the Cynomolgus monkey. Airway responsiveness to inhaled methacholine and bronchoalveolar lavage cell composition were determined 3 days before (Day 0) and 2 days after (Day 7) 3 consecutive-day (Days 3-5) inhalations of Ascaris suum extract. Plasma samples for pharmacokinetic (PK) analysis were collected to 34 days post-dose. RESULTS: AER 003 significantly reduced the development of allergen-induced AHR relative to placebo (p = 0.0003), with an improvement in PC100 of 2.24-fold (AER 003/placebo ratio of ANCOVA-adjusted geometric mean PC100 values, with 95% CI of 1.52 to 3.30). By contrast, there was no significant effect of AER 003 on lung eosinophilia (p = 0.69). The PK data indicate a 400-fold reduction in clearance/bioavailability ratio relative to a non-PEGylated IL-4/IL-13 antagonist. CONCLUSIONS: These data strengthens the evidence that heightened IL-4 and IL-13 activity plays a critical role in the pathology of allergic diseases and demonstrate the therapeutic potential of a dual IL-4/IL-13 antagonist, AER 003, for the treatment of allergic diseases.

BACKGROUND:Pitrakinra is a recombinant protein derived from human interleukin-4 (IL-4) that binds to IL-4Ralpha and acts as a competitive antagonist of IL-4 and IL-13. The studies reported here compare the dose-ranging effects of pitrakinra on allergen-induced airway hyperresponsiveness (AHR) and airway eosinophilia when administered subcutaneously (s.c.) or by inhalation to the Ascaris suum-sensitive cynomolgus monkey for the purpose of elucidating the primary site of pitrakinra's anti-asthmatic action.METHODS:Airway responsiveness to inhaled methacholine and bronchoalveolar lavage cell composition was determined before and after three allergen exposures with a 1-week course of twice-daily (b.i.d.) s.c. or inhaled pitrakinra or placebo treatment.RESULTS:Treatment with s.c. pitrakinra significantly reduced allergen-induced AHR, with a maximum effect of a 2.8- to 3.8-fold increase in methacholine PC(100) relative to control (P < 0.05) observed at b.i.d. s.c. doses of 0.05-0.5 mg/kg. Inhaled pitrakinra also significantly reduced AHR with a similar maximum effect of a 2.8- to 3.2-fold increase in methacholine PC(100) relative to control (P < 0.05) at nominal b.i.d. doses of 3-100 mg. The maximal effect on AHR following inhalation was observed at a plasma concentration which exhibited no efficacy via the subcutaneous route. The effect of pitrakinra on lung eosinophilia was not statistically significant following either route of administration, although lung eosinophil count was reduced in all studies relative to control.CONCLUSION:Local administration of pitrakinra to the lung is sufficient to inhibit AHR, one of the cardinal features of asthma, indicating the therapeutic potential of inhaled pitrakinra in the treatment of atopic asthma.

SummaryBackground Cutaneous administration of allergen provides a means to confirm an allergic status, investigate the pathogenesis of allergic diseases, and/or provide a mechanism to evaluate the benefit of new potential therapeutics.Objective Studies were performed to characterize the allergen‐induced cutaneous early‐ and late‐phase response (EPR and LPR) in the cynomolgus monkey.Methods Following intradermal injections of Ascaris suum allergen, the cutaneous weal and flare EPR was measured 15 min post‐injection, and skin biopsies were collected at 8–24 h to determine the optimal time of LPR occurrence. Biopsies were analysed for epidermal and dermal inflammatory changes.Results The EPR was dose related with a reproducible, measurable response at 1 : 10 000 and maximal at a 1 : 100 allergen dilution. In contrast, the threshold dose required for a reproducible LPR was much greater requiring a dilution of 6 : 100, suggesting independent mechanisms for the EPR and LPR. The LPR 20 h post‐allergen injection induced an inflammatory response in the upper and deep dermis. The response was characterized by a moderate perivascular to diffuse inflammation consisting of mononuclear cells, neutrophils and eosinophils. Dexamethasone, while having no effect on the EPR, reduced dermal inflammation (upper dermis, P=0.004; deep dermis, P=0.03). Similarly, dermal eosinophilia was also reduced (upper dermis, P<0.001; deep dermis, P=0.02).Conclusion Collectively, the results indicate the dose dependency of the EPR and LPR. Furthermore, our observations indicate the value of the LPR response in the cynomolgus monkey to evaluate new therapeutics for the treatment of allergic diseases such as atopic dermatitis.