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Introduction: CRSwNP patients (pts) with NSAID-ERD often have more severe disease than non–NSAID‑ERD pts. DPL, a fully human mAb, blocks the shared receptor component for IL-4/IL-13, key drivers of type 2 inflammation. Aim: To assess DPL treatment effects in severe CRSwNP pts with/without NSAID-ERD on a background of intranasal mometasone furoate in pooled populations of phase 3 trials, SINUS-24 (NCT02912468) and SINUS‑52 (NCT02898454). Methods: CRSwNP pts with a medical history of NSAID-ERD were evaluated for endpoints of: nasal polyp score (NPS), nasal congestion (NC), disease severity (VAS), CT Lund–Mackay (CT-LMK) sinus opacification score, UPSIT smell test, total symptom score (TSS), daily loss of smell, SNOT-22. Results: DPL improved NPS, NC, VAS, CT-LMK, UPSIT, TSS, loss of smell, SNOT-22 and reduced the proportion of pts requiring SCS and/or surgery by 79.4/73.8% in pts with/without NSAID-ERD, respectively (all nominal P 5% pts) in the ITT population were nasopharyngitis, headache, worsening NP and asthma, epistaxis, and injection-site erythema, all occurring with higher frequency in PBO-treated pts. Conclusion: DPL improved endoscopic, clinical, radiologic and pt-reported outcomes similarly in CRSwNP pts with/without NASID-ERD and was well tolerated.

Inhaled LPS Challenge has been used to test compounds for COPD. Systemic markers of inflammation, (e.g. neutrophil count, IL-6 levels, and CRP), are associated with risk of acute exacerbation of COPD. Whether an inhaled anti-inflammatory might affect these systemic markers, and the relationship between these markers in lung and serum is unclear. Here we present data on the effect AZD7624, an inhaled p38 inhibitor for COPD, on lung and systemic markers of inflammation after LPS challenge. 30 subjects were randomized in a double-blind, placebo-controlled cross-over study Subjects received a single inhaled dose of AZD7624 (1200 mcg) or placebo 30 minutes prior to LPS challenge, followed by sputum induction 6 hours post challenge (6.5h post dose) and blood sampling at 0.25, 6.5, 12 and 24h post dose for measurement of cell counts and inflammatory biomarkers. AZD7624 attenuated sputum neutrophil differential increase after LPS challenge by 56.8% (P In conclusion, inhaled AZD7624 significantly inhibits LPS-induced lung and systemic inflammation, and lung inflammation markers correlate with systemic markers indicating a potential for AZD7624 as an inhaled treatment for COPD.

Inhibition of p38 mitogen-activated protein kinases has been suggested as novel treatment for COPD. However, since p38 has high expression in tissues other than lung, local delivery may be crucial for an effective treatment while reducing potential unwanted side effects driven by systemic exposure. AZD7624 is a novel P38 inhibitor designed for inhaled administration for COPD. Here we examined the lung and plasma pharmacokinetic (PK) profile of AZD7624 in a rat inhalation model to predict human PK profile, which was validated in a human single ascending dose study. Rats were administrated a single dose of AZD7624 either through dry powder inhalation or intravenously. Lung tissue and plasma samples were taken up to 80 hours post dose for PK determination. AZD7624 (29, 101, 336, 631, and 1177 µg single lung deposited dose) was administrated by inhalation to healthy volunteers and plasma samples were takenfor PK determination. In the rat a long terminal half life in the lung of approximately 60 hours was observed. The ratio between lung and plasma concentration following inhalation was ∼500-1000 times during 24h while IV administration resulted in ∼10 times lower lung-plasma ratio. The human plasma PK parameters were comparable across all doses, and characterized by a rapid absorption followed by a fast distribution phase and a long terminal half-life (64 - 72 h). The human plasma PK was in good agreement with the prediction based on the rat PK, and supports the prediction of a high lung concentration in man. Hence, AZD7624 appears to have promising PK properties for inhaled treatment of COPD.

p38 mitogen-activated protein kinases are well established signaling pathways involved in toll-like receptor-mediated activation of the inflammatory response in alveolar macrophages (AM) that contributes to COPD pathogenesis. AZD7624 is a selective p38α/β inhibitor being developed as an inhaled treatment for COPD. This study addresses the translation from expression of activated p38isoforms in COPD lung to anti-inflammatory properties of AZD7624 in AM and in an acute lung inflammation rat model. Expression of activated p38 isoforms in COPD lung tissue was performed using in situ proximity ligation assay that combines p38 isoform-specific with phospho-specific p38 antibodies. The anti-inflammatory effect of AZD7624 was investigated through effects on cytokine release from LPS-stimulated AM isolated from human lung tissue. Furthermore, rats were exposed to AZD7624 by inhalation followed by LPS challenge and effects on cell recruitment and cytokines in bronchoalveolar lavage (BAL) fluid were quantified at 4 hrs post challenge. In COPD lung tissue, we observed an association of activated p38α/β to AM. In these cells, AZD7624 inhibited LPS-induced TNFα, IL6 and IL8 release with pIC 50 values of 9.1, 9.1, and 8.7 respectively. Furthermore, in the inflammation model, inhaled AZD7624 dose-dependently inhibited LPS-induced neutrophilia, TNFα and IL6 in BAL fluid, with maximal inhibition of 55%, 52% and 73% respectively. In conclusion, the expression profile of activated p38 isoforms in inflamed lung together with the anti-inflammatory activities of AZD7624 observed in this study support our clinical findings (Fageras et al. ATS 2015) and indicate a potential for AZD7624 as a novel inhaled treatment for COPD.