Zanamivir Pharmacokinetics and Pulmonary Penetration into Epithelial Lining Fluid following Intravenous or Oral Inhaled Administration to Healthy Adult Subjects▿

Zanamivir serum and pulmonary pharmacokinetics were characterized following intravenous (i.v.) or oral inhaled administration. I.v. zanamivir was given as intermittent doses of 100 mg, 200 mg, and 600 mg every 12 h (q12h) for two doses or as a continuous infusion (6-mg loading dose followed by 3 mg/h for 12 h). Oral inhaled zanamivir (two 5-mg inhalations q12h for two doses) was evaluated as well. Each zanamivir regimen was administered to six healthy subjects with serial pharmacokinetic sampling. In addition, a single bronchoalveolar lavage (BAL) fluid sample was collected at various time points and used to calculate epithelial lining fluid (ELF) drug concentrations for each subject. For intermittent i.v. administration of 100 mg, 200 mg, and 600 mg zanamivir, the median zanamivir concentrations in ELF collected 12 h after dosing were 74, 146, and 419 ng/ml, respectively, each higher than the historic mean 50% inhibitory concentrations for the neuraminidases of wild-type strains of influenza A and B viruses. Median ELF/serum zanamivir concentration ratios ranged from 55 to 79% for intermittent i.v. administration (when sampled 12 h after the last dose) and 43 to 45% for continuous infusion (when sampled 6 to 12 h after the start of the infusion). For oral inhaled zanamivir, the median zanamivir concentrations in ELF were 891 ng/ml for the first BAL fluid collection and 326 ng/ml for subsequent BAL fluid collections (when sampled 12 h after the last dose); corresponding serum drug concentrations were undetectable. This study demonstrates zanamivir's penetration into the human pulmonary compartment and supports the doses selected for the continuing development of i.v. zanamivir in clinical studies of influenza

Efficacy and safety of topically applied therapeutic ammonia oxidising bacteria in adults with mild-to-moderate atopic dermatitis and moderate-to-severe pruritus: a randomised, double-blind, placebo-controlled, dose-ranging, phase 2b trial

BACKGROUND: Topical anti-inflammatory therapy is a cornerstone of treatment for atopic dermatitis (AD). However, many unmet needs remain with existing therapies. B244 is a live topical biotherapeutic being tested for the reduction of pruritus and improvement of eczema signs in patients with AD. We aimed to assess the safety and efficacy of B244, compared to vehicle, for patients with mild-to-moderate AD and moderate-to-severe pruritus. METHODS: In this randomised, placebo-controlled, double-blind phase 2b trial, adults aged 18-65 years with mild-to-moderate AD and moderate-to-severe pruritus were enrolled across 56 sites in the USA. Patients were randomised 1:1:1 into a low-dose (optical density at 600 nm [OD] 5.0), high-dose (OD 20.0), or vehicle group for the 4-week treatment period and a 4 week follow-up period. Patients were instructed to apply the topical spray twice daily throughout the treatment period. Randomisation was centrally based (random alternating blocks of 6 and 3) and stratified by site. All participants, investigators, and those assessing outcomes were blinded to the treatment group assignments. The primary endpoint was the mean change in pruritus as measured by the Worst Itch Numeric Rating Scale (WI-NRS) at 4 weeks. Safety was tracked throughout the study. Primary efficacy analyses included the modified intent-to-treat (mITT) population, encompassing those who received at least one dose of study drug and attended at least one post-baseline visit. The safety population included all participants who received at least one does of study drug. This study is registered with ClinicalTrials.gov, NCT04490109. FINDINGS: Between June 4, 2020 and October 22, 2021, 547 eligible patients were enrolled. All study endpoints were meaningfully improved with B244 compared to vehicle. The WI-NRS score was reduced by 34% (-2.8 B244 vs -2.1 placebo, p = 0.014 and p = 0.015 for OD 20.0 and OD 5.0), from a baseline score of \u3e8. B244 was well tolerated with no serious adverse events (SAEs); treatment-emergent adverse events (TEAEs) and treatment related TEAEs were low in incidence, mild in severity, and transient. 33 (18%) of 180 patients given B244 OD 5.0, 29 (16%) of 180 patients given B244 OD 20.0, and 17 (9%) of 186 patients given placebo reported treatment-emergent adverse events; headache was the most frequent (3%, 2%, and 1%, respectively). INTERPRETATION: B244 was well tolerated and demonstrated improved efficacy compared to vehicle in all primary, secondary, and exploratory endpoints and should be further developed as a novel, natural, fast-acting topical spray treatment option for AD and associated pruritus. FUNDING: AOBiome Therapeutics