PrEP-001 prophylactic effect against rhinovirus and influenza virus - RESULTS of 2 randomized trials.

BACKGROUND: PrEP-001 Nasal Powder, a proprietary formulation of polyriboinosinic and polyribocytidylic acid effectively elicits a cellular innate immune response in nasal epithelium. The aim of these 2 studies was to investigate the safety and efficacy of PrEP-001 prophylaxis against rhinovirus (HRV-A16) and influenza-A (H3N2-IAV). METHODS: Healthy subjects randomly received 2 doses of PrEP-001 or placebo, 48 and 24 h pre-challenge with 10 TCID50 of HRV-A16 (Study 1) or H3N2-IAV (Study 2). RESULTS: In Study 1, PrEP-001 reduced median total symptom score from 38.5 to 4.5 (p = 0.004), median symptom duration from 6.0 to 1.7 days and median mucus production from 15 g to 3 g. The percentage of subjects classified as ill was reduced 3-fold (placebo 73%, PrEP-001 23%, p = 0.002). In Study 2, PrEP-001 reduced median total symptom score from 8.0 to 4.1 (p = 0.021), median symptom duration from 4.6 to 3.7 days and median mucus production from 3.6 g to 1.5 g. The percentage of subjects classified as ill was reduced 2-fold (placebo 48%, PrEP-001 24%, p = 0.064). PrEP-001 reduced peak viral shedding in both studies, as assessed by qRT-PCR of nasal lavage. Seroconversion rates were comparable between placebo and PrEP-001 (Study 1: 77% [both arms]; Study 2: placebo 73%, PrEP-001 80%). PrEP-001 was well-tolerated, with no clinically significant adverse events. CONCLUSIONS: PrEP-001 reduced the number of individuals with clinical illness and attenuated severity and duration of HRV-A16 and H3N2-IAV infections without compromising seroconversion, and was well-tolerated. This supports further evaluation of PrEP-001 as a potential pan-viral prophylaxis for upper respiratory tract infections. CLINICAL TRIAL REGISTRATION: Study 1, HRV-A16 study: EudraCT Number 2012-005579-14 (study conducted before ClinicalTrials.gov registration required). Study 2, H3N2-IAV study: EudraCT Number 2015-002895-26 and ClinicalTrials.gov: NCT03220048.

Usefulness of a novel Caco-2 cell perfusion system. I. In vitro prediction of the absorption potential of passively diffused compounds.

A simple, reliable, and user friendly system was established to cultivate Caco-2 cell monolayer for epithelial transport studies. After an initial growth period of 1 week in a CO(2) incubator, Caco-2 cells were cultivated in an automated continuous perfusion system (Minucells and Minutissue, Germany). Medium was constantly renewed at the apical and basal side of the monolayers, which resulted in a continuous supply of nutrients as well as in a continuous removal of metabolite wastes. The monolayers obtained with the new perfusion culture system were evaluated to estimate the passive transport properties of a series of model compounds. The results produced were compared to those of monolayers obtained with the standard 21-day system. The integrity of cell monolayers was checked by measuring transepithelial electrical resistance (TEER) and by the transport of the paracellular leakage marker sodium fluorescein. The results of confocal microscopy as well as TEER measurements indicated the formation of a monolayer on various support filters. The growth and differentiation of Caco-2 cells were highly dependent upon the individual support filters and extracellular matrix proteins used for Caco-2 attachment. The permeability coefficients of several model compounds across Caco-2 cells obtained with the perfusion system were approximately two-fold higher than those obtained using the traditional 21-day Snapwell-based cultures. A good correlation was found between the transport of passively diffused drugs across Caco-2 monolayers differentiated in the perfusion system and the transport according to the standard method. The rank ordering of high permeable model compounds tested through Caco-2 monolayers, differentiated in a perfusion system, was similar to the standard 21-day culture method.