Broad-Spectrum, Patient-Adaptable Inhaled Niclosamide-Lysozyme Particles are Efficacious Against Coronaviruses in Lethal Murine Infection Models

Abstract

Niclosamide (NIC) has demonstrated promising in vitro antiviral efficacy against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Though NIC is already FDA-approved, the oral formulation produces systemic drug levels that are too low to inhibit SARS-CoV-2. As an alternative, direct delivery of NIC to the respiratory tract as an aerosol could target the primary site of for SARS-CoV-2 acquisition and spread. We have developed a niclosamide powder suitable for delivery via dry powder inhaler, nebulizer, and nasal spray through the incorporation of human lysozyme (hLYS) as a carrier molecule. This novel formulation exhibits potent in vitro and in vivo activity against MERS-CoV and SARS-CoV-2 and protects against methicillin-resistance staphylococcus aureus pneumonia and inflammatory lung damage. The suitability of the formulation for all stages of the disease and low-cost development approach will ensure wide-spread utilization.

A randomized, double-blind, placebo-controlled phase 1 trial of inhaled and intranasal niclosamide: A broad spectrum antiviral candidate for treatment of COVID-19

“…They found that intranasal treatment of SARS-CoV-2- and MERS-CoV-infected transgenic mice with 240 µg/kg NIC-hLYS resulted in a significant reduction of viral titers in lung and brain, decreased levels of interstitial pneumonia and reduced inflammation on day 14 post-infection. Moreover, treatment with niclosamide resulted in 30% and 43% survival on day 10 post-infection compared to 0% survival in non-treated SARS-CoV-2 and MERS-CoV mice, respectively [12] .…”

“…Niclosamide has been identified as a potent agent against SARS-CoV-2 with an IC 50 of 0.28 µM and against other respiratory viruses in vitro , such as influenza, respiratory synctial virus and in vivo, such as MERS-CoV and SARS-CoV-2 7 , 8 , 9 , 10 , 11 , 12 , 13 . Brunaugh et al.…”

Lung Delivery Systems to Optimize Pharmacotherapy of COVID-19: A Concise Review

“…At the University of Texas, Austin, efforts have been made to formulate NIC inhalation with human lysozyme (hLYS), an abundant endogenous protein found in the upper and lower respiratory tracts.These formulations showed promising results in both in vitro studies and animal models [91].…”

“…However, NIC demonstrates poor bioavailability. Therefore, adequate therapeutic antiviral level was postulated not likely to be attained with oral formulations [85,[88][89][90].…”

Fast and scalable lipid nanoparticle formulation of niclosamide (nano NCM) effectively inhibits SARS-CoV-2 replication in vitro

“…13 The mechanism of action does not involve inhibition of viral binding, but could be due to the inhibition of intracellular acidification, fusion, 16,17 and/or direct effects on viral replication 14,16 and autophagy. 18,19 There are several ongoing clinical trials with oral NCM in COVID-19 patients (NCT04436458, NCT04399356). However, NCM is a class II drug by the biopharmaceutical classification system (BCS) with very low aqueous solubility (0.25 µg/mL) and with poor oral bioavailability, with plasma concentrations in most subjects below 0.1 µg/mL, 20,21 which is below the IC90 value.…”