Inhalational and intranasal administration
In another approach, the poor oral availability of niclosamide has been circumvented by developing a formulation optimized for inhalation and intranasal administration, aiming to achieve a high concentration in the lung (as the target tissue) whilst limiting systemic exposure to diminish side effects. Backer et al., (2021) published a randomized, double-blind, placebo-controlled Phase 1 trial assessing the safety and pharmacokinetics following inhaled (nebulized) and intranasal administration of a new formulation of niclosamide in healthy volunteers. Participants were randomly assigned to ascending single doses and five repetitive doses over 2.5 days. Inclusion criteria included a forced expiratory volume in one second (FEV1) of 80%. The study did not record any serious adverse events except mild irritation of the upper airways, increased fractional exhaled nitric oxide (FeNO) in 14.7% and an asymptomatic drop in FEV1 in 11.8% of subjects. A major limitation of the study however, was the exclusion of patients with underlying respiratory conditions such as asthma or COPD, thus excluding patients who would be at the highest risk for adverse events via the inhalational route. The maximum systemic niclosamide concentration was lower when compared to the (much higher) oral dose used for anti-helminthic treatment.
Following this Phase 1 study, three Phase 2/3 clinical trials were initiated – two investigating the efficacy of the intranasal administration only - PROTECT trial (a UK Urgent Public Health designated prophylaxis trial in 1500 vulnerable patients) and PREVENT trial (asymptomatic/mild COVID-19 patients receiving UNI91103 BD for ten consecutive days), and finally, the TACTIC-E trial which utilises a combination of intranasal and nebulised niclosamide in moderate to severe COVID-19. For the latter, combined intranasal and intra-pulmonary (via the nebulized route) administration of niclosamide has the potential to be an efficacious approach as aerosol application of niclosamide via the inhaled and intranasal routes enables local delivery at the site of disease. The targeted nasal administration is crucial since the nasopharynx and nasal cavity are both an entry point and a reservoir for SARS-CoV-2 (Gallo, Locatello, Mazzoni, Novelli, & Annunziato, 2021; Sungnak et al., 2020).
In the TACTIC-E trial, the intervention arms are SoC versus SoC plus add-on therapy with either combined nebulized and intranasal niclosamide or combined use of ambrisentan and dapagliflozin, or an unlicensed pharmaceutical preparation of a gut commensal, EDP1815 (Fisk et al., 2021; ”TACTIC-E Trial,” 2020). This stratified platform trial aims to recruit high risk patients at risk of severe COVID-19, and aims to determine if interventions can reduce the risk of progression to a composite endpoint which includes intubation or death. The trial protocol was published prior to the more recent addition of the niclosamide arm (Lu et al., 2020). There is no fixed sample size (similar to other COVID-19 platform trials), but the aim is to recruit approximately 469 participants per arm. The primary endpoint will be the clinical status at Day 14. Deep phenotyping using pharmacological biomarker data aims to better understand the mechanisms that underlie therapeutic efficacy. Overall, the breadth and spectrum of clinical trials utilising niclosamide across the different disease stages of COVID-19 will provide valuable human clinical and pharmacological data and have the potential to enable the development of niclosamide as an effective anti-COVID-19 agent, either in its own right or an as adjunct.