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.