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

Abstract

Background Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed. Methods We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1–4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined. Findings The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration. Interpretation UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials. Funding The study was funded by Innovationsfonden Denmark and UNION therapeutics.

Niclosamide shows strong antiviral activity in a human airway model of SARS-CoV-2 infection and a conserved potency against the UK B.1.1.7 and SA B.1.351 variant

“…Niclosamide has been identified as a potent inhibitor of SARS-CoV-2 in vitro and in vivo and its optimized formulation for intranasal application and inhalation, was well-tolerated in healthy volunteers in a Phase 1 trial (10)(11)(12)(13). Herein, we sought to further characterize the anti-viral properties of niclosamide by determining its potency in a human epithelial airway model of SARS-CoV-2 infection and tested its efficacy against several variants of concern of SARS-CoV-2.…”

Niclosamide reverses SARS-CoV-2 control of lipophagy

“…Notably, several repurposed drugs for COVID-19 were found to be associated with autophagy induction (Kim et al, 2012), raising the possibility that some drugs that are already in clinical use for the treatment of parasitic or bacterial infections may be acting, at least in part, via autophagy. The recent clinical testing of intranasal or inhaled NIC (Backer et al, 2021) suggests that the potential of this drug for use in mitigating COVID-19 severity is profound, compeling expansive exploration of different approaches to increase targeted delivery and efficacy.…”

SARS-CoV-2 Antiviral Therapy

“…Niclosamide inhibits SARS-CoV, MERS-CoV, and SARS CoV-2 in cell culture with EC 50 s consistently below 1 μM predominantly in Vero cells ( 333 – 335 ). Oral, inhalational, and injectable formulations of niclosamide are being studied in several small phase 1 and 2 trials ( 336 ) (NCT04399356, NCT04749173, and NCT04603924). Prophylactic intranasal niclosamide is being studied in one phase 3 trial (NCT04870333).…”