Niclosamide - UNION Therapeutics

At a glance

Originator AntibioTx
Developer UNION Therapeutics
Class Anthelmintics; Anti-inflammatories; Antibacterials; Antineoplastics; Antivirals; Benzamides; Chlorophenols; Nitrobenzenes; Skin disorder therapies; Small molecules
Mechanism of Action Mitochondrial oxidative phosphorylation uncouplers; MTOR protein inhibitors; Notch signalling pathway inhibitors; STAT3 transcription factor inhibitors; Virus internalisation inhibitors; Virus replication inhibitors

Orphan Drug Status

Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

No
New Molecular Entity No

Highest Development Phases

Phase II/III COVID 2019 infections
Phase II Atopic dermatitis; Impetigo
Phase I/II Eczema

Most Recent Events

11 Oct 2023 Adverse events data from a phase II/III PROTECT-V trial in COVID-2019-infections presented at the IDWeek 2023 (IDW-2023)
30 Mar 2022 Phase-II/III clinical trials in COVID-2019 infections (Prevention) in India (Intranasal)
23 Feb 2022 Discontinued - Phase-II for COVID-2019 infections in Germany (Intranasal) (NCT04932915) (EudraCT2021-001036-25)

Development Overview

Introduction

Niclosamide salt, designated as ATx 201, is being developed by UNION Therapeutics (formerly AntibioTx), for the treatment of impetigo, infected eczema and infected atopic dermatitis, caused by Staphylococcus aureus and some species of Streptococcus. The drug is also being developed inhalation formulation designated as UNI 91104, and intranasal formulation designated as UNI 91103, for the prevention and treatment of COVID-2019 infections, caused by coronavirus (SARS-Cov-2). Niclosamide effectively blocks replication of SARS-CoV-2 by targeting host cells to disrupt the viral life cycle. Clinical development is underway in Austria, Denmark, Canada, South Africa, Denmark, Bulgaria, Poland, India and the UK.

However, development of niclosamide salt appears to have been discontinued for COVID-2019 infections in Germany.

This profile has emerged from AntiBiotx' anti-infectives research programme [see AdisInsight drug profile 800044197].

In October 2018, AntibioTx changed its name to UNION Therapeutics^[1].

Company Agreements

In, April 2020, Union Therapeutics collaborated with Institut Pasteur Korea to test an optimised salt form of niclosamide as a treatment of COVID-19 infections.^[2]

Key Development Milestones

Atopic dermatitis

In March 2021, UNION Therapeutics completed its phase IIb trial that assessed the safety and efficacy of topical niclosamide, in adolescents and adult patients, aged 12 years and older, with mild to moderate atopic dermatitis (EudraCT2019-002771-33; NCT04339985; ATX201-207). The randomised, double-blind, dose-ranging trial was initiated in July 2019 and enrolled 210 patients in Denmark, Bulgaria and Poland. In November 2019, the company reported the first patient first visit in the study^[3]^[4].

In March 2018, AntibioTx completed a phase II trial to evaluate the safety and efficacy of niclosamide in patients with atopic dermatitis (ATx201-003; NCT03304470). This three-week, double-blind, randomised, two-arm, vehicle controlled trial was initiated in September 2017 and enrolled 31 patients in Canada^[5]. In December 2018, UNION Therapeutics released positive results from the phase II trial. Niclosamide exhibited broad anti-inflammatory effect on various biomarkers affecting core elements of atopic dermatitis pathology^[6].
In March 2018, AntibioTx completed a phase I trial that evaluated the sensitisation potential of niclosamide topical gel (2% and 4%) in healthy volunteers (ATx201-005; NCT03375957). The randomised, single-blind trial was initiated in January 2018 and enrolled 240 participants in the US^[7]. In October 2018, UNION Therapeutics released positive results from the phase I trial, which complements data from earlier trials in animals and humans and supports safety and tolerability of niclosamide in healthy and abraded skin^[8].

In November 2017, AntibioTx completed a phase I trial that evaluated the irritation potential of niclosamide topical 2% and 4% gel in healthy volunteers on intact and abraded skin (NCT03301870; ATx201-006). The double-blind, parallel, prospective, randomised trial was initiated in October 2017 and enrolled 36 healthy volunteers in the US^[9].

In March 2018, AntibioTx and Medical University of Vienna completed the phase II portion of a phase I/II trial that was evaluating the safety and efficacy of niclosamide 2% topical gel, in the treatment of skin infections of Staphylococcus aureus and Streptococcus, including eczema and atopic dermatitis (DECOLAD; EudraCT2016-003501-33; NCT03009734). The trial was initiated in December 2016 and phase I portion was completed in April 2017. The primary endpoint of the phase I part was to evaluate the tolerability of three formulations of the therapy in healthy volunteers. The best suited formulation was advanced to the phase II portion, which included patients with barrier impaired skin. The randomised, double blind, placebo-controlled trial enrolled 73 adults, including healthy volunteers in the phase I portion and patients in the phase II portion, in Austria^[10]^[11]. Earlier, in September 2016, AntibioTx had submitted a clinical trial application (CTA) to the Austrian Agency for Health and Food Safety, to initiate the study^[12]^[13]^[14]. In December 2018, UNION Therapeutics released positive results from the phase II portion of the trial^[6].

In September 2016, AntibioTx reported that a 28-day repeat dosing, initiated in May 2016, of ATx201 in Göttingen pigs was found to be well tolerated with positive PK data and very low systemic exposure, and no genotoxicity was observed^[15]^[16]^[17]. In December 2015, the company initiated a 28-day dermal toxicity study of ATx201 in Hanford Miniature Swine^[18].

COVID-2019 infections: In February 2021,

UNION therapeutics initiated a phase II/III PROTECT-V trial to test prophylactic interventions against SARS-CoV2 infection in vulnerable patient populations at particularly high risk of COVID-19 and its complications, seeking to identify treatments that either might prevent the disease from occurring or may reduce the number of cases where the disease becomes serious or life-threatening (NCT04870333; CCTU0307; EudraCT2020-004144-28). The double blind placebo controlled study intends to enroll 5000 participants in the UK^[19]. In October 2023, results from the trial were presented at the IDWeek 2023 (IDW-2023)^[20]

In February 2022, UNION therapeutics discontinued the phase II PREVENT trial that was designed to evaluate safety and efficacy of intranasal administration of niclosamide (UNI 91103) in adults with asymptomatic or mild COVID-19 (NCT04932915; UNI91103-201; EudraCT2021-001036-25). The placebo-controlled, randomised trial was designed to enrol approximately 330 patients in Germany ^[21]

In February 2021, the University of Cambridge initiated PROTECT-V phase II/III platform trial to assess if niclosamide nasal spray as a prophylactic agent against COVID-2019 infection, in kidney patients and immunocompromised patients. The randomised, double blind, placebo-controlled, event-driven trial is enrolling approximately 1 500 high-risk volunteers in the UK and India^[19]. The trial was initiated following approval by the UK's Medicines and Healthcare products Regulatory Agency (MHRA). The high-risk immunocompromised patients include dialysis patients, kidney transplant recipients and those with vasculitis or other autoimmune kidney disease or glomerulonephritis. Participants will be randomised to receive either a placebo drug or niclosamide, in addition to their standard of care^[22]^[23]. In March 2021, the National Institute for Health Research (NIHR) granted Urgent Public Health (UPH) prioritisation to the PROTECT-V trial of niclosamide for the prevention of COVID-2019 infection in kidney patients. The study sponsored by Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. Also, in the same month, the trial was expanded to India, containing the niclosamide nasal spray arm only, and the first patient was enrolled in India^[24]. In June 2023, Union Therapeutics announced that 1,233 patients from the United Kingdom and 420 patients from India were randomised to either receive intranasal niclosamide or placebo for up to 36 weeks. The study did not meet its primary endpoint, as no difference was detected between risk of infection in the niclosamide and placebo groups. No major safety signals were reported in the study ^[25]

As of October 2020, the one intranasal formulations designated as UNI91103 and one inhalation formulation designated as UNI91104 are in phase II development for COVID-2019 infections^[26]^[27] (UNION Therapeutics pipeline, October 2020).

In April 2021, UNION Therapeutics announced that the phase I study met all its endpoints and subsequently published the results in The Lancet Regional Health – Europe^[28]. In August 2020, UNION Therapeutics in collaboration with Trial Nation Denmark completed a phase I safety and tolerability study in healthy volunteers (NCT04576312, UNI911-101). This double-blind, placebo-controlled, randomised, multicentre, ascending single and multiple dose regimen study enroled 64 healthy volunteers in Denmark^[29]^[30]^[26]. In July 2020, the Danish Medicines Agency approved UNION Therapeutics' clinical trial application to initiate a clinical trial in healthy volunteers, with an optimised salt form of niclosamide, for the treatment of COVID-2019 infections^[31].

As of August 2020, studies undertaken by the Institut Pasteur Korea, niclosamide acts as a potent inhibitors of SARS-Cov-2 as per in vitro studies. Niclosamide demonstrated to prevent fatal outcomes in a murine model of COVID-19 when administered intranasally^[26]^[27]^[32].

As of April 2020, IND enabling studies are underway in Denmark, for the treatment of COVID-2019 infections (Union Therapeutics pipeline, April 2020)^[2].

Impetigo

In June 2018, AntibioTx completed a phase II trial that evaluated the safety, tolerability, systemic exposure, and activity of topical niclosamide gel (2% and 4%) treatment for 1, 2, or 5 days in outpatients with primary nonbullous or bullous impetigo (ATx201-004; NCT03429595). Evaluation of the incidences of adverse events reports and changes in significant laboratory parameters was the primary endpoint of the trial. The randomised, double blind, placebo control trial was initiated in February 2018, and enrolled 210 patients in South Africa^[33].

Financing information

In July 2020, UNION Therapeutics was awarded financial support from the Innovation Fund Denmark^[31].

Patent Information

In May 2016, European Patent Office recognised primary claims of niclosamide topical gel, as novel and inventive. Earlier, in March 2016, two additional patents were filed for niclosamide topical gel^[34]^[35].

Drug Properties & Chemical Synopsis

Route of administration Inhalation, Intranasal, Topical
Formulation Gel, Spray, unspecified
Class Anthelmintics, Anti-inflammatories, Antibacterials, Antineoplastics, Antivirals, Benzamides, Chlorophenols, Nitrobenzenes, Skin disorder therapies, Small molecules
Target MTOR protein; Notch signalling pathway; STAT3 transcription factor; Virus internalisation; Virus replication
Mechanism of Action Mitochondrial oxidative phosphorylation uncouplers; MTOR protein inhibitors; Notch signalling pathway inhibitors; STAT3 transcription factor inhibitors; Virus internalisation inhibitors; Virus replication inhibitors
WHO ATC code
P02D-A01 (Niclosamide)
EPhMRA code
D11 (Other Dermatological Preparations)

J5B9 (Antivirals, others)

P1B (Anthelmintics, Excluding Schistosomicides)
Chemical name 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide
Molecular formula C13 H8 CL2 N2 O4
SMILES C(C1C(=CC=C(C=1)Cl)O)(=O)NC1C(=CC(=CC=1)[N+](=O)[O-])Cl
Chemical Structure

Download PNG Download MOL file
CAS Registry Number 50-65-7

Indication	Biomarker Function	Biomarker Name	Number of Trials
cOVID 2019 infections	Arm Group Description	Ethanolamine 4-Nitrophenyl sulfate	1 1
cOVID 2019 infections	Eligibility Criteria	C-reactive protein (CRP)	1
cOVID 2019 infections	Outcome Measure	C-reactive protein (CRP)	1
lung disorders	Outcome Measure	C-reactive protein (CRP)	1
ulcerative proctitis	Outcome Measure	Calprotectin C-reactive protein (CRP)	1 1
ulcerative proctosigmoiditis	Outcome Measure	Calprotectin C-reactive protein (CRP)	1 1

Drug Name	Biomarker Function
Niclosamide - UNION Therapeutics	4-Nitrophenyl sulfate	Arm Group Description
	8-oxo-7-hydrodeoxyguanosine	Outcome Measure
	acrosin	Eligibility Criteria
	ALT	Eligibility Criteria
	Androgen Receptor (AR)	Detailed Description
	AR-V7	Eligibility Criteria
	C-reactive protein (CRP)	Outcome Measure
	Calprotectin	Outcome Measure
	carboxyl ester lipase	Eligibility Criteria
	Cholecalciferol	Detailed Description
	Creatinine	Eligibility Criteria, Outcome Measure
	Deacetyldiltiazem	Arm Group Label, Brief Title, Official Title
	Ethanolamine	Arm Group Description
	fibroblast activation protein alpha	Eligibility Criteria
	glomulin, FKBP associated protein	Eligibility Criteria
	Gonadotropin releasing hormone	Eligibility Criteria
	gonadotropin releasing hormone 1	Eligibility Criteria
	Insulin	Eligibility Criteria
	matrix metallopeptidase 7	Outcome Measure
	PSA	Detailed Description, Eligibility Criteria, Outcome Measure
	Testosterone	Eligibility Criteria
	Vitamin D3	Detailed Description

Drug Name	Highest Phase	Owner
Niclosamide - First Wave BioPharma	Phase II	First Wave BioPharma
Niclosamide - Ala Wai Pharma Australia	No development reported (Preclinical)	Ala Wai Pharma Australia
Niclosamide - TFF Pharmaceuticals	Phase I	TFF Pharmaceuticals
Niclosamide - Phytoption	Research	Phytoption
Niclosamide capsules - ANA Therapeutics	Phase II/III	NeuroBo Pharmaceuticals
Niclosamide intramuscular depot - Daewoong Pharmaceutical/ Institut Pasteur Korea	Phase II	Daewoong Pharmaceutical, Institut Pasteur Korea
Niclosamide - Hyundai Bioscience	Phase II/III	Hyundai Bioscience
Niclosamide - SCAI Therapeutics	Clinical Phase Unknown	SCAI Therapeutics

Organisation	Involvement	Countries
AntibioTx	Originator	Europe
UNION Therapeutics	Owner	Denmark
Innovation Fund Denmark	Funder	Denmark
Cambridge University Hospitals	Funder	United-Kingdom
University of Cambridge	Funder	United-Kingdom
Technical university of denmark	Collaborator	Denmark
Institut Pasteur Korea	Collaborator	South-Korea

Adverse drug reaction	Total safety reports	Serious reports	First reports
Chemically induced disorders	1	1	-
Eye disorders	1	1	-

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