Development of AWZ1066S, a Small Molecule Anti-Wolbachia Candidate Macrofilaricide Drug

NCT05084560 | Terminated Phase 1 DMC

• 1 other identifier: 21-059
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Lymphatic filariasis and onchocerciasis are a group of neglected tropical diseases caused by the transmission of worm larvae (microfilaria) by biting insects. Once a human is infected, the larvae mature into adult worms that release huge numbers of larvae into the lymphatics for 5-15 years. The larvae cause tissue damage resulting in the disabling diseases of elephantiasis (gross leg and scrotal swelling) and river blindness. These diseases affect 160 million people and are acknowledged major public health problems in the tropics. Current treatments mainly target the larvae but not the adult worms that live for years, meaning that repeated courses of treatment over many years are needed. These repeated courses are usually delivered at population level in the form of mass drug administration programmes. For the adult worms to be able to grow, reproduce and infect more humans they are dependent on a bacterium which lives inside them. This bacterium (Wolbachia) is not naturally found in humans. Some drugs are able to target Wolbachia, however they are unsuitable for mass drug administration programmes because they have to be given for 4-6 weeks and cannot be used in children or pregnant women. AWZ1066S is a novel drug developed in Liverpool that has been shown in experimental models to target Wolbachia and indirectly kill the adult parasitic worms after a 7 day course. After extensive safety testing in animals we are conducting a Phase 1, first in human study, to assess the safety, tolerability and pharmacokinetics of ascending single and multiple oral doses of AWZ1066S in healthy volunteers. The study is a single centre study, will last approximately 1 year and will take place in a dedicated Phase 1 trial unit. Depending on which group they are enrolled into, participants will take either one dose, two doses or seven doses and their involvement will last between 38 and 45 days. Participants will be closely monitored for adverse effects.

Conditions

Filariasis, Lymphatic; Onchocerciasis

Keywords

Lymphatic filariasis; Onchocerciasis; Wolbachia; Phase 1; Healthy volunteers; Randomized; Double blind; Placebo

Outcome Measures

Primary Outcomes (1)

• Adverse events

  Number

  From day of first dose to 10 days after last dose

Secondary Outcomes (8)

• Single dose pharmacokinetics Cmax

  From day of first dose to 10 days after last dose

• Single dose pharmacokinetics tmax

  From day of first dose to 10 days after last dose

• Single dose pharmacokinetics t1/2

  From day of first dose to 10 days after last dose

• Single dose pharmacokinetics CL/F

  From day of first dose to 10 days after last dose

• Multiple dose pharmacokinetics Cmax

  From day of first dose to 10 days after last dose

Study Arms (2)

AWZ1066S

EXPERIMENTAL

AWZ1066S Part A Cohort A1- 100mg single dose Cohort A2- 200mg single dose Cohort A3- 400mg single dose Cohort A4- 800mg fasted single dose and 800mg fed single dose Cohort A5- 1200mg single dose Cohort A6- 1600mg single dose The doses for part B will be selected following review of data from Part A. Cohort B1- AWZ1066S once daily for 7 days Cohort B2- AWZ1066S once daily for 7 days Cohort B3- AWZ1066S once daily for 7 days Cohort B4- AWZ1066S once daily for 7 days

Drug: AWZ1066S

Placebo

PLACEBO COMPARATOR

Placebo Cohort A1- equivalent placebo single dose Cohort A2- equivalent placebo single dose Cohort A3- equivalent placebo single dose Cohort A4- equivalent placebo fasted single dose and equivalent placebo fed single dose Cohort A5- equivalent placebo single dose Cohort A6- equivalent placebo single dose The doses for part B will be selected following review of data from Part A. Cohort B1- equivalent placebo once daily for 7 days Cohort B2- equivalent placebo once daily for 7 days Cohort B3- equivalent placebo once daily for 7 days Cohort B4- equivalent placebo once daily for 7 days

Drug: Placebo

Interventions

AWZ1066S DRUG

Candidate drug to treat lymphatic filariasis by targeting Wolbachia endosymbiont

AWZ1066S

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Healthy male and female participants 2 aged 18-65 years 3 BMI 18.0-35.0 kg/m2, maximum weight 100 kg 4 in good health, as determined by: 4a medical history, 4b physical examination, 4c vital signs assessment, 4d 12-lead ECG 4e clinical laboratory evaluations 5 provision of informed consent and abide by study restrictions

You may not qualify if:

• not willing to abide by contraception restrictions
• donated blood in previous 3 months, plasma previous 7 days, platelets previous 6 weeks
• consumption \>14 units of alcohol/week
• tobacco smoking
• concomitant medication, apart from treatments for mild asthma, eczema, contraception, paracetamol
• herbal remedies
• history of anaphylaxis, drug allergy, clinically significant atopic condition as determined by Investigator
• clinically significant medical history, as determined by the Investigator
• positive hepatitis, HIV serology
• live vaccine in previous 3 months, Covid-19 vaccine prior 14 days
• Participants who, in the opinion of the Investigator, should not participate in this study.

Sponsors & Collaborators

• Liverpool School of Tropical Medicine: lead
• Liverpool University Hospitals NHS Foundation Trust: collaborator
• Covance: collaborator
• Subiaco Associates Limited: collaborator
• Sylexis Limited: collaborator
• Eisai Limited: collaborator

Study Sites (1)

Liverpool University Hospitals NHS Foundation Trust

Liverpool, Merseyside, United Kingdom

Location

Related Publications (1)

• Hong WD, Benayoud F, Nixon GL, Ford L, Johnston KL, Clare RH, Cassidy A, Cook DAN, Siu A, Shiotani M, Webborn PJH, Kavanagh S, Aljayyoussi G, Murphy E, Steven A, Archer J, Struever D, Frohberger SJ, Ehrens A, Hubner MP, Hoerauf A, Roberts AP, Hubbard ATM, Tate EW, Serwa RA, Leung SC, Qie L, Berry NG, Gusovsky F, Hemingway J, Turner JD, Taylor MJ, Ward SA, O'Neill PM. AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1414-1419. doi: 10.1073/pnas.1816585116. Epub 2019 Jan 7.

  PMID: 30617067 BACKGROUND

MeSH Terms

Conditions

Elephantiasis, Filarial; Onchocerciasis

Condition Hierarchy (Ancestors)

Filariasis; Spirurida Infections; Secernentea Infections; Nematode Infections; Helminthiasis; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Lymphedema; Lymphatic Diseases; Hemic and Lymphatic Diseases; Skin Diseases, Parasitic; Skin Diseases, Infectious; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Graham Devereux, MD

  Liverpool School of Tropical Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Sequential, ascending dose design, double-blind, placebo controlled. Part A: single ascending dose design with 6 dosing levels. Part B: multiple ascending dose design with 4 dosing levels.

Study Record Dates

• First Submitted: October 5, 2021
• First Posted: October 20, 2021
• Study Start: December 10, 2021
• Primary Completion: May 22, 2023
• Study Completion: May 22, 2023
• Last Updated: September 21, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)