AWZ1066S-001 Anti Wolbachia Phase I
Research type
Research Study
Full title
A single centre, first-in-human, randomized, double-blind, placebo-controlled single and multiple ascending dose studies (SAD and MAD respectively) in healthy adult participants
IRAS ID
297338
Contact name
Graham Devereux
Contact email
Sponsor organisation
Liverpool School of Tropical Medicine
Eudract number
2021-002891-37
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
REC Reference, 21/NW/0239
Duration of Study in the UK
0 years, 6 months, 31 days
Research summary
Research Summary
Lymphatic filariasis 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. What is needed is a safe, cheap short course drug that targets adult worms. 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 have to be given for 4-6 weeks and cannot be used in children.
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 now proposing 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.
Summary of Results
Lymphatic filariasis and onchocerciasis are major public health problems in the tropics. 160 million people are affected around the world. Humans are infected when they are bitten by infected insects that pass on immature worm larvae. These larvae then develop into adult worms that release huge numbers of immature larvae into the body. The larvae damage tissues and result in the diseases of elephantiasis (gross leg and scrotal swelling) and river blindness. Current treatments target the larvae but not adult worms that live for 5-15 years. This means that repeated courses of treatment are needed over many years.The adult worms are critically dependent on a bacterium which lives inside them. This bacterium (Wolbachia) is not naturally found in humans. AWZ1066S is a novel drug developed in Liverpool that targets Wolbachia and kills the adult worms after a 7 day course. After extensive safety testing we conducted a Phase 1, first in human study, to assess the safety of AWZ1066S and how it is handled by the human body.
Healthy male and female volunteers aged 18-65 years received a single dose of AWZ1066S (or placebo) whilst resident in a Clinical Research Facility. They were then closely followed up for 10 days. In addition to checking clinical signs and symptoms, there was monitoring of blood tests, and blood levels of AWZ1066S were measured. The planned single doses of AWZ1066S ranged from 100mg to 1600mg, with each dose being given to a cohort of 8 participants, 6 receiving AWZ1066S and 2 receiving placebo. Participants were randomly allocated to AWZ1066S or placebo. The study was double blind.
In total 29 people took part, 18 (62%) were female, average age was 30.0 years (minimum 20,maximum 61). The single doses of 100mg, 200mg and 400mg of AWZ1066S were completed with no problems. However, after single 700mg doses of AWZ1066S participants developed symptoms of acute gastritis (stomach pain) and there was evidence of liver inflammation. The severity of these side events ranged from mild to severe with one participant needing a brief admission to hospital. This participant also had liver inflammation that settled with time. The study was immediately stopped because of safety concerns.
In summary, administration of a single 700mg dose of AWZ1066S was poorly tolerated and raised safety concerns. Further work is being undertaken to understand the mechanisms underlying the study findings and to explore if AWZ1066S can be given in lower doses.
REC name
North West - Greater Manchester Central Research Ethics Committee
REC reference
21/NW/0239
Date of REC Opinion
21 Oct 2021
REC opinion
Further Information Favourable Opinion