LEAD SERIES DEVELOPMENT & OPTIMISATION OF A NEW DRUG AGAINST ACTIVE AND LATENT TUBERCULOSIS

Lead Research Organisation: Liverpool School of Tropical Medicine
Department Name: Molecular and Biochemical Parasitology

Abstract

According to the most recent estimates, TB killed 1.7 million people in 2009 (approximately a death every 20seconds). Treatment for TB relies on drugs developed some 40 years ago. Unfortunately these drugs are not very good as they require long treatment regimes (6-9 months) and often they do not work due to the ability of the TB bug to develop resistance. Using a novel strategy we propose to develop a new drug that will be able to kill all of the TB bugs quickly including the resistant ones. To develop this drug we have partnered up with industry (GSK pharmaceuticals) and will use industry-like development and management methods. If we succeed in this 2 year project, we are confident that we can secure future funding from the TB Alliance so that we can eventually register our new drug within the next five or six years.

Technical Summary

A major failure of current tuberculosis (TB) therapies is that they predominantly target replicating Mycobacterium tuberculosis (Mtb) but are unable to sterilize slow growing (dormant) Mtb, leading to protracted treatment regimes and the development of drug resistance. We propose to generate a new drug against TB that is able to mitigate the shortcomings of current therapies, leading to improved treatment outcomes. Our strategy is to target the Mtb respiratory chain, specifically NADH:menaquinone oxidoreductase (ndh). This target is essential for the survival of replicating, dormant and drug resistant Mtb, and it is absent in humans. Over the past 2 years we have successfully progressed from target validation/hit identification to the discovery of novel potent (nM) inhibitors of ndh with corresponding potent (nM) in vitro sterilization activity against replicating and dormant Mtb. This proposed schedule of work is to advance these early leads through to late lead development and optimization in readiness for candidate selection.

Publications

10 25 50
 
Description Steering committee for an EU TB drug discovery consortium
Geographic Reach Asia 
Policy Influence Type Participation in advisory committee
 
Description • UK management committee member for COST Action CM1307, 'Targeted chemotherapy towards diseases caused by endoparasites" - 2014- to date
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.costcm1307.org/CM1307/Home.html
 
Description IMI EU FP7 "Model-based preclinical development of anti-tuberculosis drug combinations"
Amount € 478,278 (EUR)
Funding ID 115337 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 05/2012 
End 04/2017
 
Description MRC newton Vietnam
Amount £399,449 (GBP)
Funding ID MR/N028376/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2016 
End 07/2018
 
Description Redx Pharma PLC
Amount £98,000 (GBP)
Organisation Redx Pharma Plc 
Sector Private
Country United Kingdom
Start 10/2016 
End 07/2022
 
Description Research Grant, BMC: DPFS Full
Amount £947,594 (GBP)
Funding ID MR/S00467X/1 
Organisation MRC Biomedical Catalyst Developmental Pathway Funding Scheme (DPFS) 
Sector Public
Country United Kingdom
Start 01/2019 
End 12/2022
 
Description Wellcome Trust - Multi-User Equipment Grant
Amount £600,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2014 
End 10/2019
 
Title GFP-Mycobacterium tuberculosis 
Description We have generated a stable GFP-transformed Mtb. This allows the real-time monitoring of Mtb using fluorescence-based technologies. 
Type Of Material Cell line 
Year Produced 2013 
Provided To Others? Yes  
Impact The GFP-tagged Mtb allows the investigator to "follow" the Mtb infection, replication and viability in a variety of model systems, e.g. intracellular systems, whole blood assay etc. 
 
Title High-content imaging platform for intracellular M. tuberculosis 
Description We have set up a high-content imaging platform for the measurement of intracellular M. tuberculosis. A clinically significant sub-population of Mtb is found inside host cells, e.g. macrophages. Using our HC platform we are now able to identify drugs that are active against this sub-population. This platform will have significant utility in identifying drugs that can treat drug persistent Mtb. 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact This system is currently being evaluated as an improved in vitro system for the clinical prediction of drug activity. If found to be predictive, this system is likely to be incorporated into drug discovery pipelines used by industry and academia. 
 
Title Multi-User Equipment Grant entitled 'Supporting excellence in basic and clinical research: A flow cytometry/sorting and cell imaging platform for the genotypic and phenotypic analysis of Hazard Group 3 pathogens' 
Description Multi-User Equipment Grant entitled 'Supporting excellence in basic and clinical research: A flow cytometry/sorting and cell imaging platform for the genotypic and phenotypic analysis of Hazard Group 3 pathogens' We have set up to our knowledge the first dedicated HG3 imaging facility, able to sort and image HG3 pathogens, e.g. TB and HIV 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact It has just been set up, impact will be described next year 
 
Description AstraZeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution A collaboration is underway for both malaria and TB drug discovery. LSTM research team are providing in vitro and in vivo PD and PK models and expertise in drug discovery for these specific diseases. Aspects of this collaboration are also within the WIPO (World intellectual Property Organisation) umbrella.
Collaborator Contribution AstraZeneca are providing starting points (hits) for testing against TB and malaria and they are also providing HTS expertise, chemoinformatics and ADMET screening. AZ collaborating partners are based both in the UK and India. Aspects of this collaboration are also within the WIPO (World intellectual Property Organisation) umbrella.
Impact multidisciplinary collaboration. The project is still on going and only hit molecules identified thus far. Lead series will be identified in the next 12 months.
Start Year 2011
 
Description Collaboration with GSK 
Organisation GlaxoSmithKline (GSK)
Department Tres Cantos Medicines Development Campus
Country Spain 
Sector Private 
PI Contribution The Liverpool research team undertakes early phase drug discovery of new anti-tuberculosis compounds which includes HTS screening, predictive in vitro models, medicinal chemistry, in vitro ADMET and in vivo DMPK
Collaborator Contribution The GSK team is part of the product development team and specifically carries out in vivo antitubercular testing in their acute and chronic models
Impact The team has generated early leads targeting a novel biological target in M. tuberculosis
Start Year 2011
 
Description Drug Discovery Project to develop combination partners targeting the respiratory chain of Mycobacterium tuberculosis 
Organisation Janssen Research & Development
Country Global 
Sector Private 
PI Contribution Novel strategy to improve the efficacy of bedaquiline and NCE
Collaborator Contribution Janssen have provided Materials e.g. bedaquiline. Discussions are taking place for a formal partnership and funding by Janssen of project as well as exclusive licensing of LSTM IP to Janssen.
Impact No outputs as yet
Start Year 2015
 
Description Guangdong University of Technology, China (GDUT) 
Organisation Guangdong University of Technology
Country China 
Sector Academic/University 
PI Contribution We have set up a Liverpool-Guangdong Drug Discovery Consortium. The consortium, made up of LSTM, University of Liverpool (UoL), Department of Chemistry and the Department of Pharmacy Engineering, Guangdong University of Technology, China (GDUT), is focussed on the development of new drug therapies for the treatment of TB, Malaria and other infectious diseases. A new laboratory has been opened known as the " Liverpool-Guangzhou drug discovery joint laboratory", located at GDUT. The laboratory will accommodate a drug discovery team made up of staff and students from GDUT and other parts of China. Pre-clinical projects targeting TB as well as malaria and NTD infections will be co-developed by the consortium.
Collaborator Contribution We have set up a Liverpool-Guangdong Drug Discovery Consortium. The consortium, made up of LSTM, University of Liverpool (UoL), Department of Chemistry and the Department of Pharmacy Engineering, Guangdong University of Technology, China (GDUT), is focussed on the development of new drug therapies for the treatment of TB, Malaria and other infectious diseases. A new laboratory has been opened known as the " Liverpool-Guangzhou drug discovery joint laboratory", located at GDUT. The laboratory will accommodate a drug discovery team made up of staff and students from GDUT and other parts of China. Pre-clinical projects targeting TB as well as malaria and NTD infections will be co-developed by the consortium.
Impact Compounds have been synthesised and teaching programs are being developed by the consortium
Start Year 2014
 
Description Novel antibiotic nano formulations 
Organisation Blueberry Therapeutics
Country United Kingdom 
Sector Private 
PI Contribution Imaging and PK-PD platform to screen novel antibiotic formulations against Salmonella
Collaborator Contribution nano-formulation expertise and materials
Impact none yet
Start Year 2015
 
Description Shanghai Institute of Organic Chemistry (SIOC.) 
Organisation Shanghai Institute of Organic Chemistry (SIOC)
Country China 
Sector Academic/University 
PI Contribution Shanghai Institute of Organic Chemistry (SIOC.) and the Liverpool groups have begun a collaboration in drug discovery programs. SIOC is providing chemical compounds for screening and helping with complex synthetic routes whilst the Liverpool team is providing testing against TB, malaria and NTDs as well as full pre-clinical support (e.g. pharmacology, biology, med chem), to and clinical.
Collaborator Contribution Shanghai Institute of Organic Chemistry (SIOC.) and the Liverpool groups have begun a collaboration in drug discovery programs. SIOC is providing chemical compounds for screening and helping with complex synthetic routes whilst the Liverpool team is providing testing against TB, malaria and NTDs as well as full pre-clinical support (e.g. pharmacology, biology, med chem), to and clinical.
Impact Shanghai Institute of Organic Chemistry (SIOC.) and the Liverpool groups have begun a collaboration in drug discovery programs. SIOC is providing chemical compounds for screening and helping with complex synthetic routes whilst the Liverpool team is providing testing against TB, malaria and NTDs as well as full pre-clinical support (e.g. pharmacology, biology, med chem), to and clinical.
Start Year 2014
 
Description TB Alliance 
Organisation The Global Alliance for TB Drug Development
Country Global 
Sector Charity/Non Profit 
PI Contribution We have developed inhibitors via the MRC funded project that are at lead stage - these are being tested presently. We are also in discussions with TBA regarding our high content imaging platform, the development of which is supported via a MRC CiC award
Collaborator Contribution TBAlliance have conducted in vivo PK studies on our lead compounds and we will shortly be conducting in vivo drug efficacy experiments using their TB drug development network If successful this will form the basis of a more extensive drug development programme
Impact TBAlliance are providing support in the way of in vivo PK and TB in vivo drug efficacy models (rodent acute model) If successful this will form the basis of a more extensive drug development programme
Start Year 2014
 
Description Using pharmacokinetic - pharmacodynamic analyses to select optimal dosing for non-MDR pulmonary TB treatment failure patients in Vietnam 
Organisation Vietnam Academy of Science and Technology
Country Viet Nam 
Sector Academic/University 
PI Contribution This collaboration has been funded via the MRC-Newton call in collaboration with the MOST ministry of Vietnam
Collaborator Contribution The collaboration is between the UK and a number of institutions in VN (listed above). The project is specifically trying to address the underlying reasons for TB treatment failures but in terms of training, UK researchers are providing training in Pharmacology, specifically pharmacokinetics and PK-PD modelling, addressing a specific expertise gap in VN and the National TB Programme.
Impact Uk researchers have been involved in training VN researchers in the UK and Ethics applications have been submitted and approved for the clinical study due to begin in May 2017.
Start Year 2015
 
Description Using pharmacokinetic - pharmacodynamic analyses to select optimal dosing for non-MDR pulmonary TB treatment failure patients in Vietnam 
Organisation Vietnam National Lung Hospital
Country Viet Nam 
Sector Hospitals 
PI Contribution This collaboration has been funded via the MRC-Newton call in collaboration with the MOST ministry of Vietnam
Collaborator Contribution The collaboration is between the UK and a number of institutions in VN (listed above). The project is specifically trying to address the underlying reasons for TB treatment failures but in terms of training, UK researchers are providing training in Pharmacology, specifically pharmacokinetics and PK-PD modelling, addressing a specific expertise gap in VN and the National TB Programme.
Impact Uk researchers have been involved in training VN researchers in the UK and Ethics applications have been submitted and approved for the clinical study due to begin in May 2017.
Start Year 2015
 
Description Using pharmacokinetic - pharmacodynamic analyses to select optimal dosing for non-MDR pulmonary TB treatment failure patients in Vietnam 
Organisation Vietnam National University
Country Viet Nam 
Sector Academic/University 
PI Contribution This collaboration has been funded via the MRC-Newton call in collaboration with the MOST ministry of Vietnam
Collaborator Contribution The collaboration is between the UK and a number of institutions in VN (listed above). The project is specifically trying to address the underlying reasons for TB treatment failures but in terms of training, UK researchers are providing training in Pharmacology, specifically pharmacokinetics and PK-PD modelling, addressing a specific expertise gap in VN and the National TB Programme.
Impact Uk researchers have been involved in training VN researchers in the UK and Ethics applications have been submitted and approved for the clinical study due to begin in May 2017.
Start Year 2015
 
Title Combination Therapy 
Description Novel design of Combination Therapy for Tuberculosis drugs based on the inhibition of respiratory inhibitors. TheUK patent application has been submitted and the number is 1522232.6 The patent has been submitted and Janssen Pharmaceutica are interested in an exclusive licence - discussion are underway 
IP Reference GB1522232.6 
Protection Patent application published
Year Protection Granted
Licensed No
Impact The patent has been submitted and Janssen Pharmaceutica are interested in an exclusive licence
 
Title New Drug against TB 
Description Lead series identification. The series has activity against MDR TB and currently being assessed for in vivo efficacy 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Lead series identification. The series has activity against MDR TB and currently being assessed for in vivo efficacy. The lead series have a novel mode of action. 
 
Description Manchester Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact October 2013 Manchester Science Festival at MOSI took part in 'I'm a scientist, talk to me' with Science Grrl. Over 100,000 attendees for the festival. Spoke to children and adults, mainly 5 -17 years old.

not known
Year(s) Of Engagement Activity 2013
 
Description Press Release - New Centre for Drugs and Diagnostics 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release of the new LSTM Centre for Drugs and Diagnostics

A breakfast launch meeting was hosted at the British Society for Parasitology in Nest Gardens, 2013 with 20+ representatives of Small-Medium Enterprises
Year(s) Of Engagement Activity 2013
URL http://www.lstmliverpool.ac.uk/about-lstm/news-and-media/latest-news/launch-of-the-lstm-research-cen...
 
Description School Visit (Chester) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact 60 children attended - this was a presentation by me and interactive sessions with the children and teachers.

My visit was discussed by the headmaster at the whole school level and was reported to governors and in local news.
Year(s) Of Engagement Activity 2013
 
Description Science Festival - Lancashire 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact June 2013 the Lancashire Science Festival at UCLAN took part in 'I'm a scientist, talk to me' with Science Grrl. 2500 attendees of all ages, spoke to mainly children aged 4-12.

not known
Year(s) Of Engagement Activity 2013
URL http://sciencegrrl.co.uk/lancashire-science-festival/