Cryptococcal meningitis: addressing an urgent global health problem using a translational pharmacological approach

Lead Research Organisation: University of Liverpool
Department Name: Institute of Translational Medicine

Abstract

Cryptococcal meningitis is a frequently lethal fungal infection of the lining of the brain. The most common predisposing condition is advanced AIDS, although cryptococcal meningitis may occur in other circumstances where there is impairment of systemic immunity. Cryptococcal meningitis affects approximately one million people in the world each year and the mortality rate is 60-70%. Recent estimates suggest that cryptococcal meningitis kills more people in sub-Saharan Africa each year than tuberculosis. Unfortunately, there are relatively few active antifungal drugs to treat this infection and each has significant limitations. The best clinical outcomes result from early rapid killing of the fungus in the brain. In the UK this is usually achieved with induction therapy that consists of 2-weeks of intravenous antifungal therapy. Unfortunately, in much of the developing world, it is simply not possible to administer intravenous drugs for any length of time. Hence, the best therapy is not given and clinical outcomes are persistently unsatisfactory.
This research aims to develop new induction regimens that can be used in the developing world. Shorter regimens (even a single day) would facilitate the use of optimal induction therapy and represents an important mechanism to improve clinical outcomes. We will conduct all our research using well-validated experimental models of cryptococcal meningitis. We will study antifungal agents alone and in combination to understand the relationship between concentrations of drug(s) in the brain and the killing of the fungus. We will then use mathematical models and computer simulation techniques to identify human antifungal regimens that we predict will result in the same or better activity to the current standard of care that is delivered in the UK. After the completion of this research, we will seek further funding to conduct clinical trials in subSaharan Africa to test these new regimens. Our research offers the real possibility of making significant advances for the care of patients with a lethal and neglected disease.

Technical Summary

BACKGROUND:
Cryptococcal meningitis is an urgent global health problem. The goal of induction antifungal therapy is to achieve rapid fungal killing because this is associated with improved clinical outcomes. In the UK this is usually achieved with 2-weeks of i.v. amphotericin B deoxycholate?flucytosine. In much of the developing world there are inadequate resources to enable prolonged administration of i.v. drugs or the detection and management of drug-related toxicity. The inability to give i.v. induction therapy is a significant therapeutic obstacle. Importantly, however, the use of shorter induction regimens that still achieve rapid fungicidal activity would facilitate the administration of optimal antifungal therapy in resource poor settings. This research will use well-validated experimental models of cryptococcal meningitis and state-of-the-art mathematical modelling techniques to identify candidate antifungal regimens for resource-poor settings. These regimens can then be immediately expedited for study in clinical trials.
AIMS:
Aim #1. Identify novel induction regimens of amphotericin B deoxycholate that result in the same or better fungicidal activity as 0.7 mg/kg/day administered to humans for 14 days
Aim #II. Define the optimal dosage, schedule of administration and shortest duration of therapy of lipid preparations of amphotericin B that results in near maximal fungicidal activity
Aim #III. Define optimal combination regimens and the shortest duration of therapy that results in the same or better fungicidal activity as standard antifungal combinations administered for 14 days

METHODS: A well-validated murine model of cryptococcal meningitis will be used. The biomarker will be the fungal density in the brain. Pharmacokinetic and pharmacodynamic relationships will be elucidated by studying a range of clinically relevant regimens. Mathematical models that describe the time-course of drug concentrations (in serum and brain) and the associated antifungal effect will be fitted to each dataset. These mathematical models will be used to humanise the mouse in silico (i.e. in a simulator, drug will be given to a virtual mouse to generate a human-like concentration-time profile). The predicted antifungal effect resulting from these innovative regimens will be determined. Key findings will be further validated in a rabbit model of cryptococcal meningitis.
SCIENTIFIC AND MEDICAL OPPORTUNITIES: This research will deliver: (1) new induction regimens for amphotericin B deoxycholate; (2) new induction regimens for lipid preparations of amphotericin B; and (3) new induction antifungal combination regimens. This proposal offers the real possibility to deliver a step change in the management of cryptococcal meningitis for the developing world.
 
Description Amphotericin B Cochleates (Industrial Collaboration)
Amount £100,000 (GBP)
Organisation Matinas Biosciences 
Sector Private
Country United States
Start 04/2017 
End 12/2017
 
Description Funding to obtain preliminary data for a new antifungal compound
Amount £25,000 (GBP)
Organisation Quadram Institute Bioscience 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 10/2016
 
Title Hollow Fibre Model of Infection 
Description an in vitro model in which the concentration time profile of antibiotics in humans can be simulated 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2014 
Provided To Others? Yes  
Impact abstract submission and generation of scientific paper 
 
Title Rabbit model of cryptococcal meningitis 
Description a unique model of disease that is a faithful mimic of human pathogenesis 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact data generation, and generation of new peer reviewed publication 
 
Description Arno Therapeutics 
Organisation Arno Therapeutics
Country United States 
Sector Private 
PI Contribution Collaboration in negotiation
Collaborator Contribution antifungal agent with anticryptococcal activity
Impact research contract under negotiation
Start Year 2014
 
Description Ian Charles 
Organisation University of Technology Sydney
Country Australia 
Sector Academic/University 
PI Contribution Testing of a new agent with anti-cryptococcal activity
Collaborator Contribution New antifungal agents
Impact Research grant in preparation
Start Year 2014
 
Description John Perfect 
Organisation Duke University
Department School of Medicine Duke
Country United States 
Sector Academic/University 
PI Contribution Learning a new rabbit model of cryptococcal meningitis
Collaborator Contribution Training in rabbit model of cryptococcal meningitis
Impact data from rabbit model
Start Year 2012
 
Description Thomas Harrison 
Organisation St George's Healthcare NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution Co-author on recent paper submitted for publication on cryptococcal meningitis
Collaborator Contribution input into clinical relevance of experimental work
Impact manuscript submitted for publication
Start Year 2012
 
Description Thuy Le 
Organisation University of Oxford
Department Oxford University Clinical Research Unit Vietnam (OUCRU)
Country Viet Nam 
Sector Academic/University 
PI Contribution measurement of itraconazole and voriconazole , and PKPD modelling in patients with disseminated Penicillium marneffei
Collaborator Contribution clinical trial funded by MRC
Impact research underway
Start Year 2014
 
Description Tihana Bicanic/ Neil Stone 
Organisation St George's University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution Supervision of Wellcome Trust Fellow (Neil Stone)
Collaborator Contribution Conduct of clinical trial in Africa
Impact in progress
Start Year 2014
 
Title AMBITION Clinical Trial 
Description Trial to determine the safety and efficacy of an abbreviated regimen of liposomal amphotericin B for cryptococcal meningitis (Phase II study). Planning now for a definitive Phase III study. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Clinical findings in Phase II predicted from experimental studies funded by MRC 
URL https://clinicaltrials.gov/show/NCT02136030
 
Title Clinical trial development 
Description Experimental data used to design an definitive clinical trial 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2013
Development Status Actively seeking support
Impact Abbreviated regimens of amphotericin B will likely enable improved therapy in resource poor settings 
 
Title Clinical trial for cryptococcal meningitis 
Description clinical trial to investigate the efficacy of an abbreviated regimen of liposomal amphotericin B 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Actively seeking support
Clinical Trial? Yes
UKCRN/ISCTN Identifier TFDA14/CTR/0004/1
Impact this trial will facilitate the use of an effective antifungal agent in resource poor settings