Dr Mike Bromley talks about the role of Manchester University in the research and development of new antifungal drugs, followed by Dr Iain Page talking about our research projects in Africa that have the potential to reveal much larger numbers of people suffering from Chronic Pulmonary Aspergillosis (CPA) than is currently thought.

1. L E D B Y G R A H A M A T H E R T O N
S U P P O R T E D B Y
G E O R G I N A P O W E L L , D E B B I E K E N N E D Y & D E B H A W K E R
N A C C E N T R E M A N A G E R C H R I S H A R R I S
A S P E R G I L L U S R E S E A R C H – M I K E B R O M L E Y
A F R I C A N A S P E R G I L L O S I S – I A I N P A G E
N A T I O N A L A S P E R G I L L O S I S C E N T R E
U H S M
M A N C H E S T E R
Support Meeting for
Aspergillosis Patients & Carers
Fungal Research Trust

2. Car Parking
 £3 all day in the Nightingale Car Park (opposite
NWLC)
 Leave note in your windscreen saying
North West Lung Centre Delegate

3. Programme
 1.30 Mike Bromley – Aspergillosis Research
 1.55 Iain Page – Our work in Gulu, Africa
 2.15 Carers Discussion (Break)
 2.30 Patients Discussion (Break)
 2.45 Group discussion/Requests for information
 Itraconazole toxicity – risk of heart problems
 Low – allergy gardening (Book)
 Artificial organs – kidney
 Food for patients meeting?
 Damp homes – do you see damp/moulds?
 Travel
 3.15 Q & A from the floor or online

4. Development of the next generation
of antifungal drugs
Mike Bromley PhD

5. Do we need new anti-fungals?
• Invasive fungal diseases are common, debilitating, and
difficult to treat
• Few classes of drugs to treat invasive fungal disease
– Azoles, echinocandins, polyenes, 5FC
• Limited range of targets involved
• Drug toxicities/ drug-drug interactions / bioavailability
• Emerging resistance
– Particularly with reference to azoles and 5FC
• Unmet need
– Zygomycetes, Fusarium

6. Why would anyone bother?

7. The importance of fungal disease
• Fungal diseases have an enormous global
financial burden
– $60 billion damage to rice, wheat and maize crops
– $12.2 billion market for antifungal therapeutics
• Systemic human disease
– 37% market for therapeutics for invasive disease
(2010)

8. Is it financially viable?
Product/
Brand name
Generic name Class Company
Patent expiry
(US)
Peak annual
sales
(Million USD)
Ambisome
Liposomal
amphotericin B
Polyene Astellas/ Gilead Expired 2004 550
Abelcet
Lipid complex
amphotericin B
Polyene Elan/ Enzon Expired 2003 --
Cancidas Caspofungin Echinocandin Merck & Co Mar 2013 500
Diflucan Fluconazole Azole Pfizer Expired 2004 1200
Eraxis Anidulafungin Echinocandin Pfizer 2015 n/a
Mycamine Micafungin Echinocandin Astellas Sep 2015 350
Noxafil Posaconazole Azole
Schering-
Plough
Apr 2018 n/a
Sporanox Itraconazole Azole Janssen Expired 2000 900
Vfend Voriconazole Azole Pfizer May 2016 750
DataMonitor, 2007.

9. Current antifungal classes
Class Target Discovered Drug
Azole Lanosterol 14DM 1944 Benzimidazole
Polyene Membrane 1950 Nystatin
Candins Glucan synthase 1974 Echinocandin B
Pyrimidine
analogue
Pyrimidine biosynthesis 1961 Flucytosine

10. Commercial retrenchment from anti-
infective discovery
• Only a few major pharmaceutical companies are
currently operating anti-infective programs
– Highlights a change in the way that all drug discovery is
going
– Emphasis is now on small companies and Universities to
perform the early stage research function

11. The stages of drug discovery
Pre-clinical drug
discovery
GSK
$70 million
No P1 drug

12. Antifungals in development
Compound Drug Target Status Company
Isavuconazole Lanosterol 14DM Phase III Basilea/Astellas
KP-103 Lanosterol 14DM Phase III Kaken
SPK-843 Membrane Phase III Proaparts
Mycograb HSP90 Phase II Novartis/NeuTec
Icofungipen Isoleucyl-t-RNA synthase Phase II Plivia/Bayer
MK-3118 Glucan synthase Phase I Merck
Aminocandin Glucan synthase Phase I Novexel/AstraZeneca
FG-3622 Undisclosed Phase I F2G
Corifungin Membrane Phase I Acea Biotech
T-2307 Mitochondria Phase I Toyama
MGCD290 HOS2 (HDAc) Phase I MethylGene
EV-086 Undisclosed Preclinical Evolva
Ambruticin analog(s) Osmoregulatory system Preclinical Kosan
D75-4590 Glucan synthase Preclinical Daiichi Sankyo
VT1161 Lanosterol 14DM Preclinical Viamet
Sordarin analog(s)
FR290581
EF-2 Ribosome complex Preclinical Astellas
E1210 GWT1 (GPI-anchor) Preclinical Eisai

13. How do we do drug discovery

14. Sources of drugs

15. How do we do drug discovery

16. More advanced approaches

17. How does the drug kill the Aspergillus
• We can used advanced biological technologies to
find out how…..
• By examining the genetic (DNA) makeup of the
fungus and seeing how it responds
• We have to make sure that the mechanism of action
wont kill the patient!!!
• We compare the fungal DNA to human DNA

18. Once we know how the drug works we can do
some fancy stuff
Cyp51A

19. Computational drug modelling

20. So what next?
• EU is actively funding anti-infectives research
– IMI
• Discovery and development of new drugs combating Gram
negative infections
• Combating resistant Enterobacteriaceae, Acinetobacter,
Pseudomonas, C. difficile and MRSA
– FP7-HEALTH
• SYBARIS
• ALLFUN
– FP7-HEALTH-2013-INNOVATION-2 (2013)
• NOFUN (Development of NOvel anti-FUNgals)

21. What we hope will come from NOFUN
• NOFUN will develop the highly active and
selective drugs which have novel mechanism
of action
• We will identify a candidate for GLP toxicology

22. Paul Bowyer
Jane Gilsenen
Lydia Tabenero
David Denning
Darel Macdonald
Anna Johns
Luigina Romani (Perugia)
Duccio Cavieilari (Firenze)
Ivo Gut (Barcelona)
Misha Kapucheski (EBI)
Acknowledgements
Jean-Paul Latge
Nick Read
Elaine Bignell
Mike Birch
Jason Oliver

23. Survey of Pulmonary
Aspergillosis in association with
TB and HIV in Uganda
Chief Investigator - Dr Iain
Page, Clinical Research
Fellow, University of Manchester

24. Chronic Pulmonary Aspergillosis
• Patients deteriorate over many years
• Cough, Haemoptysis, weight loss, breathlessness
and profound fatigue common
• Diagnostic criteria
– Symptoms as above
– Abnormal CXR or CT (cavitation is main feature)
– Positive Antibodies to Aspergillus in serum
• Precipitins and Aspergillus Specific IgG commonly used
• Often associated with underlying lung damage /
cavitation
– E.g. TB or COPD

25. Chronic Necrotizing Pulmonary
Aspergillosis
• Sub-acute illness
• Deterioration and death within few weeks – months
without treatment
• Associated with AIDS
• Mimics smear negative TB, PCP etc.
• Often misdiagnosed in well resourced settings
• CXR often abnormal but can be non-specific
• Aspergillus antibody may be negative
• Aspergillus antigen tests may be positive on BAL or
blood
– E.g. Galactomannan or investigational lateral flow device

26. Existing evidence for CPA in
association with TB
• Single UK MRC survey in 1968
– Looked at pts with cavities on CXR post TB
– 25% had positive Aspergillus Precipitans 1 yr post TB
• International predicted rates (Denning et al 2011)
– 36 million cured of TB worldwide 1995-2008
– 22% South African patients have cavities post TB
– 1.1 million cases CPA predicted worldwide
– 100,000 new cases annually in African
– Prevalence of 43 per 100,000 in DRC

27. Mumbai autopsy series – HIV +ve pts
Lanjewar & Duggal, HIV Med 2001;2:266

28. Missed IFDs in AIDS – autopsy series
Antinori et al, Am J Clin Pathol 2009;132:221

29. Italian experience of aspergillosis in AIDS
Libanore et al, Infection 2002;30:341

30. Aims of the study
• Establish the prevalence of pulmonary
aspergillosis in the following groups of
patients in Gulu successfully treated for TB in
the last 7 years
• Identify or develop a simple point of care test
that (along with CXR) can diagnose CPA in
Africans
• Identify environmental and genetic risk factors
for CPA in Africans

31. Potential follow on studies
• Prospective study, lasting at least 2 years to
identify the frequency of developing CPA after
TB diagnosis and it’s impact on morbidity and
mortality
• Treatment trials of anti fungal drugs in Africa
to establish efficacy and safety with (limited
monitoring tests)

49. Carer Support www.nhs.uk/carersdirect
 Often neglected group – all attention given to patient
 Highlighted by a recent email to the Yahoo support
group – an Australian man who has watched his
active wife become much less mobile and unable to
enjoy life as they did. They have eventually found
new ways to enjoy their time together. Read the story
at
http://patientswithaspergillosis.wikispaces.com/Fro
m+a+carers+perspective

50. Carers group
 Most of us are carers for a short time – not many
volunteer or even know it is coming
 Look after your own health
 Have your own life too – don‟t let it be „taken over‟
 Hobbies
 Educate yourself about the illness that the person
you care for has – improves understanding

51. Patients group
 Saline nebulisers and their effectiveness
 Media portraying aspergillosis as easy to cure
 What is important to you isn‟t always obvious to your
carer
 When you are ill patience is inevitably shortened!

52. Whole group
 At the end of the day it is important to spend time
together , finding things you can still both do –
whether you are a couple, child/parent or even just
friends
 Gardening tips – reference book
 Topics?
 Questions?

53. Travel
 Clear trip with your doctor first!
 Organise carrying oxygen with your airline in advance -
some will support you better than others!
 Travel insurance (Staysure, Unique (asthmaUK),
http://www.moneysupermarket.com/travel-insurance/pre-
existing-medical-conditions/)
 Please give full info about ALL your medical conditions on
your proposal. If you give only partial truth and need to
claim, your whole policy might be made invalid and you
won't get anything.
 http://www.aspergillus.org.uk/newpatients/travel.html

54. Insurance

55. Travel – transporting drugs
 There are a variety of bags marketed that can
maintain cool temperatures for up to 24 hours –
search for bags used by diabetics
 http://www.diabetes.co.uk/diabetic-
products/medifridge.html

56. Q & A
 Questions?
Areas of interest online
 Mouldy homes – new guidelines – see Asp Website
 Itraconazole toxicity – risk of heart problems
 Low – allergy gardening (books purchased)
 Artificial organs – kidney
 Food for patients meeting?
 Damp homes – do you see damp/moulds?
 Travel

57. Itraconazole and Heart Failure
 Patients NEW to itraconazole should be aware of the
possibility of heart problems
 Patietns who have been taking itraconazole for over
6 – 12 months with no problems should not develop
problems in future
 ALL should be watchful for signs such as:

58. Itraconazole and Heart Failure
 The symptoms of heart failure can vary from
person to person. The main symptoms are
breathlessness, extreme tiredness, and ankle
swelling, which may extend up the legs.
 These symptoms may be caused by conditions other
than heart failure, and sometimes there may be more
than one cause for them.
 http://www.nhs.uk/Conditions/Heart-
failure/Pages/Symptoms.aspx
 If in any doubt see your doctor

59. Low allergy gardens

60. Regrown organs

61. Regrown organs - progress
 Kidney – complex organ
 Has been stripped down & rebuilt using stem cells
(rat) and then re-implanted into host
 Works with 5-10% efficiency compared with original
– thought to be sufficient to avoid transplant!

62. Food for Meeting
 Can‟t transfer funds to research
 Funds come out of NAC/NHS „hospitality‟ funds
 Could do less – tea & biscuits?

63. Thank You
“The best chance we have of beating this illness is to
work together”
Living with it, Working with it, Treating it
Fungal Research Trust