New antifungals and TB research


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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.

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New antifungals and TB research

  1. 1. L E D B Y G R A H A M A T H E R T O NS U P P O R T E D B YG 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 RN 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 SA 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 YA 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 EN 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 EU H S MM A N C H E S T E RSupport Meeting forAspergillosis Patients & CarersFungal Research Trust
  2. 2. Car Parking £3 all day in the Nightingale Car Park (oppositeNWLC) Leave note in your windscreen sayingNorth West Lung Centre Delegate
  3. 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. 4. Development of the next generationof antifungal drugsMike Bromley PhD
  5. 5. Do we need new anti-fungals?• Invasive fungal diseases are common, debilitating, anddifficult 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. 6. Why would anyone bother?
  7. 7. The importance of fungal disease• Fungal diseases have an enormous globalfinancial 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. 8. Is it financially viable?Product/Brand nameGeneric name Class CompanyPatent expiry(US)Peak annualsales(Million USD)AmbisomeLiposomalamphotericin BPolyene Astellas/ Gilead Expired 2004 550AbelcetLipid complexamphotericin BPolyene Elan/ Enzon Expired 2003 --Cancidas Caspofungin Echinocandin Merck & Co Mar 2013 500Diflucan Fluconazole Azole Pfizer Expired 2004 1200Eraxis Anidulafungin Echinocandin Pfizer 2015 n/aMycamine Micafungin Echinocandin Astellas Sep 2015 350Noxafil Posaconazole AzoleSchering-PloughApr 2018 n/aSporanox Itraconazole Azole Janssen Expired 2000 900Vfend Voriconazole Azole Pfizer May 2016 750DataMonitor, 2007.
  9. 9. Current antifungal classesClass Target Discovered DrugAzole Lanosterol 14DM 1944 BenzimidazolePolyene Membrane 1950 NystatinCandins Glucan synthase 1974 Echinocandin BPyrimidineanaloguePyrimidine biosynthesis 1961 Flucytosine
  10. 10. Commercial retrenchment from anti-infective discovery• Only a few major pharmaceutical companies arecurrently operating anti-infective programs– Highlights a change in the way that all drug discovery isgoing– Emphasis is now on small companies and Universities toperform the early stage research function
  11. 11. The stages of drug discoveryPre-clinical drugdiscoveryGSK$70 millionNo P1 drug
  12. 12. Antifungals in developmentCompound Drug Target Status CompanyIsavuconazole Lanosterol 14DM Phase III Basilea/AstellasKP-103 Lanosterol 14DM Phase III KakenSPK-843 Membrane Phase III ProapartsMycograb HSP90 Phase II Novartis/NeuTecIcofungipen Isoleucyl-t-RNA synthase Phase II Plivia/BayerMK-3118 Glucan synthase Phase I MerckAminocandin Glucan synthase Phase I Novexel/AstraZenecaFG-3622 Undisclosed Phase I F2GCorifungin Membrane Phase I Acea BiotechT-2307 Mitochondria Phase I ToyamaMGCD290 HOS2 (HDAc) Phase I MethylGeneEV-086 Undisclosed Preclinical EvolvaAmbruticin analog(s) Osmoregulatory system Preclinical KosanD75-4590 Glucan synthase Preclinical Daiichi SankyoVT1161 Lanosterol 14DM Preclinical ViametSordarin analog(s)FR290581EF-2 Ribosome complex Preclinical AstellasE1210 GWT1 (GPI-anchor) Preclinical Eisai
  13. 13. How do we do drug discovery
  14. 14. Sources of drugs
  15. 15. How do we do drug discovery
  16. 16. More advanced approaches
  17. 17. How does the drug kill the Aspergillus• We can used advanced biological technologies tofind out how…..• By examining the genetic (DNA) makeup of thefungus and seeing how it responds• We have to make sure that the mechanism of actionwont kill the patient!!!• We compare the fungal DNA to human DNA
  18. 18. Once we know how the drug works we can dosome fancy stuffCyp51A
  19. 19. Computational drug modelling
  20. 20. So what next?• EU is actively funding anti-infectives research– IMI• Discovery and development of new drugs combating Gramnegative 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. 21. What we hope will come from NOFUN• NOFUN will develop the highly active andselective drugs which have novel mechanismof action• We will identify a candidate for GLP toxicology
  22. 22. Paul BowyerJane GilsenenLydia TabeneroDavid DenningDarel MacdonaldAnna JohnsLuigina Romani (Perugia)Duccio Cavieilari (Firenze)Ivo Gut (Barcelona)Misha Kapucheski (EBI)AcknowledgementsJean-Paul LatgeNick ReadElaine BignellMike BirchJason Oliver
  23. 23. Survey of PulmonaryAspergillosis in association withTB and HIV in UgandaChief Investigator - Dr IainPage, Clinical ResearchFellow, University of Manchester
  24. 24. Chronic Pulmonary Aspergillosis• Patients deteriorate over many years• Cough, Haemoptysis, weight loss, breathlessnessand 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. 25. Chronic Necrotizing PulmonaryAspergillosis• Sub-acute illness• Deterioration and death within few weeks – monthswithout 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 orblood– E.g. Galactomannan or investigational lateral flow device
  26. 26. Existing evidence for CPA inassociation 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. 27. Mumbai autopsy series – HIV +ve ptsLanjewar & Duggal, HIV Med 2001;2:266
  28. 28. Missed IFDs in AIDS – autopsy seriesAntinori et al, Am J Clin Pathol 2009;132:221
  29. 29. Italian experience of aspergillosis in AIDSLibanore et al, Infection 2002;30:341
  30. 30. Aims of the study• Establish the prevalence of pulmonaryaspergillosis in the following groups ofpatients in Gulu successfully treated for TB inthe last 7 years• Identify or develop a simple point of care testthat (along with CXR) can diagnose CPA inAfricans• Identify environmental and genetic risk factorsfor CPA in Africans
  31. 31. Potential follow on studies• Prospective study, lasting at least 2 years toidentify the frequency of developing CPA afterTB diagnosis and it’s impact on morbidity andmortality• Treatment trials of anti fungal drugs in Africato establish efficacy and safety with (limitedmonitoring tests)
  32. 32. Carer Support Often neglected group – all attention given to patient Highlighted by a recent email to the Yahoo supportgroup – an Australian man who has watched hisactive wife become much less mobile and unable toenjoy life as they did. They have eventually foundnew ways to enjoy their time together. Read the storyat
  33. 33. Carers group Most of us are carers for a short time – not manyvolunteer 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 personyou care for has – improves understanding
  34. 34. Patients group Saline nebulisers and their effectiveness Media portraying aspergillosis as easy to cure What is important to you isn‟t always obvious to yourcarer When you are ill patience is inevitably shortened!
  35. 35. Whole group At the end of the day it is important to spend timetogether , finding things you can still both do –whether you are a couple, child/parent or even justfriends Gardening tips – reference book Topics? Questions?
  36. 36. 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), Please give full info about ALL your medical conditions onyour proposal. If you give only partial truth and need toclaim, your whole policy might be made invalid and youwont get anything.
  37. 37. Insurance
  38. 38. Travel – transporting drugs There are a variety of bags marketed that canmaintain cool temperatures for up to 24 hours –search for bags used by diabetics
  39. 39. 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
  40. 40. Itraconazole and Heart Failure Patients NEW to itraconazole should be aware of thepossibility of heart problems Patietns who have been taking itraconazole for over6 – 12 months with no problems should not developproblems in future ALL should be watchful for signs such as:
  41. 41. Itraconazole and Heart Failure The symptoms of heart failure can vary fromperson to person. The main symptoms arebreathlessness, extreme tiredness, and ankleswelling, which may extend up the legs. These symptoms may be caused by conditions otherthan heart failure, and sometimes there may be morethan one cause for them. If in any doubt see your doctor
  42. 42. Low allergy gardens
  43. 43. Regrown organs
  44. 44. 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!
  45. 45. Food for Meeting Can‟t transfer funds to research Funds come out of NAC/NHS „hospitality‟ funds Could do less – tea & biscuits?
  46. 46. Thank You“The best chance we have of beating this illness is towork together”Living with it, Working with it, Treating itFungal Research Trust