1. 1 New Drugs and Vaccines in Tuberculosis Doç. Dr. Şeref Özkara Atatürk Chest Diseases and CSER Hospital, Ankara ozkaraseref@yahoo.com

2. 2 TB Bacillus identified in 1882 Vaccine (BCG) developed in 1921 Curative treatment since 1950 It is the most deadly, most frequent treatable disease in the world. Infected 2 billion people; 9 million new cases and 1,6 million deaths annually. Present diagnostic, vaccination and treatment practices do not decrease the TB case rates. There is a 1% incerease annually (in sub-saharan Africa 4%)

3. 3 TB incidence (in 100.000) HIV prevalence among TB

4. 4 Course of TB Exposure to infectious TB case No infection Infection Primary or progressif primary disease Latent infection Exogen new infection No disease Disease Death Chronic Cure 5% 90% 95%

5. 5 NEW VACCINE IN TUBERCULOSIS

6. 6 Invention of BCG Vaccine 230 passages of M. bovis By Calmette and Guerin, 1906-1921

7. 7 BCG vaccine First used in 1921 orally. In 1940’s intradermal and percutan application. Prevents menengitis and miliary TB in childhood 60%-80% Prevention of adult TB is variable BCG is applied nearly 100 million children annually (85% of the target).

8. 8 BCG vaccine - 2 We use passaged BCG vaccines from the original Phenotypic and genotypic changes happened –Genetical loss of RD1 and other regions in the genom. –Activity decreased (?) Brosch R. Proc Natl Acad Sci U S A. 2007;104: 5596-601.

9. 9 BCG vaccine - 3 BCG can induce disease in 400 / 100.000 HIV infected children. Vaccine 2006; 25:14-18 WHO position paper states to make a HIV testing in 1,5 month old child of a HIV positive mother and apply BCG vaccine only if HIV is negative

10. 10 Developments Host’s immune response to TB is better understood. Genes and antigens of TB are evaluated Development of new ways to stimulate immune response Bağışıklık yanıtını uyaracak yeni yolların geliştirilmesi, especially with adjuvants Present antigens to immune system bay vectors

11. 11 Important new knowledge about vaccine development IFN g production is vital for resistance to Mtb infection –IFN g is produced by the immune system (CD4, CD8 T cells) Stimulate CD4 cells –ESAT (early secreted antigen for T celles, esp. ESAT6) –Ag85 (antigen 85) Certain types of CD8 T cells can produce IFN g and inhibit Mtb in the latent period TNF and it’s reseptor p55, are related with resistance to Mtb IL-12 can play a role in resistance to Mtb

12. 12 Most of the vaccine candidates –Are produced for boosting the effect –Antigens given twice –First BCG or a developed recombinant BCG and Önce BCG ya da geliştirilmiş rekombinant BCG, followed by another method –So, immune system produces response to antigens.

13. 13 Targets for new TB vaccine Exposure to infectious TB case No infection Infection Primary or progressif primary disease Latent infection Exogen new infection No disease Disease Death Chronic Cure 5% 90% 95%

14. 14 What is expected from new vaccine Inducing long term immune effect Can be applied with other vaccines Not interfere with tuberculin skin test Stable, safe and cheap

15. 15 Vaccines under study Recombinant modified BCG vaccines Live vaccines (attenuated Mtb isolates) Sub-unit vaccines DNA vaccines Vaccines given by vectors Others

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17. 17 Live Mycobacteria vaccines Attenuated Auxotrophic mutants can be used –ProC and TrpD auxotrophic mutant –Pantothena auxotrophic –Lysin auxotrophic mutant To increase Th1 response –Cytokine genes can be added –Antigen can be added To increas CD8 response –Hemolysin can be added.

18. 18 Sub-unit vaccines Sub-unit vaccines are given alone or with BCG These are Mtb antigens, together with an adjuvant, naked DNA or recombinant Mtb proteins. –Proteins or peptides –Lipid and carbohydrate antiges Should not hava adverse effect in immune suppressed. Their immunity may continue for short duration –Ag85(recombinant ag) –ESAT6(recombinant ag) –MVA-85A(recombinant modified virüs Ankara, Mtb antigen) –Mtb72-F, Mtb32C, Mtb39, Mtb32N

19. 19 DNA vaccines DNA fragments that synthetise antigens –Antigen 85A, 85B –ESAT-6 –MPT63, MPT64 –HSP65 –Lepra HSP60 –KATG DNAs coding more than one antigen given together.

20. 20 MVA-85A Oxford University Live, recombinant, carrying Ag85A from Mtb Vaccine given by viral vectors Unreplicable vaccinia virus + AG85a Ankara Can be used after exposure to the bacilli Can be used as a booster following BCG vaccination Produces important IFN g release Phase II McShane H, et al. Nat Med 2004; 10: 1240-1244

21. 21 rBCG::D ureC-IIo + Max Planck Institute Recombinant / modified BCG rBCG + urease deleted, carrying lysteriolysin O gene. Increases antigen escape from phagosomes to increase CD8 response Phase I Grode L, et al. J Clin Invest 2005; 115: 2472-2479

22. 22 rBCG30 Aeras, UCLA Recombinant / modified BCG rBCG vaccine Produces more powerful and long lasting response than BCG Phase I, development halted because of hygromycin anti-biotic gene

23. 23 Ag85B-ESAT6 Statens Serum Institute Sub-unit other than BCG Recombinant protein Produces strong immune response To be used for booster effect in BCG vaccinated previously. Phase 1

24. 24 Mtb72f GlaxoSmithKline Recombinant protein, 2 Mtb antigens (Rv1196 ve RV1025) Have an effect comparable to BCG To be used as a booster effect in BCG vaccinated previously Phase II

25. 25 SRL172 SR Pharma, Londra Immunogen for treatment Heat-killed M. vaccae Increases Th1 response to common antigens Effects regulatoruy T cells that inhibite Th2 Phase II in MDR-TB treatment

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27. 27 Vaccine Budget for Global Plan 2006-2015* *million US $ Cost Maintain and improve BCG programs1490 Discovery & translation research1376 Facilitate preclinical development15 Build capacity at vaccine trial sites1616 Ensure availability of vaccine production capacity/scale-up 217 Perform clinical trials and prepare457 Working Group operations69 Total 3641

28. 28 Vaccine introduction Pre-exposure Post-exposure in a mass-vaccination paradigm (everybody!) Post-exposure (e.g. adolescent vaccination programme) Time Incidence Vaccine Impact Post-2015 cost/benefit models for different epidemiological settings Uli Fruth 2005 New Vaccines WG

29. 29 NEW DRUG

30. 30 Present first line TB drugs DrugDiscovery yearMechanism of action Streptomycin1944Inhibitor of protein synthesis Isoniazid1952Cell wall inhibitor Pyrazinamid1952Inhibitor of cell membrane energy metabolism Ethambutol1961Cell wall inhibitor Rifampin1963Nucleic acid synthesis inhibitor

31. 31 Expected effects of a new TB vacccine Shorten treatment duration→ Powerful, intracellular effect Effective against MDR-TB → New mechanism of action HIV/AIDS patient treatment→ No drug-drug interaction Effective to latent TB → Intracellular activity (?) Ginsberg AM, Spigelman M. Nat Med. 2007; 13: 290-4

32. 32 Mechanisms of action

33. 33 Ginsberg AM, Spigelman M. Nat Med. 2007; 13: 290-4 TB drug development is a long process Limited biomarkers of drug efficacy for use in early clinical development –Failure and relapse rates are presently used –Two-month sputum culture conversion rate Long doubling time of Mtb Lengthy treatment periods (6 months and longer) Requisite long patient follow-up times (2 years and more) Relatively large patient numbers

34. 34 Challenges in drug investigation There are a few groups of bacteria –EBA (early bactericidal activity) measures effect on active bacilli –There is no good method to measure the effect on latent bacilli New projects are needed for markers to be used instead of sterilizing activity –To follow up for relapse requires minimum 18 months. To study with big number of patienst, 50 million dollars are required for each study.

35. 35 Bill&Melinda Gates Foundation, initiated a new program that will “speed up” TB drug development –To find targets for “persistence” –To find and evaluate appropriate animal models

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37. 37 TB DRUG DEVELOPMENT PIPELINE

38. 38 Diarylquinoline TMC207 Johnson & Johnson Target is ATP synthase. Stops energy production of the bacteria –Genome of TMC207 resistant isolates’ had a mutation in a sub unit of ATP synthase Andrias K, et al. Science 2005; 307: 223-7 Have the potential to decrease tretament duration to 2 months Effective in MDR-TB Can be given one weekly Phase II studies are running.

39. 39 Diarilkinolin TMC207 - 2 PROBLEMS Metabolized by cytocrom P450 3A4 enzyme and decreases the level of serum RIF level (%50). EBA compared with RIF and INH is less in the first 4 days and similar in 5-7 days Good safety and tolerability Tibotec is planning for phase II in MDR-TB

40. 40 Gatifloxacin Bayer, TB Alliance More effective than Oflo. and Cipro. in vitro EBA in 2 days is high, also high with INH and RIF Phase III studies are running. Aim is to study th safety and effectiveness of 4 months regimen containing gatifloxacin –2HRZG/2(HRG) 3 2HRZE/4HR –2 year follow up for relapse after the treatment There are problems related with the effect on blood glycose

41. 41 Moxifloxacin Bayer Regimen containin M, sterilizes murine lung faster than standart regimens Also effective to slow and intermittant growing bacteria Does not metabolized by cytocrom P450

42. 42 Moxifloxacin TBTC Study 27 2HRZM/4HR 2HRZE/4HR –Culture conversion is more in 4 weeks, similar in 2 months –Culture conversion of Africans is less than North American patients (%63-%85) –Safe and tolarable Burman WJ, et al. Am J Respir Crit Care Med 2006; 174: 331-338 –4 months treatment will be evaluated in Phase III study.

43. 43 NITROIMIDAZOLS PA-824 TB Alliance OPC-67863 Japon Otsuka Şirketi Pro-drugs. Activated by cellular enzymes Have activity against M. tuberculosis Effective to cell wall mycolic acid Mutations in resistant strains, prevents the active molecule forming from pro-drug

44. 44 PA-824 TB Alliance Have important characteristics of INH and RIF Have been tested about safety, tolerability and pharmacokinetic parameters EBA studies in South Africa Long term effectivity studies will be done. –2 months, combined regimen Phase II study is running. Manjunatha UH. Proc Natl Acad Sci USA 2006; 103:431-6.

45. 45 OPC-67683 Japan Otsuka Company Phase 1 safety, tolerabilitiy, pharmacokinetic and EBA tests have been completed at 400 mg dose Long term effectivity studies will be done. –2 months, combined regimen Phase II study is running. Matsumoto M, et al. PLoS Med. 2006: 3.

46. 46 LL-3858 (new pyrrol), Sudoterb Lupin Company When given with first line drugs, sterilizes murine lungs and spleens in shorter duratin than first line drugs. Can shorten treatment time to 2-3 months Phase 1 clinical studies are running Arora, S. IUATLD Syposium 31 October 2004

47. 47 SQ-109 (an etylenediamin) Sequella Company Synergic effect with INH and RIF Phase I study began Can replace 2 TB drugs and shorten the treatment duration 25% First study in human will be conducted in 2007

48. 48 Ethical Committee Aproval An aproval was obtained in 16 months in Brazil An application to NIH returned with 178 comments and after corrections, application returned with 120 new comments.

49. 49 TB drugs in clinical evaluation

50. 50 Drug Development Budget for Global Plan 2006-2015* *million US $ Cost Early stage drug development and research2,419 Phase I clinical trials80 Phase II clinical trials573 Phase III clinical trials1,720 Regulatory approval and registration6 Working Group Operations2 Total4,800

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52. 52 Thank you