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New Drugs and Vaccines in Tuberculosis

New Drugs and Vaccines in Tuberculosis. Doç. Dr. Şeref Özkara Atatürk Chest Diseases and CSER Hospital, Ankara ozkaraseref@yahoo.com. TB. Bacillus identified in 1882 Vaccine (BCG) developed in 1921 Curative treatment since 1950

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New Drugs and Vaccines in Tuberculosis

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

  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. TB incidence (in 100.000) HIV prevalence among TB

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

  5. NEW VACCINE IN TUBERCULOSIS

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

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

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

  16. 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.

  17. 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

  18. 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.

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. Vaccine Budget for Global Plan 2006-2015* *million US $

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

  27. NEW DRUG

  28. Present first line TB drugs Drug Discovery year Mechanism of action Streptomycin 1944 Inhibitor of protein synthesis Isoniazid 1952 Cell wall inhibitor Pyrazinamid 1952 Inhibitor of cell membrane energy metabolism Ethambutol 1961 Cell wall inhibitor Rifampin 1963 Nucleic acid synthesis inhibitor

  29. 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

  30. Mechanisms of action

  31. 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 Ginsberg AM, Spigelman M. Nat Med. 2007; 13: 290-4

  32. 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.

  33. 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

  34. TB DRUG DEVELOPMENT PIPELINE

  35. 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. Diarylquinoline TMC207

  36. 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

  37. 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

  38. 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

  39. 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.

  40. 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 NITROIMIDAZOLS

  41. 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.

  42. 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.

  43. 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

  44. 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

  45. 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.

  46. TB drugs in clinical evaluation

  47. Drug Development Budget for Global Plan 2006-2015* *million US $

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