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New Drugs and Vaccines in Tuberculosis

Doç. Dr. Şeref ÖzkaraAtatürk Chest Diseases and CSER Hospital,

Ankaraozkaraseref@yahoo.com

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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%)

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TB incidence (in 100.000)

HIV prevalence among TB

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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%5%

90%95%

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NEW VACCINE IN TUBERCULOSIS

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Invention of BCG Vaccine

230 passages of M. bovis

By Calmette and Guerin, 1906-1921

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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).

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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.

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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

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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

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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

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• 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.

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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%5%

90%95%

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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

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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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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.

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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

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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.

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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

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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

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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

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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

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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

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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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Vaccine Budget for Global Plan 2006-2015*

*million US $

CostMaintain and improve BCG programs 1490

Discovery & translation research 1376

Facilitate preclinical development 15

Build capacity at vaccine trial sites 16

Ensure availability of vaccine production capacity/scale-up

217

Perform clinical trials and prepare 457

Working Group operations 69

Total 3641

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Vaccine introduction

Pre-exposure

Post-exposure in a mass-vaccination paradigm

(everybody!)

Post-exposure (e.g. adolescent vaccination programme)

Time

Inci

den

ce

Vaccine Impact Post-2015cost/benefit models for

different epidemiological settings

Uli Fruth 2005 New Vaccines WG

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NEW DRUG

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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

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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

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Mechanisms of action

33Ginsberg 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

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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.

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• 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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TB DRUG DEVELOPMENT PIPELINE

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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.

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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

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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

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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

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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.

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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

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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.

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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.

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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

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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

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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.

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TB drugs in clinical evaluation

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Drug Development Budget for Global Plan 2006-2015*

*million US $

CostEarly stage drug development and research 2,419

Phase I clinical trials 80

Phase II clinical trials 573

Phase III clinical trials 1,720

Regulatory approval and registration 6

Working Group Operations 2

Total 4,800

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Thank you