Novel Tuberculosis Drugs of the 21 st Century

Transcription

1 ovel Tuberculosis Drugs of the 21 st Century 2 Br H PA-824 CF 3 TMC207 Philip Bentley ctober 7, 2009

2 Introduction Tuberculosis (TB)- An infectious disease of humans and animals caused by the tubercle bacillus and characterized by the formation of tubercles on the lungs and other tissues of the body, often developing long after the initial infection. Tubercle bacillus- A rod- shaped aerobic bacterium (Mycobacterium tuberculosis) that causes tuberculosis. Pickett, J.P., et al., Eds. The American Heritage College dictionary, 4 th ed.; Houghton Mifflin Company: Boston, MA, 2002; p Image taken from: Jabado,.; Gros, P. ature 2005, 434, (7034),

3 An Ancient Disease Consumption and white plague Hippocrates, the ancient Greek physician, noted that phthisis (consumption) was the most widespread and fatal disease of his time. (>2,000 yrs ago) Found in skulls and spines of Egyptian mummies (4,000 yrs old) obel Prize Website: readmore.html (accessed September 15, 2009). 3

4 Today As of March 24, 2009 (World TB Day) 9.27 million EW cases in Asian and African countries account for 80% of global TB Cost to diagnose and treat 1.4 million cases in high burden regions $16.9 billion Donald, P. R.; van Helden, P. D.. Engl. J. Med. 2009, 360, (23),

5 Pathogenesis of TB Mode of Infection Ingestion (intestines) Consumption of contaminated milk Inhalation (lungs) Intake of airborne pathogens Deposited in Lymph nodes (~2 weeks) Reddy, C.A. Veterinary Pathogenic Bacteriology, Department of Microbiology & Molecular Genetics: Michigan State University, 2008, pp194. Jabado,.; Gros, P. ature 2005, 434, (7034),

6 Pathogenesis of TB Regional Lymph nodes AfewDays Bloodstream 1-2 weeks Throughout Body Cell-mediated immune Response Also, latent forms (1/3 population) rganism uptaken by activated macrophage infection progresses to Tuberculosis Reddy, C.A. Veterinary Pathogenic Bacteriology, Department of Microbiology & Molecular Genetics: Michigan State University, 2008, pp194. Jabado,.; Gros, P. ature 2005, 434, (7034),

7 Main Challenge Vs. ormal bacteria cell wall TB cell wall Image from: 7

8 Main Challenge Trehalose = H CH 3 (CH 2 ) 17 (CH 2 ) 10 (CH 2 ) 17 (CH 2 ) 23 CH 3 H CH 3 (CH 2 ) 17 (CH 2 ) 10 (CH 2 ) 17 (CH 2 ) 23 CH 3 H 3 C H H R= CH 3 (CH 2 ) 17 (CH 2 ) 10 (CH 2 ) 17 H 3 C CH 3 (CH 2 ) 23 CH 3 H CH 3 (CH 2 ) 17 (CH 2 ) 10 (CH 2 ) 17 (CH 2 ) 23 CH 3 TB cell wall H 3 C H CH 3 (CH 2 ) 17 (CH 2 ) 10 (CH 2 ) 17 (CH 2 ) 23 CH 3 Tonge, P. J. at. Struct. Mol. Biol. 2000, 7, Yuan, Y.; Barry, C. E., III Proc. atl. Acad. Sci. U. S. A. 1996, 93, Image from: 8

9 Mycolyl Transfer Mechanism ag85c protein Ronning, D. R.; Klabunde, T.; Besra, G. S.; Vissa, V. D.; Belisle, J. T.; Sacchettini, J. C. at. Struct. Biol. 2000, 7,

10 Strides Towards a Cure obel Prizes Awarded in Physiology and Medicine Robert Koch Discovery of Mycobacterium tuberculosis in 1882 Selman Waksman Isolated active antibiotic from Streptomyces griseus in 1943 obel Prize Website: readmore.html (accessed September 15, 2009). 10

11 History of Drug Therapy Alkaline mineral water, mercury, antimony, cod-liver oil, copper salts Roman physicians recommended Bathing in human urine, eating wolf liver, and drinking elephant blood Streptomycin (1943) Intravenous administration First reported TB resistance (1947) Para-aminosalicylic acid (1949) Prevented TB resistance eed for long term use H H HC H H H 3 C H H CH 3 Streptomycin H H 2 H 2 H H 2 H 2 Borchardt, J.K. Drug ews Perspect. 2002, 15, (8),

12 History of Drug Therapy Isoniazid (1952) Prodrug: Inhibits mycolic acid synthesis Prevents latent to active TB H H 2 Isoniazid Pyrazinamide (1954) Mechanism of action uncertain Disrupts plasma membrane? Disrupts energy metabolism? Rouche Phamaceuticals in the U.S.: About US. (accessed ct 4, 2009). Timmins, G. S.; Deretic, V. Mol. Microbiol. 2006, 62, Borchardt, J.K. Drug ews Perspect. 2002, 15, (8),

13 History of Drug Therapy Ethambutol (1962) inhibits the synthesis of arabinogalactan Rifampin (rifampicin) (1965) Inhibits RA synthesis Can eliminate dormant bacteria H H H H H H Rifampin Belanger, A. E.; Besra, G. S.; Ford, M. E.; Mikusova, K.; Belisle, J. T.; Brennan, P. J.; Inamine, J. M. Proc. atl. Acad. Sci. U. S. A. 1996, 93, Tonge, P. J. at. Struct. Mol. Biol. 2000, 7, Borchardt, J.K. Drug ews Perspect. 2002, 15, (8),

14 Combination Drug Therapy Isoniazid and rifampin greatly decrease TB chance of survival Isoniazid, rifampin, and pyrazinamide (Aventis: Rifater) shortened drug therapy Isoniazid, rifampin, pyrazinamide, and ethambutol if resistant to isoniazid Isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin if resistant to both isoniazid and rifampin Borchardt, J.K. Drug ews Perspect. 2002, 15, (8),

15 Summary of the Drug Regime H H H H H H Rifampin H 2 Pyrazinamide Borchardt, J.K. Drug ews Perspect. 2002, 15, (8),

16 TB in the United States TB Case otifications (USA) Infected # of Persons Year Global tuberculosis control: epidemiology, strategy, financing: WH report 2009 (Publication no. WH/HTM/TB/ ). Geneva: World Health rganization, Weis, S. E.; Slocum, P. C.; Blais, F. X.; King, B. ; unn, M.; Matney, G. B.; Gomez, E.; Foresman, B. H.. Engl. J. Med. 1994, 330, 17),

17 Multi Drug Resistance (MDR) Global tuberculosis control: epidemiology, strategy, financing: WH report 2009 (Publication no. WH/HTM/TB/ ). Geneva: World Health rganization, Donald, P. R.; van Helden, P. D.. Engl. J. Med. 2009, 360, (23),

18 eed for 21 st Century Drugs Development of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains (ot a single new compound since 1965) Help reduce cost of MDR treatment ($15,000 for a 2 year treatment course) Minimize fatalities (30 million claimed btw 2000 and 2020) Borchardt, J.K. Drug ews Perspect. 2002, 15, (8),

19 Drugs with Promising Results 2 PA-824 CF 3 Br H TMC207 19

20 Clinical Trial Phases Phase of Clinical Trial Preclinical umber of Patients.A. Phase I Phase II >100 Phase III 100s-1000s What they test In-vivo (Animal) and in-vitro Metabolic and pharmacologic properties Test drug effectiveness & Side effects and risks Efficacy, safety, benefit to risk Gain FDA approval Phase IV --- Long term effects ational Marrow Donor Program: What is a Clinical Trial? Undrstnd_Disease_Treat/Undrstnd_Treat_pt/Lrn_Clinical_Trials/What_is_a_Clinical_Trial/index.ht ml (accessed ct 1, 2009). 20

21 PA Phase II o cross-resistance Potentially inhibits drug-sensitive and drug- resistant strains In vitro activity against non-replicating TB Unique mechanism of action Inhibits TB cell wall mycolic acid synthesis Pro-drug metabolized by TB CF 3 Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D..; Krelswirth, B..; Barry, C. E.; Baker, W. R. ature 2000, 405, (6789),

22 Synthesis of PA- 824 TBAF = F Baker, W. R.; Cai, S.; Keeler, E. L. 96-US10904, , ,

23 Synthesis of PA- 824 Baker, W. R.; Cai, S.; Keeler, E. L. 96-US10904, , ,

24 PA- 824: Activity Against MDR TB Drug Resistance MIC 90 (µg/ ml) [PA-824] MIC 90 (µg/ ml) [isoniazid] Drug susceptible strains to to 0.06 R I, R 0.03 I, R, E 0.03 I, S, E 0.25 I, R, S, E 0.03 I, R, E, P 0.06 I, S, E, P 0.25 I= isoniazid; R= rifampin; E= ethambutol; S= streptomycin; P= pyrazinamide Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D..; Krelswirth, B..; Barry, C. E.; Baker, W. R. ature 2000, 405, (6789),

25 Activity Against on- Replicating TB Log 10 CFU Activity on on-replicating TB Control PA-824 Isoniazid Drug anaerobic o drug, aerobic Time (days) Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D..; Krelswirth, B..; Barry, C. E.; Baker, W. R. ature 2000, 405, (6789),

26 PA- 824: Mechanisms of Action Two suggested mechanisms Disruption of the mycolic acids of the TB cell envelope Intracellular release via a deazaflavin-dependent nitroreductase (Ddn) and the reduced form of cofactor F 420 Yuan, Y.; Zhu, Y.; Crane, D. D.; Barry, C. E., III, Mol. Microbiol. 1998, 29, (6), Singh, R.; Manjunatha, U.; Boshoff, H. I. M.; Ha, Y. H.; iyomrattanakit, P.; Ledwidge, R.; Dowd, C. S.; Lee, I. Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T. H.; Jiricek, J.; Barry, C. E., III Science 2008, 322, (5906),

27 PA- 824: Mechanisms of Action Yuan, Y.; Zhu, Y.; Crane, D. D.; Barry, C. E., III, Mol. Microbiol. 1998, 29, (6), Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D..; Krelswirth, B..; Barry, C. E.; Baker, W. R. ature 2000, 405, (6789),

28 PA- 824: Mechanisms of Action Activity as a Prodrug Little mycolic acid repair Singh, R.; Manjunatha, U.; Boshoff, H. I. M.; Ha, Y. H.; iyomrattanakit, P.; Ledwidge, R.; Dowd, C. S.; Lee, I. Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T. H.; Jiricek, J.; Barry, C. E., III Science 2008, 322, (5906),

29 reduction H H H R R 5 R 4 protonation hydrolysis reduction 5a R H 5b R H 5c R H H reduction H 2 6a R 6b R 6c R Singh, R.; Manjunatha, U.; Boshoff, H. I. M.; Ha, Y. H.; iyomrattanakit, P.; Ledwidge, R.; Dowd, C. S.; Lee, I. Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T. H.; Jiricek, J.; Barry, C. E., III Science 2008, 322, (5906),

30 PA- 824: Mechanisms of Action Deazaflavin- dependent nitroreductase (Ddn) AD Singh, R.; Manjunatha, U.; Boshoff, H. I. M.; Ha, Y. H.; iyomrattanakit, P.; Ledwidge, R.; Dowd, C. S.; Lee, I. Y.; Kim, P.; Zhang, L.; Kang, S.; Keller, T. H.; Jiricek, J.; Barry, C. E., III Science 2008, 322, (5906),

31 PC Completed Phase II o cross-resistance Inhibits drug-sensitive and drug-resistant strains Similar mechanism of action to PA- 824 CF 3 Inhibits TB cell wall mycolic acid synthesis Pro-drug metabolized by TB Decreased time on drug regime High efficacy in immunocompromised mice suggesting treatment for TB/HIV patients Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. PLoS Med. 2006, 3, (11),

32 Synthesis of PC Cl H 2 + Et 3,AcEt, o C,6h 87% 2 Cl H 2 K 2 C 3,MeH, r.t.,2h 97% 2 Cl H H )MsCl,py.,<15 o C,2h 2.)DBU,AcEt,r.t.,2h (75%for2steps) 2 Cl 9 Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med. Chem. 2006, 49, (26),

33 Synthesis of PC Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med. Chem. 2006, 49, (26),

34 Synthesis of PC Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med. Chem. 2006, 49, (26),

35 PC : Pharmacokinetics TB Strain (MIC 90 ) MIC 90 (µg/ml) rifampin- susceptible (0.288: 24x) isoniazid- susceptible (0.099: 8x) ethambutol- susceptible (3.636: 303x) streptomycin- susceptible (2.938: 244x) Average (0.012) Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. PLoS Med. 2006, 3, (11),

36 PC : Pharmacokinetics TB Strain (MIC 90 ) MIC 90 (µg/ml) rifampin- susceptible rifampin- resistant isoniazid- susceptible isoniazid- resistant ethambutol- susceptible ethambutol- resistant streptomycin- susceptible streptomycin- resistant Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. PLoS Med. 2006, 3, (11),

37 PC : Pharmacokinetics 7 6/6 RP RIEP 6 Log 10 CFU /6 6/6 6/6 6/6 6/6 6/6 1/6 0/ Time (month) 1/6 4/5 0/6 # of mice with CFU / total # mice 0/6 = PC ; R= rifampin; P= pyrazinamide; I= isoniazid; E= ethambutol Matsumoto, M.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.; Komatsu, M. PLoS Med. 2006, 3, (11),

38 PC : Mechanism of Action Same Mechanism of action as PA- 824 Yuan, Y.; Zhu, Y.; Crane, D. D.; Barry, C. E., III, Mol. Microbiol. 1998, 29, (6), Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Yuan, Y.; McMurray, D..; Krelswirth, B..; Barry, C. E.; Baker, W. R. ature 2000, 405, (6789),

39 TMC207 (R207910) Phase II Unique mechanism of action Inhibits membrane-bound ATP synthase Potentially inhibits drug-sensitive and drugresistant strains Reduced time to negative sputum culture Diacon, A. H.; Pym, A.; Grobusch, M.; Patientia, R.; Rustomjee, R.; Page-Shipp, L.; Pistorius, C.; Krause, R.; Bogoshi, M.; Churchyard, G.; Venter, A.; Allen, J.; Palomino, J. C.; De Marez, T.; van Heeswijk, R. P. G.; Lounis,.; Meyvisch, P.; Verbeeck, J.; Parys, W.; de Beule, K.; Andries, K.; Mceeley, D. F.. Engl. J. Med. 2009, 360, (23),

40 Synthesis of TMC207 Van Gestel, J. F. E.; Guillemont, J. E. G.; Venet, M. G.; Poignet, H. J. J.; Decrane, L. F. B.; Vernier, D. F. J.; dds, F. C , , ,

41 Synthesis of TMC207 Van Gestel, J. F. E.; Guillemont, J. E. G.; Venet, M. G.; Poignet, H. J. J.; Decrane, L. F. B.; Vernier, D. F. J.; dds, F. C , , ,

42 TMC207: Pharmacokinetic Studies log 10 CFU Untreated (Day 0) 1 month 2 month 0% 20% 0% 0% 0% Untreated T R I P Monotherapy % of mice culture (-) after 2 month T = TMC207 R = rifampin I = isoniazid P = pyrazinamide Ibrahim, M.; Andries, K.; Lounis,.; Chauffour, A.; Truffot-Pernot, C.; Jarlier, V.; Veziris,. Antimicrob. Agents Chemother. 2007, 51, Andries, K.; Verhasselt, P.; Guillemont, J.; Goehlmann, H. W. H.; eefs, J.-M.; Winkler, H.; Van Gestel, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis,.; Jarlier, V. Science 2005, 307, (5707),

43 TMC207: Pharmacokinetic Studies Untreated (Day 0) 1 month 2 month lo og 10 CFU % 20% 100% 30% 20% 20% 0% 0% % of mice culture (-) after 2 month T = TMC207 P = pyrazinamide R = rifampin I = isoniazid Two- drug therapy Ibrahim, M.; Andries, K.; Lounis,.; Chauffour, A.; Truffot-Pernot, C.; Jarlier, V.; Veziris,. Antimicrob. Agents Chemother. 2007, 51, Andries, K.; Verhasselt, P.; Guillemont, J.; Goehlmann, H. W. H.; eefs, J.-M.; Winkler, H.; Van Gestel, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis,.; Jarlier, V. Science 2005, 307, (5707),

44 TMC207: Pharmacokinetic Studies Untreated (Day 0) 1 month 2 month lo og 10 CFU % 20% 100% 70% 78% 20% 0% % of mice culture (-) after 2 month T = TMC207 P = pyrazinamide R = rifampin I = isoniazid Three- drug therapy Ibrahim, M.; Andries, K.; Lounis,.; Chauffour, A.; Truffot-Pernot, C.; Jarlier, V.; Veziris,. Antimicrob. Agents Chemother. 2007, 51, Andries, K.; Verhasselt, P.; Guillemont, J.; Goehlmann, H. W. H.; eefs, J.-M.; Winkler, H.; Van Gestel, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis,.; Jarlier, V. Science 2005, 307, (5707),

45 Phase II Key Findings Median Log 10 CFU Count (Week 1) TMC207 () Placebo () 4.7 (8) 5.2 (13) (Week 2) 1.8 (9) 3.5 (11) (Week 4) ~0 (6) 2.6 (12) (Week 6) ~0 (5) 2.2 (11) (Week 8) ~0 (7) ~0 (7) Side Effects (ausea) (+) to (-) culture in 8 weeks 26% (23) 4% (24) 48% (23) [10:21] 9% (24) [2:23] Diacon, A. H.; Pym, A.; Grobusch, M.; Patientia, R.; Rustomjee, R.; Page-Shipp, L.; Pistorius, C.; Krause, R.; Bogoshi, M.; Churchyard, G.; Venter, A.; Allen, J.; Palomino, J. C.; De Marez, T.; van Heeswijk, R. P. G.; Lounis,.; Meyvisch, P.; Verbeeck, J.; Parys, W.; de Beule, K.; Andries, K.; Mceeley, D. F.. Engl. J. Med. 2009, 360, (23),

46 TMC207: Mechanism of Action a-subunit Arg-186 H 2 H Glu-61 c-subunit Image taken from: 46

47 TMC207: Mechanism of Action Inhibition of c-subunit of ATP synthase de Jonge, M. R.; Koymans, L. H. M.; Guillemont, J. E. G.; Koul, A.; Andries, K. Proteins: Struct. Funct. Bioinf. 2007, 67, (4),

48 PA- 824 Activity against non-replicating PC In Summary High efficacy in immunocompromised TMC207 Increased potency against multidrug resistant strains All of the Above Activity against drug-susceptible and resistant stains 48

49 The Take Home Message Although excellent promise, If used incorrectly, resistance will develop Understanding disease evolution Better approach to treating a target disease 49

50 Acknowledgements Prof. Xuefei Huang Prof. Babak Borhan Group Members Bo, Gopi, Mohammad, Dino, Gilbert, Hovig, Vivian Medha, Ashley, Dennis, Steve 50

51 Go State! Image from: 51