Perspectives for new treatments for MDR-TB

Transcription

1 Perspectives for new treatments for MDR-TB

2 Life cycle of M. tuberculosis Active TB in million cases >1.4 million deaths Latent TB >2 billion cases Switzerland 564 cases (18 MDR) 2 Koul et al Nature 469,

3 TB colossal global health problem Confounded by HIV, diabetes, drug resistance 3

4 MDR and XDR-TB World Health Organization, Global tuberculosis report

5 The reality 2016 P. Douste-Blazy (UNITAID) We still need publicly funded research to defeat this ancient scourge! 5

6 Oral, bactericidal activity, ideally sterilizing Effective X persisters (extra/intracellular) Novel MoA: active against MDR- & XDR-TB No antagonism with other TB drugs Compatibility with ART, T2D No DDI Big ask! Toxicologically acceptable for dosing >2 months Therapy ideally results in cure within 2 months 6

7 Repurposed drugs Fluoroquinolones Gatifloxacin Moxifloxacin Rifamycins Riminophenazine Rifapentine Clofazimine Oxazolidinones Linezolid Sutezolid AZD5847 Beta-lactams 7 Meropenem Clavulanate Zumla et al Nat Rev Drug Dis

8 Diarylquinolines - TMC207 (bedaquiline) Nitroimidazole derivatives: PA-824 (pretomanid), TBA354, OPC67683 (delaminid) Ethylene diamines - SQ109 Imidazopyridine - Q203 Benzothiazinones BTZ043, PBTZ169 8

9 Need new drugs but it s not so easy! Target based screens failed Phenotypic screens - poor hit rate due to intrinsic resistance Compounds unsuitable? Designed for other therapeutic areas Promiscuous targets. More vulnerable? Pipeline insufficiently robust 9 Lechartier et al 2014 EMBO Mol Med

10 Global TB drug pipeline Details can be found at World Health Organization, Global tuberculosis report 2016 Working Group on New TB Drugs,

11 Failed in the clinic GFX MFX SQ109? TBA354 PMD? AZD5847 STZ? Insufficient investment in discovery? 11 Warner & Mizrahi 2014 N Engl J Med. 371: Heinrich et al J Antimicrob Chemother. 70: Furin et al Antimicrob Agents Chemother. online

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13 Benzothiazinones (BTZ) as antimycobacterial agents BTZ043 PBTZ169 2-[4-R-piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one 13 PCT/EP2006/ PCT/IB2011/055209

14 Benzothiazinones (BTZ) as antimycobacterial agents Highly active against M. tuberculosis (MIC 1-10 ng/ml) and other actinobacteria Active against all clinical isolates including MDR- and XDR-TB One pot synthesis, 4 steps, 70% yield, from commercially available reagents Excellent CoG Fine safety profile 14 Makarov et al Science 324: 801 Makarov et al EMBO Mol Med Pasca et al AAC 54: 1616

15 15 Makarov et al Science 324:801

16 Death in real time! 7H g/ml 7H9 98 h 240 h 265 h Stain a b 16 N. Dhar, J. McKinney. EPFL

17 Target DprE1 A B C 17 G. Manina & G. Riccardi. U Pavia

18 BTZ & DPA pathway 18 MIC of PBTZ169 against M. tuberculosis H37Rv 0.3 ng/ml (INH 50; EMB 1000) DPA biosynthesis pathway (Wolucka, 2008)

19 PBTZ DprE Kremer et al. (2006) in Tuberculosis and the Tubercle Bacillus. ASM Press 19

20 20 Neres et. al Science Translational Med Makarov et al EMBO Mol Med

21 PBTZ169 - microbiology Synergy with BDQ additive with all others 21 Makarov et al EMBO Mol Med

22 PBTZ169 very active in mice PBTZ169 & BDQ synergistic PBTZ169 & BDQ/PZA more effective than RHZ Active in GP & ZF models TB, LEP & BU 22 Makarov et al. 2014

23 PBZ a robust combination PBZ >> RHZ in mouse Quicker, more robust cure Treatment shortening potential? 23

24 Exciting candidate Compatible with all known/potential TB drugs Synergistic with BDQ & CFM PBZ regimen highly promising Excellent safety profile 2010 patent licensed to multinational but rights returned in

25 Created im4tb to manage PBTZ169 program im4tb not-forprofit fondation created by EPFL im4tb aims to support, promote and actively participate in drug discovery and drug development concerning TB and similar poverty-related and neglected diseases 25

26 Clinical trials Phase I 1 st 2016 Moscow; -2 nd CRC, CHUV, Lausanne in Q Phase IIa Russia underway; (IHI, Tanzania) 2018? 26

27 Many thanks to Benoit Lechartier Andréanne Lupien Ruben Hartkoorn João Neres Florence Pojer Claudia Sala Anthony Vocat Ming Zhang Vadim Makarov Claire Allardyce Emilyne Blattes Jean-Yves Gillon Laurence Mauro Antonia di Mecco Iain Old Sacha Sidjanski M. Petkova N. Shevkun R. Bolgarin