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Perspectives for new treatments for MDR-TB
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Life cycle of M. tuberculosis
2 Koul et al. 2011 Nature 469, 483–490
Latent TB>2 billion cases
Active TB in 201510.4 million cases >1.4 million deaths
Switzerland564 cases (18 MDR)
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• TB – colossal global health problem
• Confounded by HIV, diabetes, drug resistance3
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MDR and XDR-TB
4
World Health Organization, Global tuberculosis report 2016
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The reality
5
2016 P. Douste-Blazy (UNITAID)“We still need publicly funded research to defeat this ancient
scourge!”
2016 P. Douste-Blazy (UNITAID)“We still need publicly funded research to defeat this ancient
scourge!”
2016 P. Douste-Blazy (UNITAID)“We still need publicly funded research to defeat this ancient
scourge!”
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• 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
• Toxicologically acceptable for dosing >2 months
• Therapy ideally results in cure within 2 months
Big ask!
6
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Repurposed drugs
Fluoroquinolones
Rifamycins
Oxazolidinones
Beta-lactams
Gatifloxacin Moxifloxacin
Sutezolid AZD5847
Rifapentine
Meropenem Clavulanate
Linezolid
Riminophenazine
Clofazimine
7Zumla et al. 2013 Nat Rev Drug Dis
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8
• Diarylquinolines - TMC207 (bedaquiline)
• Nitroimidazole derivatives: PA-824 (pretomanid), TBA354, OPC67683 (delaminid)
• Ethylene diamines - SQ109• Imidazopyridine - Q203• Benzothiazinones – BTZ043, PBTZ169
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yNeed new drugs but
it’s not so easy!
9Lechartier et al 2014 EMBO Mol Med
• 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
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Global TB drug pipeline 2016
1010
Details can be found at http://www.newtbdrugs.org/pipeline.php.World Health Organization, Global tuberculosis report 2016Working Group on New TB Drugs, 2016 – www.newtbdrugs.org
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Failed in the clinic GFX
MFX
SQ109?
TBA354
PMD?
AZD5847
STZ?
Warner & Mizrahi 2014 N Engl J Med. 371:1642-3.Heinrich et al. 2015 J Antimicrob Chemother. 70:1558-66.
Furin et al. 2016 Antimicrob Agents Chemother. online
11
Insufficient investment in discovery?
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Benzothiazinones (BTZ) as antimycobacterial agents
2-[4-R-piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one2-[4-R-piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one
PBTZ169PBTZ169
2-[4-R-piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one
PBTZ169
13 PCT/EP2006/004942PCT/IB2011/055209
BTZ043BTZ043BTZ043
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14
Benzothiazinones (BTZ) as antimycobacterial agents
• Highly active against M. tuberculosis (MIC 1-10 ng/ml)and other actinobacteria
• Active against all clinical isolates includingMDR- and XDR-TB
• One pot synthesis, 4 steps, 70% yield, fromcommercially available reagents
• Excellent CoG• Fine safety profile
Makarov et al. 2009 Science 324: 801Makarov et al. 2014 EMBO Mol Med
Pasca et al. 2010 AAC 54: 1616
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Makarov et al. 2009 Science 324:80115
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Death in real time!7H9 10526043 0.2 g/ml 7H998 h 240 h 265 h
a b
N. Dhar, J. McKinney. EPFL
Stain
16
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A B
C
Target – DprE1
G. Manina & G. Riccardi. U Pavia17
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MIC of PBTZ169 against M. tuberculosis H37Rv 0.3 ng/ml (INH 50; EMB 1000)
DPA biosynthesis pathway (Wolucka, 2008)
BTZ & DPA pathway
18
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PBTZ
Kremer et al. (2006) in Tuberculosis and the Tubercle Bacillus. ASM Press
DprE
19
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Neres et. al. 2012 Science Translational MedMakarov et al. 2014 EMBO Mol Med
20
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PBTZ169 - microbiologySynergy with BDQ
additive with all others
Makarov et al. 2014 EMBO Mol Med21
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• PBTZ169 & BDQ synergistic
• PBTZ169 & BDQ/PZA more effective than RHZ
• Active in GP & ZF models
• TB, LEP & BU
PBTZ169 – very active in mice
Makarov et al. 201422
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PBZ – a robust combination
23
• PBZ >> RHZ in mouse• Quicker, more robust cure• Treatment shortening potential?
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• Exciting candidate• Compatible with all known/potential TB drugs• Synergistic with BDQ & CFM• PBZ regimen highly promising• Excellent safety profile
24
2010 patent licensed to multinational but rights returned in 2012
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Created iM4TB to manage PBTZ169 program
25
• iM4TB – not-for-profit fondationcreated by EPFL
• iM4TB aims to support, promoteand actively participate in drugdiscovery and drug developmentconcerning TB and similarpoverty-related and neglecteddiseases
• www.im4tb.org
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Clinical trials
Phase I – 1st 2016 Moscow;
- 2nd CRC, CHUV, Lausanne in Q2 2017
Phase IIa – Russia underway;(IHI, Tanzania)2018?26
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Many thanks to…Benoit LechartierAndréanne LupienRuben HartkoornJoão NeresFlorence PojerClaudia SalaAnthony VocatMing Zhang
Vadim Makarov
M. PetkovaN. ShevkunR. Bolgarin
Claire AllardyceEmilyne Blattes
Jean-Yves GillonLaurence Mauro
Antonia di MeccoIain Old
Sacha Sidjanski