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Perspectives for new treatments for MDR-TB
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)
• TB – colossal global health problem
• Confounded by HIV, diabetes, drug resistance3
MDR and XDR-TB
4
World Health Organization, Global tuberculosis report 2016
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!”
• 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
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
8
• Diarylquinolines - TMC207 (bedaquiline)
• Nitroimidazole derivatives: PA-824 (pretomanid), TBA354, OPC67683 (delaminid)
• Ethylene diamines - SQ109• Imidazopyridine - Q203• Benzothiazinones – BTZ043, PBTZ169
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
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
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?
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
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
Makarov et al. 2009 Science 324:80115
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
A B
C
Target – DprE1
G. Manina & G. Riccardi. U Pavia17
MIC of PBTZ169 against M. tuberculosis H37Rv 0.3 ng/ml (INH 50; EMB 1000)
DPA biosynthesis pathway (Wolucka, 2008)
BTZ & DPA pathway
18
PBTZ
Kremer et al. (2006) in Tuberculosis and the Tubercle Bacillus. ASM Press
DprE
19
Neres et. al. 2012 Science Translational MedMakarov et al. 2014 EMBO Mol Med
20
PBTZ169 - microbiologySynergy with BDQ
additive with all others
Makarov et al. 2014 EMBO Mol Med21
• 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
PBZ – a robust combination
23
• PBZ >> RHZ in mouse• Quicker, more robust cure• Treatment shortening potential?
• 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
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
Clinical trials
Phase I – 1st 2016 Moscow;
- 2nd CRC, CHUV, Lausanne in Q2 2017
Phase IIa – Russia underway;(IHI, Tanzania)2018?26
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