Perspectives for new treatments for MDR-TB - tbinfo.ch cycle of M. tuberculosis 2 Koul et al. 2011...

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

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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

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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

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PBTZ

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

DprE

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Neres et. al. 2012 Science Translational MedMakarov et al. 2014 EMBO Mol Med

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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

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• 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

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2010 patent licensed to multinational but rights returned in 2012

Created iM4TB to manage PBTZ169 program

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• 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