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