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Abteilung für Infektions- und Tropenmedizin

KLINIKUM DER UNIVERSITÄT MÜNCHEN®

BTZ043

Benzothiazinones – a novel class of antituberuclosis drugs

Michael Hoelscher



BTZ043 - HISTORY

2008 Novel compound discovered by Vadim Makarov at Hans-Knöll-Institute, JenaBenzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis.

Makarov V, et. al. Science. 2009 May 8;324(5928):801-4.

2009 Preclinical Development was outsourced to Alere Inc.

2012 Alere decided to stop the development program and strictly focus

on diagnostic assays

2014 DZIF decided to fund the finalization of the preclinical

development of BTZ043

2015 DZIF, LMU, HKI and FZ Borstel agreed to conduct the further

development together under the project lead of LMU



DZIF – THE GERMAN CENTER FOR INFECTION RESEARCH

Founded 2012

BMBF funded (€38.5m annual funding rate)

35 partner institutions, cross-sectoral

Non-for profit legal association (e.V.)

To address grand challenges of infection medicine

Expected to take a translational (bench-to-bedside) and collaborative research

approach

9 thematic units (TTU), 6 infrastructures (TI)

2014: ca. 270 FTE under funding

3



4

Infrastructure:7 Partner Sites, 32 Institutions

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5.5TTU Hepatitis

5.4TTU HIV

5.6TTU Gastro-

intestinal Infections

5.2TTU Tuberculosis

5.3TTU Malaria

5.1TTU Emerging

Infections

5.8TTU Healthcare-

associated Infections

5.9TTU Novel Anti-

infectives

5.7 TTU Infections of the Immuno-

compromised Host

Grand Challenges

EmergingInfections

Global Infections

Immuno-compromised

Host

Therapy-resistant Infections

6.2DZIF Clinical

Trial Unit

6.1DZIF Product Development

Unit

6.5DZIF Natural Compound

Library

6.4DZIF

Biobanking

6.6DZIF

Bioinformatics

6.3DZIF

African Partner Sites

Translational Infrastructures

6.7 DZIF

Academy

Thematic Translational Units

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The MycoDrug Platform

National Reference Center for Mycobacteria (Kranzer, FZB)MIC (MGIT) using susceptible, MDR-, XDR- Mtb Strains; Stress test (Wayne Model)

Microbial Interface Biology (Reiling, FZB; Rybniker, Cologne)In vitro Drug Efficacy by Fluorescence (GFP-Mtb)

In vitro Drug Efficacy in human primary macrophages (CFU/Fluorescence)In vitro Toxicity Test System (Primary macrophages)

Animal models (Ch. Hoelscher, FZB)In vivo Drug/Regimen Efficacy in Mice (Balb/C), IL13tg mice Granuloma Model, PK/PD

Clinical development (Heinrich/Hoelscher, Munich)Phase I-IIc partly through PanACEA

Compounds (HKI natural compound library)

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ADME, Preclinical toxicology (Dreisbach/Hoelscher, Munich)Subcontracts to CRO‘s



MODE OF ACTION

BTZ 043 efficiently inhibits Mtb cell wall synthesis by blocking the

decaprenyl- phosphoribose-2′-epimerase (DprE1), necessary for the

synthesis of D-Arabinofuranose, a component of arabinogalactan and

arabinomannan.

Due to this mechanism it is highly selective for Mycobacteria species

and does not affect the gut flora.

BTZ 043 binds covalently to the enzyme and blocks it irreversibly

Claudia Trefzer; Henrieta Škovierová; Silvia Buroni; Adela Bobovská; Simone Nenci; Elisabetta Molteni; Florence Pojer; Maria R. Pasca; Vadim

Makarov; Stewart T. Cole; Giovanna Riccardi; Katarína Mikušová; Kai Johnsson; J. Am. Chem. Soc. 2012, 134, 912-915.



In vitro efficacy testing

In vivo testing

Phase III

• MIC 1-10 ng/ml• All clinical (n=200)

isolates tested aresensitive

• Mutation rate < 108

BTZ043 - DEVELOPMENT PATHWAY



Efficacy of BTZ043 in Mtb infected BALB/C mice



PK data for this experiment is underway

Efficacy in BALB/c miceEfficacy of BTZ043 in Mtb infected BALB/C mice



In vitro efficacy testing

In vivo testing

Safety pharma-cology

In vivo toxicology

• MIC 1-10 ng/ml• All clinical (n=200)

isolates tested aresensitive

• Suggested synergywith bedaquillineand Q203

• Mutation rate < 108

Pharmaco-kinetics

• No inductionof CY P450

• hERG negative• No significant

inhibition ofenzymes andreceptors

• Irwin Test negative

Geno-toxicity

• Ames Test andeucariontic in vitro & in vivo assaysnegative

• Rats: 7 + 28 dayscompleted

• NOAEL 170mg/kg

• Mini Pigs: 7 days completed

• NOAEL 180mg/kg

• HED would be36g for a 70kg person

• 10mg/kg is theanticipated dose in humans, history data showthat at least 300 times the MIC in plasma is reached

Phase Ia

• Completion ofpreclinicaldevelopment in Q2 2017

GMP production scale up

BTZ043 - DEVELOPMENT PATHWAY



BTZ043 is part of the PanACEA strategy



ACKNOWLEDGEMENTS:

HANS-KNÖLL INSTITUTE JENA:

Axel Brakhage Michael Ramm Florian Kloss

RESEARCH CENTER BORSTEL: Christoph Hölscher Kerstin Walter Norbert Reiling Katharina Kranzer Stefan Niemann

DZIF PRODUCT DEVELOPMENT UNIT: Thomas Hesterkamp Lisa Heitmann

UNIVERSITY OF MUNICH: Julia Dreisbach Norbert Heinrich Elmar Saathoff

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