Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BTZ043
Benzothiazinones – a novel class of antituberuclosis drugs
Michael Hoelscher
Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
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
Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
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
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Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
4
Infrastructure:7 Partner Sites, 32 Institutions
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Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
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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Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
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
Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
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.
Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
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
Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
Efficacy of BTZ043 in Mtb infected BALB/C mice
Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
PK data for this experiment is underway
Efficacy in BALB/c miceEfficacy of BTZ043 in Mtb infected BALB/C mice
Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
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
Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
BTZ043 is part of the PanACEA strategy
Abteilung für Infektions- und Tropenmedizin
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
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