PBTZ 169

Antitubercular drugs

Project objective

Development, set up of full scale production, registration and introduction to the market of an innovative medicine for the treatment of tuberculosis, including its multiple drug resistant and extensive drug resistant forms.

Project description

Transfer of a medicine of foreign design based on a benzothiazinone derivative intended for the treatment of tuberculosis including its drug resistant forms.

Application areas

Infectious diseases: treatment of the pulmonary tuberculosis including its drug resistant varieties.

Benefits of the project

  • "First in class" anti-tuberculosis drug
  • A unique target: the enzyme of the Mycobacterium DprE1 cell wall. Scientifically proven mechanism of action.
  • Bactericidal effect, activity against forms of tuberculosis with MDR and XDR, including HIV+
  • Low probability of M. tuberculosis resistance development
  • The favorable safety profile is confirmed in the course of preclinical and clinical studies.
  • Synergism and additive effect with drugs of combined anti-tuberculosis therapy

Patents/licenses/certificates

License agreement between NEARMEDIC PLUS and the Polytechnic University of Lausanne (École Polytechnique Fédérale de Lausanne - EPFL) of 25.05.2014 providing NEARMEDIC PLUS with exclusive rights for the manufacture and registration of PBTZ169 in the Russian Federation, with the aim of its further sale and wide introduction into clinical practice in Russia, the EAPO countries (EAPO - Eurasian Patent Organization), as well as in Ukraine, Mongolia, and Georgia.

International patent applications: WO / 2012/066518 and WO2016 / 151011.

Publications

  1. Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Mol Med. 2014 Mar; 6 (3): 372-83.
  2. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science. 2009 May 8; 324 (5928): 801-4.
  3. Clinical isolates of Mycobacterium tuberculosis in four European hospitals are uniformly susceptible to benzothiazinones. Antimicrob Agents Chemother. 2010 Apr; 54 (4): 1616-8.
  4. Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl- β-D-ribose 2'-epimerase DprE1 of Mycobacterium tuberculosis. J Am Chem Soc. 2010 Oct 6; 132 (39): 13663-5.
  5. Benzothiazinones are suicide inhibi-tors of mycobacterial decaprenylphosphoryl-β-D-ribofuranose 2'-oxidase DprE1. J Am Chem Soc. 2012 Jan 18; 134 (2): 912-5.
  6. Structural basis for benzothia-zinone-mediated killing of Mycobacterium tuberculosis. Science. Trans Med. 2012 Sep 5; 4 (150): 121.
  7. In vitro combination studies of Benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012 Nov; 56 (11): 5790
  8. In vitro activities of the new antitubercular agents PA-824 and BTZ043 against Nocardia brasiliensis Antimicrob Agents Chemother. 2012 Jul; 56 (7): 3984
  9. In vitro activity of the prospective drug PBTZ169, hydrochloride towards clinical strains of Mycobacterium tuberculosis with XDR. L. N. Chernousova et al. Tuberculosis and pulmonary diseases 2016, issue 9, volume 94.
  10. Drug resistant tuberculosis: prospects of accelerated diagnosis and chemotherapy L.N. Chernousova et al. Bacteriology, 2017, volume 2, No. 1, p.p. 25–34
  11. Biological and structural characterization of the Mycobacterium smegmatis nitroreductase NfnB, and its role in benzothiazinone resistance. Mol Microbiol. 2010 Sep; 77(5):1172-85.

Awards

  1. Swiss-Russian Innovations Prize (Silver, 2015) Development and validation of a quantitative determination method for the antitubercular drug PBTZ169 in biological media. Stepanova et al. Pharmaceutical Chemistry Journal, Vol. 52, No. 3, June, 2018

Project is supported by

  • École polytechnique fédérale de Lausanne (Switzerland)
    École polytechnique fédérale de Lausanne (Switzerland)
  • Innovative Medicine for Tuberculosis Foundation (Switzerland)
    Innovative Medicine for Tuberculosis Foundation (Switzerland)
  • Central Research Institute for Tuberculosis (Moscow)
    Central Research Institute for Tuberculosis (Moscow)
  • Russian Society of Phthisiologists
    Russian Society of Phthisiologists
  • RF Ministry of Industry and Trade (in the framework of state contract and production set-up subsidy)
    RF Ministry of Industry and Trade (in the framework of state contract and production set-up subsidy)
  • OOO OST Rus – partner in clinical studies
    OOO OST Rus – partner in clinical studies

Project status

The drug has undergone pre-clinical trials in Russia and Europe. In Russia, Phase 1 and Phase 2A of clinical trials (CT) were successfully completed in 2016. At the moment Phase 1B of CT in Russia is about to be completed. In Europe, stage 1 of CT Phase 1 was completed in 2018. A permit for Phase 2Bof CT has been received in Russia. The transfer of production of the pharmaceutical substance and dosage form to the NEARMEDIC Pharma plant in Obninsk as well as construction and installation works on the synthesis site are being completed, the equipment will be launched in 2019.