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New Tuberculosis Agent Enters Clinical Trials

Scientists of two Research Associations and Enterprises Join Forces for this Purpose

The first antibiotic against tuberculosis developed in Germany is now being tested in clinical trials. The newly developed test substance with the identification BTZ043 is also also effective against multiresistant pathogens which make a treatment at least increasingly difficult worldwide. The project is managed by scientists of the Leibniz-Institut for Natural Product Research and Infection Biology – Hans-Knöll-Institut – (Leibniz-HKI) of Jena and the Munich Ludwig-Maximilians-Universität (LMU). The consortium InfectControl 2020 and the Deutsche Zentrum für Infektionsforschung [German Centre for Infection Research (DZIF)] facilitate a large part of the studies. HAPILA GmbH of Gera is responsible for the GMP manufacture of the active substances. The activities of the company are supported by the Free State of Thuringia and InfectControl 2020.

New Tuberculosis Agent Enters Clinical Trials
In the recent decades the problem of antibiotic resistance has been dramatically increasing worldwide. Today we are facing the challenge that there are more and more resistant pathogens against which only few antibiotics help. In the case of tuberculosis, the situation is particularly difficult as for its treatment always several antibiotics have to be administered simultaneously. To make matters worse, the pathogens causing tuberculosis are increasingly more resistant against these antibiotics. In order to develop new forms of therapy, several new active pharmaceutical ingredients are thus urgently needed, ideally with different mechanisms of action.

Active Pharmaceutical Ingredient Purposefully Hits New Contact Point at the Pathogen

BTZ043 belongs to a new class of antibiotics, the benzothiazinones. As the representative of this family of substances, BTZ043 was the first to gain worldwide patent protection for its effect against the pathogen causing tuberculosis. “The active ingredient irreversibly binds to an enzyme which the mycobacteria – the pathogens causing tuberculosis – need to construct the cell wall after the bacteria“, Dr Florian Kloß explains. He is the head of the transfer group Antiinfektiva subsidised by InfectControl 2020 at the Leibniz-HKI. “This enzyme thus cannot work any longer, in the cell walls of the mycobacteria holes occur and they drain off“, supplements the DZIF scientist Prof Michael Hoelscher, director of the tropical Institute of the Munich Ludwig-Maximilians-Universität. This attack of the tuberculosis pathogen is so pointed that BTZ043 fights the pathogens, but not any other bacteria which are important for us.

Clinical Trials Test Tolerability

After the approval by the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) [Federal Institute for Drugs and Medical Devices] and the ethics committee of the Bayerische Landesärztekammer [Bavarian medical board] now the first participants can be recruited for the clinical study of BTZ043. Under the direction of Prof Hoelscher up to 40 volunteering participants will receive the antibiotic at the study center of the company Nuvisan in Neu-Ulm. “We want to make sure that the drug is absorbed and tolerated well by the body. For this purpose a very low dose is administered nonrecurringly, which is then increased step-by-step with the following participants“, Hoelscher explains the proceedings. It is the objective of the trial to reach the dosage which has shown a good efficacy in the animal model. This efficient dosage is far below the maximum amount which was tested with animals and was still tolerated well.

Together Against Infections

A team of scientists and entrepreneurs has been involved in developing the tuberculosis medication. The active pharmaceutical ingredient BTZ043 was discovered at the Leibniz HKI of Jena. Since 2014 the Leibniz HKI and the clinical centre of the Munich Ludwig-Maximilians-Universität among others in the consortium InfectControl 2020 and in the DZIF have been cooperating to further develop the drug. The two research associations InfectControl 2020 and DZIF are programs initiated by the Bundesministerium für Bildung und Forschung [Federal Ministry for Education and Research] to subsidise the infection antibiotics research in Germany. The Leibniz-HKI is in charge of the development of the analytic detection methods and the precise examination of the absorption, distribution, metabolization and excretion in animal experimentation and with human beings. As a sponsor, the clinical centre of the LMU it is in charge of the preclinical and clinical development as well as of the quality and safety of the drug product. The GMP manufacture of the highly efficient active substance is performed at HAPILA GmbH of Gera, an independent medium-sized pharmaceutical and chemical enterprise. In addition to that, HAPILA develops the manufacturing process in compliance with all the relevant specifications of the pharmaceutical law as well as of internationally valid regulations. The development of the drug product costing several million euro is possible only by collective financing by private enterprises and the state. “We are very proud of contributing to the development of this tuberculosis drug which is so urgently needed and we will also accompany the further clinical studies with active substances from Gera “, says Dr Uwe Müller, CEO of HAPILA GmbH. “To be able to accept this challenge being very great for a small enterprise such as HAPILA has only been possible due to the support of the Free State of Thuringia via the Thüringer Aufbaubank Erfurt [Thuringia and development bank]“.

On InfectControl 2020

The BTZ project is a part of the German consortium InfectControl 2020 acting nationwide. In this research association science and economy have joined forces in order to avoid infectious diseases long-term, to recognise them earlier and to fight them consequently. InfectControl 2020 is subsidised by the Bundesministerium für Bildung und Forschung [Federal Ministry for Education and Research].



Upper picture - Florian Kloß/HKI: A structural model of the anti-tuberculosis ingredient BTZ043
Lower pictures - Andreas Wiesner/DZIF: BTZ043 blocks an enzyme which is involved in the construction of the cell wall of the pathogen causing tuberculosis, the mycobacterium tuberculosis. The content of the cell thus is drained off through the defective places and the cell wall. On the right side there is a comparative photograph without treatment with BTZ043