BTZ-043 - potential game changer in the fight against tuberculosis
Around 1.6 million people die every year from an infection with Mycobacterium tuberculosis - making tuberculosis the bacterial infectious disease with the highest number of fatalities worldwide. As the pathogen can "hide" in individual cells and in encapsulated granulomas, both from the body's immune response and from treatment with medication, treatment is particularly difficult. It is carried out as a combination therapy with several antibiotics, which must be taken over a period of up to two years. The problem is that many tuberculosis bacteria are now resistant to the standard drugs used. This is why scientists and the World Health Organization (WHO) are focusing on the development of new antibiotics. A drug candidate known as BTZ-043 is particularly promising.
Active ingredient research relies on strong partners
The active ingredient BTZ-043 is the first antibiotic developed in Germany for decades. It was discovered by researchers at the Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI) in Jena. Since 2014, the Leibniz-HKI and the Tropical Institute at LMU Klinikum München have joined forces in a research collaboration to advance the preclinical development of the active ingredient. By the time the second phase of clinical development is completed, the project will have cost around 60 million euros. The German Federal Ministry of Education and Research (BMBF) is providing around 50 percent of the funding, either directly or through the German Center for Infection Research (DZIF).
Further funding is being provided by the European-African "European & Developing Countries Clinical Trials Partnership" (EDCTP), the European "Innovative Medicines Initiative" (IMI), the Bavarian State Ministry of Science and the Arts and the Free State of Thuringia.
Alongside HIV/AIDS and malaria, tuberculosis is one of the most common infectious diseases worldwide. Although tuberculosis is generally treatable with medication, it often leads to death in poorer countries, as they often lack the financial resources for treatment. In addition, the treatment of tuberculosis extends over many months and requires the simultaneous administration of several antibiotics, which is often associated with severe side effects.
In Germany, tuberculosis has almost disappeared. However, one challenge here is the treatment of people who (re)enter Germany from regions with multi-resistant strains of the pathogen - for example from Eastern Europe, but also from South-East Asia, Africa and the Western Pacific region.
World Tuberculosis Day on March 24 each year is a reminder of how dangerous this disease continues to be and aims to raise awareness among researchers, industry and politicians that further treatment options are urgently needed. This date was chosen because Robert Koch announced the discovery of the tuberculosis bacterium in Berlin on March 24, 1882.
Promising study results in Germany and South Africa
Early clinical studies confirm that BTZ-043 is highly effective and safe. "The active ingredient belongs to a new class of antibiotics. It inhibits an enzyme in the tuberculosis pathogens that is needed to build up the bacterial cell wall," says Professor Axel Brakhage, Director of the Leibniz-HKI in Jena. "This inhibition causes the cell to disintegrate and ultimately the pathogen to die."
The drug has now been tested in two clinical trials. The phase I trial of BTZ-043 on healthy volunteers took place in Germany; in the first trial on patients (phase IIa), the active substance was tested in Cape Town, South Africa. The aim was to find the best possible dose to ensure the highest efficacy and best tolerability. "The results of these studies are very promising," says Professor Michael Hoelscher from LMU Klinikum München. A significant reduction in the bacterial load was observed after just 14 days of monotherapy. "This means that the treatment effect is on a par with the most effective tuberculosis drugs currently available."
In the further development of BTZ-043, the focus is now on finding effective combination partners. As a rule, a combination of three to four drugs is used to prevent resistance. The right combination drugs, the right dose and ultimately also the right duration of therapy are being investigated both within the PanACEA II consortium in the STEP2C study and in ongoing phase II clinical trials within the "Academia and Industry United Innovation and Treatment for Tuberculosis" (UNITE4TB) research consortium. This consortium, led by Professor Hoelscher as scientific coordinator, brings together 30 partners from 13 countries. Studies evaluating a total of seven different combination therapies with BTZ-043 over a four-month period will be launched this year in twelve countries on four continents.
Joint research against tuberculosis
Public funding plays just as important a role in the development of new medicines, which are primarily intended for poorer countries, as partnership-based cooperation between science and industry. To combat tuberculosis, for example, 30 partners from 13 countries founded the UNITE4TB consortium, which began its work in June 2021. Funded with 185 million euros, UNITE4TB is the largest public-private collaboration for the clinical development of tuberculosis drugs in the history of the European Union. The German Center for Infection Research (DZIF) and the LMU Klinikum München are also involved. At European level, the research platform is supported by the Innovative Medicines Initiative (IMI), a public-private cooperation that now operates under the name "Innovative Health Initiative" (IHI). The Federal Ministry of Education and Research (BMBF) is funding this project via the two German partners - the LMU Klinikum München and the DZIF - with around 25 million euros. The LMU Klinikum München is contributing a further five million euros and the pharmaceutical companies involved are each contributing 20 million euros. The European Union is doubling these funds as part of the IMI partnership.
BMBF funding also went to the InfectControl consortium of the Germany-wide Twenty20 Partnership for Innovation initiative, which brings together partners from science and industry, and the European-African PanACEA consortium. This platform for conducting therapy studies and preparing highly qualified clinical trials provides crucial data for the work at UNITE4TB and is funded by the European & Developing Countries Clinical Trials Partnership(EDCTP).
