Tuberculosis: A race against time

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To stimulate global research on tuberculosis treatments, the UNITE4TB consortium has commenced its work. It is a global network that includes academic institutions and pharmaceutical companies, with the primary aim to identify a new and effective combinational therapy for tuberculosis, based on drugs that are under development. The Scientific Lead of the project, Professor Michael Hoelscher (Director of the Division of Infectious Diseases and Tropical Medicine at the LMU University Hospital Munich ) tells us more.

One third of the world’s population is now infected with tuberculosis. Why is the disease so difficult to treat?

Michael Hoelscher: Over 90% of infected individuals have what is called ‘latent’ tuberculosis. In such cases, any decline in the efficacy of the infected individual’s immune response reactivates the dormant bacteria and allows them to propagate. So we not only have to kill the actively dividing bacteria in the lung, but also the dormant bacteria in granulomas. Granulomas can be thought of as capsules of a few centimeters in diameter that are filled with dead phagocytes and dormant mycobacteria – and it is extremely difficult for drugs to penetrate into these capsules.

For decades, patients infected with tuberculosis have been treated with a cocktail of antibiotics. For the past several years, you have been working on new anti-tuberculosis drugs. Why is this necessary?

Michael Hoelscher: A combination of four different antibiotics served as an effective treatment for around 40 years, and in most countries the incidence of tuberculosis has drastically declined. It was a tremendously successful therapy. However, the incidence of infections is rising again, and new strains have developed resistances against one or more drugs. In some parts of the world, 30% of all diagnosed cases are multi-drug-resistant tuberculosis cases. In terms of the incidence of antibiotic resistance, tuberculosis is the biggest problem worldwide, and it causes many deaths.

How high is the risk of contracting the disease in Germany?

Michael Hoelscher: It’s very low. We currently have between seven and nine cases per 100,000 inhabitants. From a global point of view, however, tuberculosis is a significant problem. Until the emergence of the COVID-19 pandemic, the bacterium was the biggest threat among all infectious diseases. UNITE4TB is designed to combat this threat.

Romania has the highest incidence of tuberculosis in Europe. Why is that so?

Michael Hoelscher: The simple answer is that tuberculosis is a disease of the poor. The rate at which the infection spreads depends on the overall level of prosperity, on how crowded living conditions are and on the quality of the healthcare system. But other factors are at work as well. For a long time, it was assumed that tuberculosis could be eliminated in Africa. But then the HIV epidemic occurred and because HIV weakens the immune system, the incidence of tuberculosis infections increased.

How much progress has been made so far in the development of new drugs?

Michael Hoelscher: Many of the drugs that are part of the UNITE4TB project are now in clinical development. The Division of Infectious Diseases and Tropical Medicine at the LMU University Hospital is participating with the drug candidate BTZ-043, which has been under development since 2014. The antibiotic was discovered by the Hans Knöll Institute in Jena, and they expressed interest in cooperating with us in a clinical development partnership. Since then, we have been an equal partner in its development. In fact, we are the only University Hospital in Germany that is directly involved in an effort to bring a new drug onto the market. Usually, academic institutions carry out Phase I trials of new drug candidates – small-scale studies designed to test the compound for potentially significant side-effects. Following a successful Phase I, they normally give/sell the patent rights to a pharmaceutical company, because the costs of further clinical development are extremely high. In the case of poverty related diseases, these costs are largely paid by the State. We were confident that we possessed sufficient expertise in clinical development to do this part of the job ourselves, so that the profits would remain in the public sector. More importantly, this would mean that an institution, which is not obliged to take decisions solely on the basis of economic considerations, would retain control of the process.

What is the role of the Tropical Institute in the UNITE4TB consortium?

Michael Hoelscher: Not only did our Institute initiate the research project and contributed an active ingredient candidate of its own, we also convinced others to help finance the venture. The German Federal Ministry of Education and Research has provided 25 million euros in funding for UNITE4TB at LMU and the LMU/LMU University Hospital through the German Center for Infection Research (DZIF) and the University Hospital itself has contributed 5 million, while pharmaceutical companies have contributed 20 million each. The European Commission doubles these funds within the Innovative Medicines Initiative (IMI) program. In all, 185 million euros have been made available for UNITE4TB. Our Institute is also responsible for the scientific coordination of the consortium. For example, we play a central role in the design of the study and the analysis of the results, in the development of novel biomarkers and in the implementation of Phase IIb/c trials.

And in which development phase is BTZ-043 at the moment?

Michael Hoelscher: Its efficacy against tuberculosis has been confirmed in a 2-week monotherapy. Within UNITE4TB, the next step is to find the combination of drugs that most effectively complement its effect. Then comes Phase 3, which determines whether the treatment is approved or not. The costs of this phase are around 150 million euros. Of course, the idea of undertaking such a large project in a university environment requires a considerable amount of daring. Politics encourages us to think in translational terms and to develop our ideas to the point where patients can benefit from them. After all, countries like the US and the UK have already taken this route. We can also learn that we don’t have to wait for specific calls from funders. We ourselves can initiate projects and help to shape research agendas and research policy.