A key phase II trial, being run under the PanACEA umbrella, has begun testing a highly promising new TB drug.

The international PanACEA consortium was set up to accelerate development of new TB drugs, by coordinating activities across multiple groups, promoting use of novel laboratory techniques, and using innovative trial designs (such as the innovative ‘multi-arm, multi-study’ MAMS trial, an adaptive trial comparing ways to shorten TB treatment).

A further priority in TB control is the development of additional agents for multidrug-resistant (MDR) and extremely drug-resistant (XDR) TB. These require more intensive treatment, and survival rates are very poor, especially for XDR-TB.

In its latest project, the PanACEA consortium is evaluating a highly promising new drug known as BTZ-043, an inhibitor of cell wall synthesis in Mycobacterium tuberculosis (Mtb). BTZ-043 is highly selective for mycobacteria and is active on all Mtb isolates tested, including MDR and XDR strains.

Following a successful phase I trial, the PanACEA trial, launched in November 2019, is the first time BTZ-043 has been given to patients in Africa. The drug is being given to 80 patients in Cape Town, South Africa, initially to identify the most appropriate dose. The efficacy of the optimised dose will then be compared with standard TB treatment.

Identified in 2014, BTZ-043 has moved rapidly from discovery through to clinical trials. The existing PanACEA infrastructure has meant that sites could be rapidly mobilised to test this exciting new agent, from an entirely new chemical family and with activity against hard-to-treat drug-resistant TB.

In 2019, BTZ043 was tested for the first time in sub-Saharan Africa by PanACEA. What is the importance of this milestone for the consortium?

As treatment options for drug-sensitive TB are limited, and resistance against TB treatment is increasing, the development of new drugs is as important as ever.

BTZ043 is a new and promising chemical entity that has been successfully trialled in a phase 1A study among healthy volunteers. Currently, we are aiming to identify the BTZ043 dose with an optimal safety and bactericidal activity profile. To address this, we started a prospective phase 1B/2A study in 2019, investigating multiple oral doses of BTZ043 in subjects with drug-susceptible pulmonary tuberculosis. This will ultimately lead to the selection of the dose that will be studied as part of a multi-compound regimen in a large group of TB patients.

What progress was made in 2019?

In addition to the start of the BTZ043 trial, we also reached an important milestone in preparation for the SUDOCU trial (optimal dose selection of sutezolid, another new compound) and the STEP2C trial, a large phase 2 trial with multiple arms comparing high-dose rifampicin and a new regimen with sutezolid. We have also been preparing for the PHENORIF trial, a metabolic phenotyping study that will clarify whether high-dose rifampicin has a similar drug-drug interaction potential compared to standard-dose rifampicin.

The year 2019 also marked the completion of the HIGHRIF trial, concluding a journey to identify the maximum tolerated dose of rifampicin that started in the 1960s. The results will be important for follow-up clinical trials and implementation of high-dose rifampicin.

For all trials we developed a comprehensive training and mentoring programme for capacity building in trial-related disciplines such as Good Clinical Practice, clinical management, clinical pharmacology, medical microbiology and financial management among all the consortium’s participating sites.

What comes next?

In 2020 we will complete the BTZ043 phase 2 study and start enrolment into the SUDOCU and PHENORIF trials. We will also begin preparations for our largest trial, STEP2C, which will run in all PanACEA clinical trial sites.