Tuberculosis kills over a million people annually, making it a leading cause of death worldwide. It is caused by a bacterium called Mycobacterium tuberculosis, and treatment consists of a combination of drugs taken for at least six months, or even longer in the growing numbers of patients whose disease is resistant to frontline treatments.
We urgently need new and innovative approaches to treating TB, and one promising potential TB treatment has benefitted from the support of both the Innovative Medicines Initiative (IMI) and the European and Developing Countries Clinical Trials Partnership (EDCTP) during the course of its development.
Breathing new life into an old drug
Called alpibectir, the novel treatment works by boosting the activity of a decades-old TB drug called ethionamide. Ethionamide is recommended for the treatment of drug-resistant TB, and while it works well, patients have to take high doses for it to be truly effective. The problem is that these high doses often cause such severe side effects (such as nausea and vomiting) that many patients stop taking it.
In recent years, scientists have started to hunt for ways to boost the activity of ethionamide so that we can lower the dose and spare patients from the worst side effects. The breakthrough came when a multidisciplinary team discovered molecules capable of doing just this. The team, from the University of Lille and Pasteur Institute of Lille, Swiss SME BioVersys and pharmaceutical company GSK, was a perfect example of a private-public partnership.
Studies in the lab showed that one of these molecules, now known as alpibectir, is so good at boosting the activity of ethionamide that it could allow doctors to cut the dose by two-thirds, from over 750 mg to around 250 mg. What’s more, alpibectir is able to overcome some of the resistance mechanisms that the TB bug has developed against ethionamide, and it remains potent against multi-drug resistant strains of TB.
Initial findings: it’s safe and tolerable
BioVersys and GSK continued to develop the drug, and in late 2020 it entered phase 1 clinical trials under the IMI2 project TRIC-TB. The trial, involving 80 healthy volunteers, demonstrated the safety and tolerability of alpibectir; the results were published in the Journal of Antimicrobial Chemotherapy.
A smooth move from IMI2 to EDCTP2…
The next step was to test alpibectir, in combination with low doses of ethionamide, in people with TB. The phase 2 clinical trial started in late 2022 under the EDCTP2 project bEto-TB.
The goal of this trial was to assess the safety and tolerability of different doses of the alpibectir-ethionamide combination (called AlpE), as well as its ability to kill TB bacteria, in patients with newly-diagnosed TB. Trial participants took either AlpE or the standard frontline TB drug isoniazid for 7 days. The results revealed AlpE to be well tolerated, safe and, crucially, as good at killing TB bacteria as isoniazid. This suggests that AlpE could potentially replace isoniazid as a frontline drug; this is important because around 10% of TB cases are resistant to isoniazid.
… and back to IMI2
The success of these trials prompted the decision to launch a further phase 2 trial, this time assessing AlpE over a period of 14 days in combination with the standard frontline drugs used to treat TB. This trial, dubbed ENABLE, is being run via the IMI2 project UNITE4TB, which is working to accelerate the development of novel TB drugs and drug combinations via innovative trial designs deployed across a global clinical trial network. ENABLE started earlier this year and expects to recruit 60 patients. The first results are expected in mid-2026.
The team hopes that the data from the bEto-TB and UNITE4TB studies will provide further insights into the safety, tolerability, and TB-killing ability of AlpE. The data will also help them pin down the optimal doses of alpibectir and ethionamide in the combination, information that will be key to moving AlpE into phase 3 clinical trials.
Meanwhile the European Medicines Agency has granted orphan designation to AlpE for the treatment of TB. Orphan designation is granted to drug candidates addressing life-threatening or chronically debilitating diseases affecting fewer than 5 in 10 000 people in the EU.
“Working to change the trajectory of the TB epidemic”
“Tuberculosis (TB) remains a public health threat, disproportionately affecting vulnerable communities in high-burden countries around the world,” said UNITE4TB project lead David Barros-Aguirre Head of Global Health Medicines R&D at GSK. “The start of the Phase 2a clinical trial with alpibectir-ethionamide (AlpE), in combination with first-line TB drugs, signals an important step forward to combat drug resistant TB. Through our longstanding partnership with BioVersys, and UNITE4TB, we are working to change the trajectory of the TB epidemic.”
“Our partnership with GSK, to advance the development of alpibectir to reach patients in need, combined with the continued public sector support from the UNITE4TB programme, shows how public-private partnerships can work on delivering solutions for global health,” added BioVersys founder and CEO Marc Gitzinger.
Meanwhile the fact that alpibectir has been able to move seamlessly from IMI2 to EDCTP and then back to IMI2 highlights the synergies between the two health partnerships.
“Tuberculosis is a major threat to public health worldwide and we urgently need effective new and improved treatment and prevention therapies for all at-risk populations,” said Michael Makanga, Executive Director of Global Health EDCTP3. “I am delighted that EDCTP has been able to contribute to the development of a promising new treatment.”
“The challenges involved in the development of new TB treatments are too great for any organisation or even country to overcome alone,” said IHI Executive Director Niklas Blomberg. “Partnerships like IMI/IHI and EDCTP have the ability to bring together players from different sectors, countries and disciplines to create consortia capable of contributing meaningfully to the fight against TB.”
TRIC-TB and UNITE4TB are supported under the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry. Both projects are part of IMI’s AMR Accelerator Programme.