NTM lung disease is notoriously difficult to treat and typically consists of multiple antibiotics taken over many months. Credit: mi_viri via Shutterstock.

AN2 Therapeutics recently announced its decision to voluntarily pause enrollment of the Phase III portion of its Phase II/III EBO-301 trial due to potentially lower-than-expected efficacy data obtained from the Phase II portion of the trial.

EBO-301 (NCT05327803) is a pivotal trial evaluating the orally administered antibiotic, epetraborole, in patients with treatment-refractory Mycobacterium avium complex (MAC) lung disease, a nontuberculous mycobacterial (NTM) infection.

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NTM refers to infection with a group of bacteria within the Mycobacterium genus, which excludes Mycobacterium tuberculosis (tuberculosis) and Mycobacterium leprae (leprosy). MAC bacteria naturally reside in soil and water, including airborne soil/dust particles and water in the home. Exposure to MAC bacteria occurs daily, but for most healthy individuals it does not result in an infection. NTM are opportunistic pathogens that are responsible for causing infections in patients with pre-existing health conditions or compromised immune systems.

Symptoms of NTM lung disease include cough, fever, weight loss, weakness, and respiratory insufficiency. NTM lung disease is notoriously difficult to treat and typically consists of multiple antibiotics taken over many months. However, in many instances, NTM infections can become treatment-refractory, leaving patients with limited therapeutic options. For these reasons, there is a pressing need for the development of new antibiotics.

According to GlobalData, the NTM late-stage development pipeline (Phases II–III) for the seven major pharmaceutical markets (7MM) (US, France, Germany, Italy, Spain, UK, and Japan) comprises only seven products, including epetraborole. Of these seven products, five are antibiotics and two are recombinant proteins. Furthermore, four of these products are already marketed drugs seeking label expansions to include NTM infections, whereas the remaining three are new pipeline drugs. Despite the high level of unmet need surrounding NTM treatment, the late-stage product development pipeline displays limited therapeutics, particularly now that the fate of epetraborole is unknown.

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In preclinical studies, epetraborole demonstrated superior microbiological efficacy when combined with standard-of-care (SOC) agents, compared to SOC alone. The addition of epetraborole to SOC increased bacterial killing and resulted in a reduction of lung colony-forming units (CFUs) in NTM animal models. Likewise, a Phase I dose-ranging study found that epetraborole was well tolerated, with 92% of adverse events (AEs) being mild. Commonly observed AEs included nausea (23.1%), headache (17.9%), and diarrhea (10.3%). Epetraborole has been granted fast track designation and qualified infectious disease product designation by the FDA, as well as orphan drug designation by both the FDA and the European Commission.

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A blinded aggregate analysis of ongoing EBO-301 Phase II data did not highlight any safety concerns. Rather, it indicated that both treatment groups—epetraborole + optimised background regimen (OBR) and placebo + OBR—showed potentially lower-than-expected efficacy. The paused enrollment will allow researchers to further evaluate the study data, and will also allow the independent Data Safety Monitoring Board (DSMB) to conduct an unblinded assessment and recommend the next steps. The patients who are already enrolled in the Phase II/III trial will be allowed to continue the study.

The successful development of NTM therapies is a complex undertaking. If AN2 Therapeutics can successfully continue the development of epetraborole, this product would be a much-needed addition to the NTM market. However, if epetraborole exits the NTM pipeline, more focus may be shifted to other late-stage products such as Spero Therapeutics’s fobrepodacin (SPR720) and Janssen’s bedaquiline.