麻豆传媒

DENVER -- In patients with tuberculosis (TB), a novel fixed-dose combination of alpibectir-ethionamide had similar levels of bactericidal activity as isoniazid, with no serious adverse events and good tolerability, a phase II randomized controlled trial showed.

Time to positivity for cultures from overnight sputum samples among patients receiving alpibectir-ethionamide was 45.28 hours (95% CI 28.78–78.12) compared with 48.41 hours (95% CI 42.02–54.89) for cultures from patients who received isoniazid, reported Jeantelle Du Preez, MBChB, of TASK Applied Science in Cape Town, South Africa, at the Conference on Retroviruses and Opportunistic Infections.

"TB is still a major concern worldwide, both in people living with HIV and those without, and ethionamide is quite an old anti-TB drug that is recommended for use as a second agent in drug-resistant TB and TB meningitis," Du Preez told attendees. "The problem with ethionamide is, in practice, it has been deprioritized due to intolerability at standard doses."

That intolerability primarily involves severe gastrointestinal side effects because of the very high doses of ethionamide necessary to achieve bioactivation. However, alpibectir enhances the bioactivation of ethionamide through alternative pathways, so combining the drugs can allow for use of lower doses of ethionamide and, ideally, fewer adverse events.

Based on the findings of this study, "alpibectir-ethionamide may potentially be added to the growing list of novel anti-tuberculosis agents for drug-susceptible and drug-resistant TB," Du Preez said.

Kelly Dooley, MD, PhD, MPH, director of the division of infectious disease at Vanderbilt University Medical Center in Nashville, Tennessee, who was not involved in the study, agreed that this combination shows promise.

"We need new drugs for TB, and what's exciting about this activator of ethionamide is that it's bioactivating a drug that we know pretty well and that we know works well but that just has a toxicity profile that is unacceptable," Dooley told 麻豆传媒. "So this represents a novel strategy to repurpose in a smarter way those drugs that we think might potentially have a new place in our armamentarium that we thought we should just retire because of the safety issues."

Increasing incidence of bedaquiline resistance necessitates new multiple-drug combinations "to address the emerging drug resistance problem," Dooley said, "so this is a nice possibility to use in those multi-drug regimens, provided that it had activity against inhA-mutated strains. Because the pathway of ethionamide is via inhA inhibition, we just need them to show those data to reassure us that those strains are treatable because we don't want a drug that works for some people with inhA resistance and not others."

The study involved 17 adults ages 18-65 with new, untreated pulmonary TB, which is susceptible to rifampicin and isoniazid. The 14 patients in the intervention arm received 9 mg of alpibectir and 250 mg of ethionamide for 7 days, and the three control patients received 300 mg of isoniazid for 7 days.

The only significant differences between the groups were an older mean age (35.1 vs 25.7) and a higher proportion of males (87% vs 33%) in the alpibectir-ethionamide group. However, baseline time to positivity was similar in both groups, and the majority of participants in both groups had cavitary disease in baseline lung x-rays.

Bactericidal activity was determined by change in time to positivity in liquid cultures from overnight sputum samples collected from participants daily from pre-treatment through day 7 of treatment. Safety and tolerability were assessed daily.

No grade ≥3 adverse events occurred in either group. All adverse events in the isoniazid group were mild. In the alpibectir-ethionamide group, most adverse events were mild (68.4%), and 31.6% were moderate. Four participants in the alpibectir-ethionamide group experienced adverse events that were potentially related to the drug, including one nervous system disorder and three gastrointestinal disorders (diarrhea and flatulence). Two of the isoniazid patients had potentially drug-related adverse events, both of which were nervous system disorders, such as reduced vibratory sense and hyperreflexia.

An exploratory endpoint was plasma concentration of ethionamide and its metabolite ethionamide sulfoxide from samples collected on day 7. Concentrations were similar overall, but ethionamide sulfoxide had slightly higher exposure. Each 100 h*ng/mL increase resulted in a 3.68% increase in time to positivity.

The study team is continuing to evaluate differing doses of alpibectir and ethionamide to determine the optimal combination.

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