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FDA Panel Backs Drug for MDR/XDR Tuberculosis

An FDA advisory committee recommended approval for pretomanid, a novel antibacterial to be used with other therapies to treat multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis.

In a 14-4 vote, according to a news release from the non-profit drug developer, TB Alliance, the FDA committee backed the safety and efficacy of pretomanid in combination with bedaquiline and linezolid for adults with MDR, XDR, and non-responsive, treatment-intolerant forms of tuberculosis.

“We are encouraged by the advisory committee’s vote in favor of pretomanid for use in combination with bedaquiline and linezolid for the treatment of highly-resistant forms of TB and we look forward to the FDA’s final action,” said Mel Spigelman, president and CEO of TB Alliance, in a statement.

Pretomanid was described in FDA briefing documents as a nitroimidazooxazine antimycobacterial drug. The drug was developed to be used with bedaquiline and linezolid, the TB Alliance said. The regimen is sometimes abbreviated as BPaL or B-L-Pa.

It earned orphan drug, Fast Track, and Qualified Infectious Disease Product designations, the FDA said.

The primary study under review was the open-label phase III Nix-TB trial in South Africa. It was designed to assess the safety and efficacy of the combination therapy bedaquiline plus linezolid plus pretomanid in patients with drug-resistant forms of tuberculosis. The final sample had 109 patients, but an interim analysis of the first 45 subjects of the trial was presented to the FDA.

Patients were ages 14 or older and either could not bear children or were using birth control, and had either documented extensively drug-resistant or multi-drug resistant tuberculosis, and a chest X-ray consistent with pulmonary tuberculosis, the FDA said. They were a mean age of 35, 53% were men, and about three-quarters were black or African. The primary efficacy endpoint was defined as bacteriologic failure, relapse, or clinical failure through follow-up for 6 months after the end of treatment.

Overall, 4o out of 45 patients had favorable outcomes (88.9%, 95% CI 75.9%-96.3%), with the FDA noting “because the lower confidence limit of 75.9% greatly exceeded the predefined threshold of 50%, this single-arm study met statistical criteria for declaring efficacy of B-L-Pa.”

Four of five patients with unfavorable outcomes in the interim analysis died at 5 to 8 weeks after initiation of study therapy; the fifth poor outcome was a fatal relapse after the end of treatment.

Eight patients died overall in the Nix-TB trial, the FDA noted. Other adverse events included peripheral neuropathy, optic neuropathy, hematopoietic cytopenias, and acute pancreatitis. They added that in most cases, these adverse events were managed by dosing interruptions or reductions of linezolid or dosing reductions of the entire regimen.

The FDA’s decision on the drug is expected in August, the TB Alliance said. The FDA does not have to follow the recommendations of its advisory committees, but it often does.