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FDA Grants Accelerated Approval for Sirturo (Bedaquiline) as Part of Combination Therapy for Adults With Drug-Resistant TB

Drug inhibits enzyme essential for energy generation in TB bacterium (Dec. 31)

The FDA has granted accelerated approval to Sirturo (bedaquiline, Janssen Therapeutics) for the treatment of pulmonary multi–drug-resistant tuberculosis (MDR-TB) as part of combination therapy in adults. The accelerated approval is based on the surrogate endpoint of time to sputum culture conversion.

Sirturo (bedaquiline) is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (aged 18 years or older) with pulmonary MDR-TB. The drug inhibits mycobacterial adenosine 5'-triphosphate (ATP) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis.

The FDA’s accelerated approval of Sirturo was based on data from two clinical trials. In both studies, the primary endpoint was the time to sputum culture conversion (defined as the interval in days between the first dose of study drug and the date of the first of two consecutive negative sputum cultures collected at least 25 days apart during treatment).

Study 1 was a placebo-controlled, double-blind, randomized trial conducted in newly diagnosed patients with MDR-TB. The patients were randomly assigned to treatment with either Sirturo and other drugs used to treat MDR-TB (n = 79) or placebo plus other drugs used to treat MDR-TB (n=81); the other drugs used to treat MDR-TB consisted of a combination of five other antimycobacterial drugs (ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone or available alternative).

Sirturo was administered at a dosage of 400 mg once daily for the first 2 weeks, followed by 200 mg three times per week for the following 22 weeks. After 24 weeks of treatment with either Sirturo or placebo, the patients continued to receive their other drugs used to treat MDR-TB until a treatment duration of 18 to 24 months was achieved, or at least 12 months after the first confirmed negative culture.

The Sirturo group had decreased times to culture conversion and improved culture conversion rates compared with the placebo group at week 24. The median time to culture conversion was 83 days for the Sirturo group versus 125 days for the placebo group.

Study 2 was a smaller, placebo-controlled trial with a design similar to that of Study 1 except that Sirturo or placebo was given for only 8 weeks instead of 24 weeks. The patients were randomly assigned to treatment with either Sirturo and other drugs used to treat MDR-TB (n = 23) or placebo and other drugs used to treat MDR-TB (n = 24).

The Sirturo group had a decreased time to culture conversion and improved culture conversion rates compared with the placebo group at week 8. At weeks 8 and 24, the differences in culture conversion proportions were 38.9% and 15.7%, respectively.

The safety and efficacy of Sirturo have not been established for the treatment of latent infection due to M. tuberculosis or for the treatment of drug-sensitive TB. In addition, there are no data on the treatment of extra-pulmonary (e.g., central nervous system) TB with Sirturo. Therefore, the use of Sirturo in these settings is not recommended.

The prescribing information for Sirturo includes boxed warnings regarding an increased risk of death and the occurrence of QT prolongation. The most common adverse drug reactions were nausea, arthralgia, and headache.

Source: Janssen Therapeutics; December 31, 2012.

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