The U.S. Food and Drug Administration (FDA) recently announced conventional approval for Johnson & Johnson's Sirturo (bedaquiline) as part of a combination therapy for adults and children aged 5 years and older weighing at least 15 kg who have tuberculosis (TB) due to resistance to at least rifampin and isoniazid. This FDA approval is based on confirmatory trials demonstrating the drug's clinical benefit.
Sirturo is a diarylquinoline antimycobacterial drug that initially received accelerated approval from the FDA in 2012 based on an analysis of sputum culture clearance time in two phase 2 controlled trials in patients with multidrug-resistant TB. Sirturo is the first drug approved for the treatment of multidrug-resistant TB and is intended for combination therapy with other medications. Sirturo works through a novel mechanism of action—inhibiting enzymes required for the replication and dissemination of Mycobacterium tuberculosis in the body.
This is the first targeted tuberculosis drug with a novel mechanism of action since rifampin was introduced in 1970. Currently, this drug is a core component of the World Health Organization's recommended guidelines for the treatment of drug-resistant tuberculosis, with three out of every four treated multidrug-resistant tuberculosis patients receiving a bedaquiline-containing regimen.
The conventional approval was based on data from the Phase 3 STREAM study (ClinicalTrials.gov identifier: NCT02409290). This open-label, positive-controlled, randomized trial evaluated the efficacy and safety of bedaquiline in combination with other oral anti-tuberculosis drugs for 40 weeks in patients with sputum smear-positive pulmonary tuberculosis (caused by Mycobacterium tuberculosis and resistant to at least rifampin). The study included four treatment groups (A, B, C, and D); however, due to changes in the standards of care for tuberculosis treatment, two study groups (A and D) were discontinued.
Group B patients (n=202) received 40 weeks of treatment including moxifloxacin (n=140) or levofloxacin (n=62), clofazimine, ethambutol, and pyrazinamide, with supplementation of kanamycin, high-dose isoniazid, and prothionamide during the first 16 weeks.
Group C patients (n=211) received 40 weeks of treatment with bedaquiline, levofloxacin, clofazimine, ethambutol, and pyrazinamide, with supplementation of high-dose isoniazid and prothionamide during the first 16 weeks.
The primary endpoint of the confirmatory trial was to assess whether the proportion of patients with good efficacy outcomes in Group C was not lower than that in Group B at week 76. Good efficacy was defined as two consecutive negative cultures with no adverse outcomes.
The modified intention-to-treat populations for Groups C and B included 196 and 187 patients, respectively. The results showed that 82.7% of patients in the bedaquiline group (Group C) had a good response at week 76, compared to 71.1% in the active control group (Group B) (treatment difference, 11% [95% CI, 2.9–19]). Adverse reactions occurred in 17.3% of patients treated with bedaquiline and 28.9% of patients in the active control group.
Causes of adverse reactions included the need for modification or extension of treatment (8.2% in Group C, 23% in Group B), no culture results within week 76 (6.1% in Group C, 3.7% in Group B), and death at week 76 ([missing data] in Group C). The success rate was 2.6% in Group C and 1.1% in Group B, or at least one of the last two cultures was positive at week 76 (0.5% in Group C and 1.1% in Group B).
Long-term efficacy data up to week 132 included 74.5% (146/196) of patients in Group C and 77.5% (145/187) of patients in Group B. The difference in good outcomes between the two treatment groups at week 132 was 9% (95% CI, 0.6–17.5).
Sirturo is available in 20 mg tablets. Administration should be performed via direct observation therapy.
