FDA grants traditional approval to TB treatment Sirturo

The Food and Drug Administration (FDA) has granted traditional approval to Sirturo^® (bedaquiline) for use as part of combination therapy in adult and pediatric patients (5 years and older and weighing at least 15kg) with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampin and isoniazid.

Sirturo, a diarylquinoline antimycobacterial drug, had originally received accelerated approval in 2012 based on an analysis of time to sputum culture conversion from 2 controlled phase 2 trials in patients with pulmonary multidrug resistant TB. Traditional approval was granted based on data from the phase 3 STREAM study (ClinicalTrials.gov Identifier: NCT02409290).

The open-label, active-controlled, randomized trial evaluated the efficacy and safety of bedaquiline, coadministered with other oral anti-TB drugs for 40 weeks in patients with sputum smear-positive pulmonary TB caused by M. tuberculosis that was resistant to at least rifampin. The study included 4 treatment arms (Arms A, B, C, and D), however, due to changes in the standard of care for TB treatment, 2 study arms (A and D) were stopped.

Patients in Arm B (n=202) received a 40-week treatment of moxifloxacin (n=140) or levofloxacin (n=62), clofazimine, ethambutol, pyrazinamide, supplemented by kanamycin, high-dose isoniazid and prothionamide in the first 16 weeks. Those in Arm C (n=211) received a 40-week treatment of bedaquiline, levofloxacin, clofazimine, ethambutol, and pyrazinamide, supplemented by high-dose isoniazid and prothionamide in the first 16 weeks.

The primary endpoint of the confirmatory trial was to assess whether the proportion of patients with a favorable efficacy outcome in Arm C was noninferior to that in Arm B at week 76. A favorable outcome was defined as the last 2 consecutive cultures being negative, and with no unfavorable outcome.

A total of 196 and 187 patients were included in the modified intent-to-treat population in Arm C and Arm B, respectively. Findings showed 82.7% of patients in the bedaquiline group (Arm C) had a favorable response at week 76 compared with 71.1% of the active control group (Arm B) (treatment difference, 11% [95% CI, 2.9-19]. Unfavorable outcomes occurred in 17.3% of bedaquiline-treated patients and 28.9% of patients who received active control.

Reasons for an unfavorable outcome included the need for treatment modification or extension (8.2% in Arm C vs 23% in Arm B), no culture results within the week 76 window (6.1% in Arm C vs 3.7% in Arm B), death through week 76 (2.6% in Arm C vs 1.1% in Arm B), or at least 1 of the last 2 cultures being positive at week 76 (0.5% in Arm C vs 1.1% in Arm B).

Long-term efficacy data through week 132 included 74.5% (146/196) of patients in Arm C and 77.5% (145/187) of patients in Arm B. The difference between the 2 treatment groups with regard to favorable outcome at week 132 was 9% (95% CI, 0.6-17.5).

Sirturo is supplied as a 20mg tablet. It should be administered by directly observed therapy.

References: