The US Food and Drug Administration (FDA) has granted accelerated approval to Janssen Therapeutics' Sirturo (bedaquiline) tablets for the treatment of pulmonary multi-drug resistant tuberculosis (MDRTB) as part of combination therapy in adults. The accelerated approval is based on the surrogate endpoint of time to sputum culture conversion.

“Sirturo was first discovered in our laboratories more than a decade ago and it is gratifying to see our discovery and development lead to the accelerated approval of the first TB therapy in 40 years with a new mechanism of action. This underscores our commitment as a company to discover, develop and responsibly deliver innovative medicines that address serious unmet medical needs,” said Paul Stoffels, MD, chief scientific officer and worldwide chairman, Pharmaceuticals, Johnson & Johnson.

Sirturo inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis. Sirturo is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (= 18 years) with pulmonary MDR-TB. Reserve Sirturo for use when an effective treatment regimen cannot otherwise be provided. Sirturo should be administered by directly observed therapy (DOT). This indication is based on analysis of time to sputum culture conversion from two controlled phase 2 trials in patients with pulmonary MDR-TB. The safety and efficacy of Sirturo for the treatment of latent infection due to Mycobacterium tuberculosis has not been established. The safety and efficacy of Sirturo for the treatment of drug-sensitive TB has not been established. In addition, there are no data on the treatment with Sirturo of extra-pulmonary TB (e.g., central nervous system). Therefore, use of Sirturo in these settings is not recommended.

The prescribing information for Sirturo includes Boxed Warnings regarding increased risk of death and occurrence of QT prolongation. The Warnings and Precautions section provides additional information regarding these risks and includes risk of hepatic-related adverse drug reactions, drug interactions, use in HIV-TB co-infected patients and treatment failure. The most common adverse drug reactions were nausea, arthralgia and headache. Additional adverse events were hemoptysis and chest pain.

MDR-TB is considered an orphan disease in the US, with 98 reported patients in 2011. MDR-TB is characterised by resistance to two of the most powerful medicines in today’s four-drug standard TB treatment regimen. MDR-TB treatment is complex and requires up to two years of treatment with companion drugs in accordance with national TB treatment guidelines and local MDR-TB treatment practice, along with extensive medical supervision. The World Health Organisation (WHO) estimates more than two million people will develop MDR-TB between 2011 and 2015.

“The accelerated approval of Sirturo is a significant step in the fight against MDR-TB, which is a more difficult to treat form of TB that affects approximately 630,000 people in the world and is on the rise in many areas worldwide,” said Dr Stoffels.

“This is the first time a new drug is being introduced specifically for MDR-TB, for which the current needs are so great,” said Lee Reichman, MD, executive director, New Jersey Medical School Global Tuberculosis Institute. “It is an important step in the development of new compounds for this serious and contagious disease.”

The FDA accelerated approval of Sirturo was based on data from TMC207-C208 Study 1 and Study 2. The primary endpoint was 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. TMC207-C208 Study 1 is a placebo-controlled, double-blind, randomized trial conducted in newly diagnosed patients with multi-drug resistant pulmonary Mycobacterium tuberculosis. Patients were randomized to receive treatment with either Sirturo and other drugs used to treat MDR-TB (Sirturo treatment group) (n=79) or placebo plus other drugs to treat MDR-TB (placebo treatment group) (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 as 400 mg once daily for the first two weeks and as 200 mg three times per week for the following 22 weeks. After the 24 week study drug ( Sirturo or placebo) treatment phase, patients continued to receive their other drugs used to treat MDR-TB until a total treatment duration of 18 to 24 months was achieved, or at least 12 months after the first confirmed negative culture.

Sirturo was discovered by researchers at Janssen and is currently under review by three regulatory bodies including the European Medicines Agency (EU), State Food and Drug Administration (China) and Medicines Control Council (South Africa).

Janssen is dedicated to addressing and solving some of the most important unmet medical needs of our time in HIV and other infectious diseases.