FDA Advisory Committee recommends accelerated approval of bedaquiline for drug-resistant TB

Bedaquiline, the first agent in a new class of TB drug, has been recommended for accelerated approval by the Anti-Infective Drugs Advisory Committee of the United States Food and Drug Administration (FDA).

The committee voted unanimously (18 to 0) that the efficacy findings from studies of bedaquiline support the proposed indication for the treatment of multidrug-resistant tuberculosis (MDR-TB) as part of combination therapy in adults. The committee also agreed that the safety findings supported the proposed indication, by a vote of 11 to 7.

AIDS activist organisation Treatment Action Group (TAG), along with the Global TB Community Advisory Board (TB CAB), HIV i-Base, South Africa’s Treatment Action Campaign (TAC), Médecins sans Frontières (MSF) and the Southern African HIV Clinicians’ Society, support early appropriate access to bedaquiline for patients with drug-resistant TB (DR-TB).

In a statement to the committee Mark Harrington, Executive Director of TAG, said: “If the FDA grants approval to bedaquiline, it will provide a major incentive for new sponsors and companies to introduce more new drugs, classes, compounds, combinations, and regimens into the clinical pipeline.”

Although TAG welcomed the FDA’s review, Harrington cautioned that the FDA should stipulate that the necessary and required post-marketing studies must be conducted. He called for:

• paediatric studies.

• cardiac studies of important potential drug-drug interactions such as with Otsuka’s delamanid (OPC67683), the nitroimidazooxazole recently submitted for review by the European Medicines Agency (EMA).

• drug-drug interaction studies with commonly used antiretroviral therapies such as atazanavir, darunavir, efavirenz, raltegravir, and other drugs likely to be used in combination by people with HIV and MDR-TB.

• appropriate, rationally designed studies of optimal regimens to treat drug-sensitive TB (DS-TB), DR-TB, and latent TB infection (LTBI).

• development of appropriate genotypic and phenotypic drug susceptibility and resistance surveillance (DST, DRS) tests to help guide practice and protect patients from the emergence of unnecessary drug resistance.

Bedaquiline is a diarylquinoline and is the first drug in this class for the treatment of drug-resistant TB. It is patented by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson.

In a phase II randomised controlled trial, bedaquiline was given to 23 patients and placebo to 24 patients, for eight weeks. All participants received standard MDR-TB regimens as well. Bedaquiline significantly reduced the time-to-culture conversion during 24 weeks of follow-up (HR 2.3; 95%CI: 1.1 - 4.7; p=0.03). Forty-eight per cent of the patients on bedaquiline became sputum-negative versus 9% of patients on placebo.

Nausea was the only adverse event reported to occur significantly more often in the bedaquiline group (26 vs 4%, p=0.04). A study with two-year follow up data has been published and confirms the initial outcomes.

Twenty-four week data from an open-label trial of bedaquiline in approximately 200 participants show that adding bedaquiline to an individualised MDR-TB regimen was well tolerated and resulted in an overall 81% culture conversion rate at week 24, with median times to culture conversion of 8 weeks for patients with MDR-TB, 12 weeks for patients with pre-extensively drug-resistant TB (XDR-TB), and 24 weeks for patients with XDR-TB.

A phase 1 study in healthy volunteers showed no substantial reduction in bedaquiline levels when coadministered with efavirenz.

QT prolongation has been observed in patients treated with bedaquiline. The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. A prolonged QT interval is a risk factor for cardiac arrhythmias. Further safety data on the effects of bedaquiline on the QT interval are needed.