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FDA Advisory Committee recommends accelerated approval of bedaquiline for drug-resistant TB
Lesley Odendal, 2012-12-03 14:40:00
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 (18-0) 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 11-7.
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 Frontieres (MSF) and the Southern African HIV Clinicians’ Society, support early appropriate access to bedaquline for patients with drug-resistant TB.
In a statement to the committee Mark Harrington, Executive Director of TAG, said: “If the FDA grants approval to bedaquline, 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 design studies of optimal regimens to treat drug-sensitive (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 patients 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). 48% 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 patients 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-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 co-administered 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 bedaquline on the QT interval are needed.
The case for early approval of bedaquiline in South Africa
Nathan Geffen, treasurer of the Treatment Action Campaign in South Africa and member of the Global TB CAB gave a presentation on the case for pre-approval access to bedaquiline in South Africa at the first Southern African HIV Clinicians Society conference, held in Cape Town last week.
Geffen called for the drug to be made available to patients with drug-resistant TB before it is approved. “This demand was made as far back as the World Lung Conference in Mexico in 2009. Yet little progress towards pre-approval access has been made in South Africa. The South African medicines regulatory authority, the Medicines Control Council (MCC), has responded sceptically.”
At least 13,000 cases of drug-resistant tuberculosis are estimated to occur in South Africa each year, one of the highest burdens of drug-resistant tuberculosis (DR-TB) in the world. Treatment for multi-drug resistant TB can last up to 18 months, many of the drugs cause serious side effects, and as Geffen explained, the evidence base for the use of many drugs in the MDR-TB treatment regimen is slender. Mortality and morbidity in MDR-TB patients are extremely high, and no more than half of patients are successfully treated.
“Given this situation, it is reasonable for patients with drug-resistant TB to consider taking experimental medicines that have some good quality safety and efficacy evidence,” argued Geffen.
One of the main concerns with pre-approving drugs is who should bear responsibility for the risk of patients experiencing severe adverse events. According to Geffen, until a drug is registered, if it is used outside a clinical trial setting as part of pre-approval access, then the pharmaceutical company that manufacturers, tests or holds the patent on the drug should not be responsible for the risk.
“This means that it is very important that doctors tell patients of the risk of taking an experimental drug. Patients have to be aware that the experimental drug they are taking has not yet been fully tested,” said Geffen
“We are a decade into the development of bedaquiline and we still have not had it approved. I think this speaks to the lack of interest and commitment by the pharmaceutical company,” said Geffen.
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