Fast TB Treatment Slow To Advance

Drug Development: Much heralded as a tuberculosis-fighting compound, bedaquiline’s impact remains to be seen

Bethany Halford

This photo of a chest X-ray and patient was taken in India, where some 3 million people have tuberculosis, according to the World Health Organization.<br /> Credit: Arul Loke/TB Alliance

This photo of a chest X-ray and patient was taken in India, where some 3 million people have tuberculosis, according to the World Health Organization.
Credit: Arul Loke/TB Alliance

Ten years ago, researchers at Johnson & Johnson announced they were beginning clinical trials to treat tuberculosis with a novel diarylquinoline compound. It was the first antibacterial agent selective for TB to enter clinical trials in 40 years (Science 2004, DOI: 10.1126/science.1106753).

The compound, known today as bedaquiline and marketed as Sirturo, has a mechanism of action that’s distinct from all other TB-fighting drugs. It inhibits the proton pump of the Mycobacterium tuberculosis bacterium’s ATP synthase enzyme, a first for any antibiotic.

Researchers initially speculated the compound could dramatically cut the duration of treatment regimens for both multi-drug-resistant TB and drug-susceptible TB. “We were almost drooling over the possibility of using bedaquiline to treat drug-susceptible TB,” which accounts for up to 90% of all TB cases worldwide, says Neil W. Schluger, a TB expert at Columbia University Medical Center. “In animal models, if you combined bedaquiline with the right other companion drugs, it looked as if you could cure active TB in two months, as compared to the standard regimens, which are six months long,” he explains.

Although the global number of TB infections is smaller today than it was a decade ago, the disease’s decline has been slow. Last year, 9 million people fell ill with TB and 1.5 million died from the disease, according to the World Health Organization.09251-cover41-bedaquiline

The Food & Drug Administration fast-tracked bedaquiline’s approval to treat multi-drug-resistant TB in 2012, but the drug has yet to make a dramatic dent in the disease. The reason for that is twofold, Schluger says.

The first problem is getting the drug into the hands of patients who need it. Although roughly a half-million people have multi-drug-resistant TB worldwide, those patients live in countries that have poorly functioning TB control programs, Schluger notes. Many patients are never diagnosed, and only 20% ever receive treatment.

The second reason for the slow uptake is a peculiarity that emerged during bedaquiline’s clinical trials. The drug was approved based on Phase II trials that showed it works in combination with other TB drugs to clear bacteria from the sputum of TB patients more rapidly than in patients taking regimens without bedaquiline. But in the follow-up studies, the bedaquiline group experienced a higher mortality rate.

Experts note that the Phase II studies were small, so it’s difficult to say exactly what happened. “It’s very hard to come up with a way that links those deaths to use of bedaquiline,” Schluger says. “There’s nothing really obvious as to why those patients died.”

“Most of those deaths occurred long after the patients finished taking the therapy,” adds Mel Spigelman, president and chief executive officer of the Global Alliance for TB Drug Development, a nonprofit aimed at developing new TB drugs. “I think most people believe that it was probably just bad luck, but it’s something that everyone is obviously concerned about.”

Despite the need, few companies are very interested in making new TB drugs, Schluger points out, so no new drugs have been approved since bedaquiline came out. “Kudos to Johnson & Johnson for pushing ahead with a drug that’s not going to have an enormous market value,” he says.

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