Half-century-old TB drugs get a facelift in new cocktails

November 30, 2010

The first-line regime of tuberculosis drugs has remained virtually unchanged for a half century. But instead of improving on these medications, some researchers say it’s time to scour the lists of already-approved drugs for other indications or start from scratch to curb the more than 1.7 million deaths from tuberculosis (TB) each year.

In early November, for example, the New York–based TB Alliance announced the launch of a clinical trial to test a radically different drug cocktail. “We see this as a paradigm shift in methodology,” says Ann Ginsberg, the organization’s chief medical officer, “And it’s been one that industry as well as regulators at institutions like the [US Food and Drug Administration] have been very supportive of.”

Standard first-line treatment for TB consists of a cocktail of at least four drugs mixed and matched over six months. Because of side effects such as nausea, many people fail to properly adhere to this regime. And because 90% of the disease is typically cleared in the first few weeks, patients quickly see the medicine as causing more strife than the condition, says Mario Raviglione, director of the Stop TB Department, an international organization housed by the World Health Organization.

The recently announced phase 2 drug trial run by the TB Alliance will test a three-drug combination, dubbed NC001. It contains PA-824, an entirely new chemical compound, along with moxifloxacin (commonly used to treat pneumonia) and the common TB drug pyrazinamide.

What could potentially be even more important about the trial, however, is the streamlined form it is taking, Ginsberg says. Typically, introducing any single one of the drugs into a TB trial would take the form of swapping the drug out with one of the four most commonly used first-line drugs. By simply jumping to testing an entirely new combination, what could have been more than a three-decade-long process of trial and error could potentially be reduced to eight to ten years, Ginsberg adds.

Other researchers are taking a different approach to finding fasttrack TB treatments. A team from the University of California–San Diego and the University of Leeds in the UK has examined the known proteome of the TB pathogen to find drug targets linked to hundreds of FDA-approved drugs (PLoS Comp. Biol. 6, e1000976, 2010). “There may be a great TB treatment out there that is already approved and could be repurposed to a TB market very quickly, if only we can find it,” says Philip Bourne, a pharmacologist with the University of California–San Diego and lead author of the study.

There’s still a lot of searching to be done before the work produces hits, Bourne says. The group’s paper cites one drug currently used for neurodegenerative diseases that has some impact on TB but would have to be used in too-high doses.