registrational studies.” Finally, Harrington said that even as work on developing biomarkers proceeds, it may be possible to use indicators such as time to sputum smear conversion or culture conversion as surrogate markers to accelerate approval of new drugs for drug-resistant TB, given the unmet medical need.

THE PIPELINE FOR NEW DRUGS

Ann Ginsberg of the TB Alliance gave an overview of the pipeline for new TB drugs. The current drug classes—both first- and second-line drugs—were all discovered between the 1940s and the 1970s (see Figure 7-1). From then until 5 years ago, there was little work on TB drug development.

To find effective treatments for MDR and XDR TB, it is important to establish treatment regimens that are better tolerated, more efficacious, and more affordable. The root of the drug resistance problem is the complexity and length of drug-sensitive regimens. Thus it is critical to have shorter, simpler regimens for drug-sensitive TB. To meet this need, it will be necessary to develop new drugs that will shorten and simplify treatment. They must be effective against those mycobacteria that persist now in the face of drugs to which they are genetically susceptible. Ideally, one wants drugs with novel mechanisms of action that are equally effective against MDR and XDR and drug-sensitive strains of TB. They must also be effective and have minimal drug–drug interactions for both HIV-positive and HIV-negative patients. Additionally, they should be able to be delivered orally once a day or less frequently if possible, and obviously be low cost.

Ginsberg discussed the strategies that are being explored to achieve these goals. Figure 7-2 shows the variety of targets being pursued. One can see that the bulk of current drugs—listed in black—are cell wall active. This means they work well against the most rapidly replicating mycobacteria, but are probably not effective against persistent organisms that are replicating slowly or not at all. Cell wall active drugs are consequently unlikely to shorten therapy, an objective that requires drugs acting against other kinds of targets. Many new discovery projects—listed in red—are focused on energy metabolism. TMC207 from Tibotec (a subsidiary of Johnson & Johnson) is the most developed drug candidate that has targeted that pathway successfully and will likely contribute to shortening therapy.

The ideal is to find new drugs that simultaneously will be effective in drug-resistant TB using novel mechanisms of action and will shorten treatment. Current drugs that shorten treatment include rifampin, which combined with pyrazinamide is the most effective of the current drugs in shortening therapy and which inhibits RNA polymerase. The fluoroquinolones, which have the potential to shorten therapy, work against DNA gyrase. TMC207 works against adenosine triphosphate (ATP) synthase.



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