In early July, Janssen Research and Development, part of the New Jersey drug giant Johnson & Johnson, announced that it had requested US approval of a new compound called bedaquiline to treat multidrug-resistant tuberculosis (MDR-TB). If approved by the country's Food and Drug Administration (FDA), the medication would be the first tuberculosis drug with a new mechanism of action in four decades, as well as the only drug specifically indicated for MDR-TB, which roughly 650,000 people are living with worldwide, according to the World Health Organization.

The announcement created much fanfare, but Janssen isn't the first company to seek approval for a novel compound to fight MDR-TB. Last December, the Japanese drugmaker Otsuka Pharmaceutical filed for approval of its compound, delamanid, in Europe. With additional incentives signed into law in the US last month, multiple players are vying for the lead in the MDR-TB drug development niche.

At present, treating drug-resistant tuberculosis involves a bevy of regular tuberculosis medicines that, in many cases, must be administered for as long as two years or more. And the drugs don't always work. The hope is that new medicines will shorten treatment times and improve cure rates. Janssen hasn't definitively proven that bedaquiline can do that, but initial results from two phase 2 trials presented at each of the last two Union World Conferences on Lung Health look promising. In the first, a two-year trial of 161 individuals with MDR-TB, participants who received the compound on top of the standard five-drug cocktail for six months experienced a 79% clearance rate of the pathogen from their sputum, compared with 58% in the group that had a placebo added to the regimen. Janssen plans to launch a 600-person phase 3 trial later this year that will examine whether bedaquiline plus an experimental regimen can cut the treatment time for MDR-TB from two years to nine months.

In June, Otsuka published a phase 2 randomized trial of delamanid that included 481 individuals with MDR-TB. Delamanid plus the existing MDR-TB regimen cleared bacteria in nearly half of the participants in the first two months compared with 30% of participants who received the placebo plus standard treatment, the researchers found (N. Engl. J. Med. 366, 2151–2160, 2012).

Although Janssen's and Otsuka's MDR-TB drugs have fared similarly in trials, their mechanisms of action differ markedly. Bedaquline kills Mycobacterium tuberculosis by targeting the key energy enzyme adenosine triphosphate (ATP) synthase, something no other antibiotic does. Delamanid, in contrast, inhibits production of mycolic acid, a molecule found in the bacterium's cell wall.

Which compound will win out if both are approved remains to be seen. Eric Nuermberger, of the Johns Hopkins University School of Medicine's Center for Tuberculosis Research in Baltimore, notes that bedaquiline seems more potent in animal models, but “there's certainly no data from the clinical trials that suggests superiority of one over the other.” Notably, bedaquiline has a major drawback: a strong drug-drug interaction with a common first-line drug used to treat tuberculosis. Rifampin speeds up the metabolism of bedaquiline, which means that less of the compound reaches the bacteria.

Extensive drug development

Researchers are investigating a third compound to treat MDR-TB—Zyvox (linezolid), which is marketed by New York–based Pfizer and has already been approved by FDA to treat other infections such as pneumonia. In a meta-analysis published earlier this year that spanned 12 studies from three continents, researchers found that 99 of 121 patients were successfully treated with Zyvox-containing regimens (Eur. Respir. J. doi:10.1183/09031936.00022912, 2012). One disadvantage of Zyvox is that it can have toxic effects involving the bone marrow and the peripheral nervous system, especially when administered for long periods. Other drugs in the same class as Zyvox are currently being developed to treat tuberculosis, including Pfizer's sutezolid, now in phase 2 trials. The hope is that these newer drugs will be safer, says Robert Horsburgh, an epidemiologist at Boston University and chairman of RESIST-TB, an initiative aimed at promoting research into new treatments for drug-resistant tuberculosis.

Warning heard: MDR-TB patients need drugs. Credit: Newscom

Other novel compounds are in the pipeline as well. For example, Maryland-based biotech Sequella is developing a tuberculosis treatment called SQ109, which is currently in phase 2 testing. Last year, Maxwell Biotech, a Russian venture capital fund, licensed the rights to develop the compound for MDR-TB in Russia and neighboring countries.

The fact that several companies are seeking approval for drugs to treat MDR-TB as opposed to drug-susceptible tuberculosis is not surprising, says Nuermberger. “It's easier to show treatment benefit, because the treatments that we have for multidrug-resistant TB are vastly inferior to the regimens that we have to treat drug-susceptible disease,” he says.

Pharmaceutical companies will soon have another incentive for going after MDR-TB. The fifth reauthorization of the US Prescription Drug User Fee Act (PDUFA), signed into law on 9 July, includes a subsection called the Generating Antibiotic Incentives Now (GAIN) Act that aims to spur development of antibiotics for drug-resistant bacteria, including MDR-TB. Drugmakers that ask for approval of medicines to treat these pathogens will receive priority review, as well as five additional years of market exclusivity and fast-track status. “The goal there is to try to put some more enticements on the table for companies to develop new antimicrobial drugs,” says Brad Tebbets, an infectious disease analyst at Global Data, a London-based research firm that tracks the pharmaceutical industry.