Physicians running out of options for treating people with multi-drug resistant tuberculosis (MDR-TB) were given cause for hope a couple weeks ago when the results of a follow-up study on a new drug, called Delamanid by its originators, Otsuka Pharmaceutical of Japan (Modern Medicine article). The results confirmed and extended the findings reported in June that a relatively short course of the drug (2 months) decreased a primary indication of infection (TB bacteria in sputum) to zero in half of the MDR-TB cases (standard therapy was 30%) (Bloomberg News article and Gler et al. 2012). The drug was also tested in patients for whom all other drugs had failed (called XDR-TB for “extensively resistant”) and worked but to a lesser degree than in the MDR-TB group. Not only would Delamanid be the first new TB drug invented in 40 years, but, if it cures more quickly than the standard MDR-TB regime which is multiple drugs for two years (TB Treatment), it may mean lower costs overall and less chance for the TB to evolve resistance. With an estimated 8.7 million new cases and 1.4 million deaths last year mostly in the developing world (WHO Global TB Report 2012), new drugs are clearly needed.
Of course, there are still some sticky wickets in getting Delamanid into use. One is completion of the Phase III trial that started in 2011 and regulatory review and approval. Although the FDA has three programs to accelerate approval for drugs for unmet need (FDA for Consumers), it has limited resources and the programs are popular routes with the hundreds of cancer drugs in development. Another is that the main strategy in TB treatment is to use multiple drugs in different combinations, doses, and protocols to minimize resistance development (TB Drugs), and Delamanid has only been tested alone. Testing it with existing or other new drugs will be complicated and take time. The problem of how to test TB drug combinations is being addressed by Critical Path to TB Drug Regimes program of the Critical Path Institute of Phoenix (CPTR), about which I wrote in March 2010 (“A New Deal Against TB”). But, as I surmised in that post, the CPTR took on a large organizational and operational task and, as far as I can tell, hasn’t made much progress. A recent press release by the Institute noted that the CTPR was “engaging” the FDA and “progressing on efforts to evaluate drug evaluation tools to accelerate the development of new TB drug combinations” but gave no specifics (CPTR press release). While a group of TB experts is encouraging Otsuka to start combination testing now, it is offering technical but not financial assistance (Treatment Action Group letter).
The third wicket, and one that Otsuka has thought about to their credit, is that Delamanid must be used appropriately and sparingly to be effective as long as possible. As was reported in the Bloomberg article, Otsuka will be selling to doctors “who know how to use the drug” to sustain its effectiveness and is anticipating modest revenues from its sale. The same article reported one estimate of the annual sales in the major market counties is $127 million per year, not much when the development costs are likely several times that and the company will be under considerable pressure to donate the drug to public health programs in low income countries. While low expected revenues are a particular problem for Otsuka’s share holders, they point to the really big problem: how to develop drugs (and diagnostics) that are needed for TB, a global disease, but for which the global society hasn’t figured out how to pay.
While we US citizens can sit back and say TB is somebody else’s problem, there are indications that may not be the case in the near future. As anyone who watched the movie, Contagion, knows, epidemics occur when the bug can’t be detected and killed quickly or vaccinated against and when it is transmitted easily. Diagnosis of TB is usually made three months after initial infection and is treated with a six-month course of drugs; the vaccine we in the US got as kids is good for about ten years (there are nine new ones in development); and TB is spread through aerosols (coughing) with an infectivity of about 22% (Wikipedia article). And there are indications TB is evolving out of its current and inadequate public health box. As was found in a survey in China and reported in the New England Journal of Medicine (NEJM) in June (Zhao et al. 2012 and Reuters article), the incidence of MDR-TB in China is now nearly 10% of new cases, or about 1 million cases per year. While this may be good news for Otsuka’s shareholders, in a NEJM commentary (Chaisson and Nuermberger 2012), two TB experts wrote the results suggest that, against conventional wisdom, MDR-TB is being transmitted from person to person. I’d like to think this finding has public health researchers scrambling to confirm the result, look for similar increase in incidence in other countries, and figure out if the MDR-TB strain(s) are more or less infective than the standard type. A bit worrisome to say the least.