Multidrug resistant [MDR] TB is the front line in the global battle against infectious disease. It accounts for more than 5 per cent of new cases of TB, which itself takes more than 2 million lives per year – a death toll second only to HIV. More important, multidrug resistant TB is now found in all regions, including the rich OECD countries; this is no longer a scourge of the poor. And its prevalence is increasing, so much so that long-term progress in eliminating TB depends on beating it back with a combination of new potent drugs and preventive public health measures.
That drug option has lain basically dormant for more than 40 years – until now.
Results of a Phase II (b) clinical trial published on June 6 in the New England Journal of Medicine suggest promise for a new drug sponsored by Japan’s Otsuka Pharmaceuticals that removes the major drug resistant strains of the TB bacillus by inhibiting mycolic acid synthesis in the lung. If approved, the drug, delamanid, will be the first new treatment option against MDR TB since the early 1960s. Currently, patients with the condition must rely on a combination of four to six drugs, some with significant side effects, to be taken daily for as long as two years. The regimen is impractical, particularly in resource-poor settings, meaning that the cure rate remains elusive. Significantly, the NEJM review of the trial concludes that delamanid, if authorized for clinical use, would give physician an additional, less complex, option in treating patients with the MDR strain.
Specifically, the randomized controlled study, which enrolled 481 patients from age 18 to 64 in nine countries, including the US, found that, with twice a day administration of delamanid plus a standard background drug regimen, 45. 4 per cent of the trial population experienced full sputum conversion of MDR bacillus, versus 29.6 per cent for the group receiving the background drugs and placebo. This means investigators met the trial’s primary endpoint.
Dr. Lawrence Geiter, a co-author of the NEJM paper and Otsuka’s Vice-President for Novel Products TB, told Pharm Exec that the practical read off from the trial is that delamanid is faster and less toxic in fighting MDR infection than existing therapies. “The trial shows that patients can resume their normal activities quicker and there is potential here for also shortening the overall course of treatment, though this requires additional proof points through follow up studies.” Geiter added that the promise of delamanid is only one element in a coordinated “case management” approach to MDR that requires not only access to new drugs, but also patient support, diagnostic screening and other public health interventions.
Based on the trial results, Otsuka has filed a Market Authorization Application [MAA] at the European Medicines Agency and is hopeful that a decision may be taken sometime later in 2013. The company is also considering filing for authorization in some of the nine countries [Philippines, Peru, Latvia, Estonia, China, Japan, Korea, Egypt and the US] where the trial was conducted. The company is conducting a Phase III study of delamanid that will also cover patients with HIV and are on antiretrovirals, as co-morbidity of TB and AIDS is quite high in developing countries. Finally, in recognition of the need for a total case management strategy in defeating TB overall, Otsuka is developing models of patient care jointly with other stakeholders. The aim is to minimize potential resistance to new TB medicines, so that they are used rationally once they are placed on the market.
Several other drug companies are taking an interest in this area, with J&J’s Tibotec Division moving up fast with another MDR drug in the works. Market economics and a clear circumstance of unmet medical need make a compelling case for innovation: in the US, hospitalization charges for a patient with MDR TB average around $600,000, while in developing countries the cost of administering the current standard package of multidrug therapy often exceeds the annual income of the recipient. Drugs alone may not provide the answer to a curable condition that has persisted for centuries, but they certainly frame the questions that point us toward solutions.