Series 2100 www.thelancet.com Vol 375 June 12, 2010 Lancet 2010; 375: 2100–09 Published Online May 19, 2010 DOI:10.1016/S0140- 6736(10)60359-9 This is the fifth in a Series of eight papers about tuberculosis Global Alliance for TB Drug Development, New York, NY, USA (Z Ma PhD); Stop TB Partnership Secretariat, Stop TB Department, WHO, Geneva, Switzerland (C Lienhardt PhD); Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa (H McIlleron PhD); Medical Research Council Clinical Trials Unit, London, UK (Prof A J Nunn MSc); and Tianjin Centres for Disease Control and Prevention, Tianjin, China (Prof X Wang MD) Correspondence to: Dr Zhenkun Ma, Global Alliance for TB Drug Development, 40 Wall Street, New York, NY 10005, USA zhenkun.ma@tballiance.org Tuberculosis 5 Global tuberculosis drug development pipeline: the need and the reality Zhenkun Ma, Christian Lienhardt, Helen McIlleron, Andrew J Nunn, Xiexiu Wang Drugs for tuberculosis are inadequate to address the many inherent and emerging challenges of treatment. In the past decade, ten compounds have progressed into the clinical development pipeline, including six new compounds specifically developed for tuberculosis. Despite this progress, the global drug pipeline for tuberculosis is still insufficient to address the unmet needs of treatment. Additional and sustainable efforts, and funding are needed to further improve the pipeline. The key challenges in the development of new treatments are the needs for novel drug combinations, new trial designs, studies in paediatric populations, increased clinical trial capacity, clear regulatory guidelines, and biomarkers for prediction of long-term outcome. Despite substantial progress in efforts to control tuberculosis, the global burden of this disease remains high. To eliminate tuberculosis as a public health concern by 2050, all responsible parties need to work together to strengthen the global antituberculosis drug pipeline and support the development of new antituberculosis drug regimens. Introduction Rifampicin, discovered 40 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class are part of a 6-month, regimen that is ineffective against multidrug- resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, and are difficult to use with many antiretroviral drugs. Ten compounds have progressed to the clinical development pipeline for the treatment of tuberculosis. These compounds, if properly developed, have the potential to become part of a future regimen that could greatly affect the global tuberculosis control effort. The potential benefits of new drugs in development were investigated in a modelling study. 1 The results of this study suggest that the combination of a 2-month treatment regimen that cures 95% of MDR tuberculosis, a generalised nucleic acid amplification test, and a joint pre-exposure and post-exposure vaccine could potentially reduce the incidence of this disease by 71% by 2050. 1 The combination of preventive treatment for latent tuberculosis infection and a 2-month drug regimen might reduce incidence by 94%. 1 In this review, we discuss the unmet needs in the treatment of tuberculosis, the global pipeline of new compounds that are in clinical development, and draw attention to the challenges in drug research and development. Issues associated with vaccines and diagnostic tests are reviewed in other reports in The Lancet Series about tuberculosis. 2,3 Search strategy and selection criteria The databases we searched included PubMed, Medline, SciFinder, and Cochrane Library. We mainly focused on papers published during the past 5 years in peer-reviewed journals. Some older papers were also included if they were judged to be important by the authors. Search terms included “tuberculosis”, “multidrug-resistant tuberculosis”, “latent tuberculosis infection”, “tuberculosis and human immunodeficiency virus”, “paediatric tuberculosis”, “tuberculosis therapy”, “tuberculosis regimen”, “new tuberculosis drug”, “tuberculosis drug development”, “tuberculosis drug clinical trial”, “novel regimen for tuberculosis”, “fluoroquinolone”, “nitroimidazole”, “diarylquinoline”, “rifamycin”, “oxazolidinone”, “ethylenediamine”, “moxifloxacin”, “gatifloxacin”, “PA-824”, “OPC-67683”, “TMC-207”, “rifapentine”, “linezolid”, “PNU- 100480”, “SQ-109”, and “LL-3858”. There were no language restrictions. Reviewers suggested several references. Additional information was obtained from our personal collections of peer-reviewed papers. Key messages • Drugs for tuberculosis are inadequate to address the many inherent and emerging challenges of treatment. Development of new technology for biomedical intervention should be a top priority of the global tuberculosis control and elimination agenda. • Substantial progress has been made in development of new drugs during the past decade, with ten compounds progressing through the clinical development pipeline, including six new compounds specifically developed for tuberculosis. • Despite this progress, the global tuberculosis drug pipeline is insufficient to address the unmet needs for treatment. Additional and sustainable funding is needed to further improve the pipeline. • The main challenges in the development of new treatments are the needs for novel drug regimens, new trial designs, studies in paediatric populations, increased clinical trial capacity, clear regulatory guidelines, and biomarkers for prediction of the long- term outcome. • Despite substantial progress in efforts to control spread of tuberculosis, the disease burden remains high globally. To eliminate tuberculosis as a public health concern by 2050, all responsible parties need to work together to support the development of new regimens for treatment of tuberculosis.