Where are the innovations in tuberculosis drug discovery?

Abstract

WHO has released a report that highlights a serious lack of antibiotics in clinical development; a worrying finding in an era of antimicrobial resistance. The report identifies a particular shortage of antibiotics under development for multidrug-resistant tuberculosis, which is a disease that kills a quarter of a million people every year. The WHO analysis aimed to identify products that were in clinical development up to May, 2017, for the treatment of tuberculosis, Clostridium difficile, and diseases caused by pathogens on the WHO priority pathogen list. WHO also assessed whether these products were innovative. Their definition of innovative was based on whether they were a new chemical class, had a new target or binding site, had a new mode of action, or had no cross resistance to other antibiotic classes. For tuberculosis, they found that only seven products are currently in clinical development. Five of these products are categorised as innovative, but only one—pretomanid—is in phase 3 clinical development. These figures are an improvement on 2000, when no tuberculosis drugs were in clinical development and the TB Alliance was formed to address the issue. However, the figures are still well short of the targets set out by the Stop TB Partnership Global Plan 2011–2105. Additionally, only two new antibiotics for tuberculosis have reached the market in over 70 years—delamanid and bedaquiline—but limited access to these newly licensed drugs has been highlighted, with fewer than 5% of people in need being treated with them according to Medecins Sans Frontieres. Reasons for the restricted access include their high price, and the drugs not being registered in many high-burden countries. The limited drug pipeline for tuberculosis can be attributed to a substantial lack of funding. According to the US-based Treatment Action Group, global funding for all tuberculosis research and development almost doubled between 2005 and 2011; however, funding has plateaued since 2009. In 2015, total global funding was US$620 million, which is far from the 2011–2015 Global Plan's target of $2·2 billion. Treatment Action Group notes that the reduced funding in 2015 was due to the payment cycles of major funders, and declining investment from the largest pharmaceutical funder, Otsuka, whose new drug delamanid is in the final stages of phase 3 clinical trials. In this context, it is welcome news that the Global Antibiotic Research and Development Partnership (GARDP) announced more than €56 million has been raised to fund an initiative to fight antibiotic resistance. The partnership was launched in May, 2016, by WHO and the Drugs for Neglected Diseases initiative, with the aim of developing and delivering new treatments for bacterial infections for which drug resistance is present or emerging, or for which current treatments are inadequate. GARDP will target products that the pharmaceutical industry will likely not develop due to lack of profitability or other reasons, and will pilot the use of alternative incentive models, removing the link between the cost of research and development and the sales of antibiotics. GARDP has four main focus areas: sexually transmitted infections, a programme to revive abandoned antibiotic development projects, neonatal sepsis, and paediatric antibiotics. However, it has no specific programme to tackle multidrug-resistant tuberculosis. Despite poor funding for tuberculosis research and development, the latest analyses of the Global Burden of Disease study show that deaths caused by tuberculosis in 2016 were down by nearly 21% since 2006, and the incidence of tuberculosis was down by 1·7%. However, this rate of decline is not sufficient to meet the UN Sustainable Development Goal to end the epidemic of tuberculosis by 2030, with not a single country projected to achieve this goal. The identification of new drugs is not the only strategy for tackling tuberculosis; efforts are also being made to improve diagnosis, infection prevention and control, and to ensure appropriate use of existing and future antibiotics in the human, animal, and agricultural sectors. But without innovations in the market to help develop new treatments for multidrug-resistant tuberculosis, the UN Sustainable Development Goal will remain out of reach.