Robert Don, Discovery & Preclinical Director, and Charles Mowbray, Head of Drug Discovery, DNDi
Important advances have been made in recent years to optimize the use of existing medicines to treat neglected tropical diseases (NTDs) but, while providing urgently needed improvements on previous treatments, they are often still not ideal. There remains an urgent need to design and develop modern drugs to treat these diseases.
Though a persistent deficiency in truly new therapeutics for neglected diseases – Of the 336 brand-new drugs (new chemical entities, or NCEs) approved for all diseases in 2000-2011, only four, or 1%, were for neglected diseases; – for the first time in many decades, a research pipeline of new drug candidates has been created for these diseases. This was notably made possible with the emergence of product development partnerships (PDPs), such as DNDi, which aim to create synergies and alliances with public and private partners involved in the R&D process for drug development through a collaborative approach. DNDi has, for instance, established a robust research pipeline including 12 NCEs in pre-clinical and clinical development. However, given the rate of attrition in drug discovery and development, particularly for infectious diseases, it is important to strengthen the pipeline by introducing additional new chemical entities (NCEs) into the drug development pathway in the timeliest manner.
Discovery research is the earliest stage of drug research and development (R&D), helping to identify novel drugs that offer significant improvements over current therapies. Modern drug discovery fostered by the PDP approach offers opportunities to speed up and make the R&D process more efficient.
One of the main challenges for PDPs to develop and deliver new and more adapted drugs, is to gain access to good compound libraries, knowledge, and data from public and private partners to expedite early stage innovation and identify new hits and/or interesting classes of compounds. In recent years, many pharmaceutical and biotechnological companies have expressed and demonstrated their interest to be part of the fight against neglected diseases. They have opened their libraries and shared their expertise, know-how and capabilities. Since 2003, DNDi signed about 28 agreements with pharmaceutical companies and 17 agreements with biotechnology companies. As a result, since 2006, DNDi has screened over 1 million compounds and has increased its screening capacity. Between 2003 and 2007, 1,200 and 6,000 compounds were screened per year compared to 215,000 compounds screened in 2013.
Innovative mechanisms to strengthen the drug discovery pipeline have been implemented, and which increase the level of openness to make data more widely available to the scientific community. This is, for example, the case for MMV’s open access Malaria Box, which comprises a set of 400 compounds selected and assembled from hits had been placed in the public domain, and were provided to hundreds of researchers around the world.
Similar to the Pathogen Box – a ‘sister’ of the Malaria Box – for neglected diseases, there is a strong need to set up such mechanisms in order to increase the number and quality of chemical series being developed for NTDs, and to develop these more quickly, cost effectively, and sustainably. It is also vital to bring a broader range of expertise and experience from pharmaceutical partners. Ideally, we should be able to take the precious hits (‘needle in a haystack’) identified from prior high throughput screening campaigns and effectively expand the hit series and also identify novel related series. To this end, computationally (in silico) searching in multiple corporate libraries could be performed simultaneously, i.e., making the best use of the initial ‘needle’ by looking in other ‘haystacks’ for similar needles. Such a mechanism would reduce the time taken to progress new high throughput screening hits into full lead optimization and also reduce the time and cost for the optimization stage by providing well annotated series and clear guidance for the medicinal chemistry programmes.
Continued and increased open access to knowledge and data, and the need to share newly generated knowledge to facilitate advancement of science are also key to avoid duplication of efforts and enable a more efficient R&D process.
Dr Robert Don, Discovery & Preclinical Director, and Dr Charles Mowbray, Head of Drug Discovery, DNDi