Links between the pharmaceutical industry and the not-for-profit sector are leading to promising candidates for treating neglected and tropical diseases. Natasha Little explores the strategy of the Bill & Melinda Gates Foundation, which has led to a portfolio of over 100 products.
Taking a fully integrative approach is bringing results in the field of new medicines development. “It sounds obvious: we aim to achieve the greatest impact in the shortest period of time [and] with the least human and financial resources,” said Dan Hartman, director of integrated development at the Bill & Melinda Gates Foundation, “but you really have to think hard about how to pull everything together from drug discovery to delivery.” The foundation now has a portfolio of over 100 products and awarded USD 4.2bn to 1,600 grant recipients in 2015. How has this been achieved? “We start with disease strategies,” explained Dr Hartman. “Our strategy for malaria, for example, is total global eradication.” The foundation then creates target profiles of the products which would be needed to achieve these goals, for example, a medicine that is faster-acting than those currently available. When development is outsourced to partners, it then has a powerful method for decision making: “If the data doesn’t match the target product profile we can decide to kill [the drug candidate] in a very confident manner,” said Dr Hartman.
Speeding things up
Another tactic is to create accelerator programmes — partnerships between pharmaceutical companies and research organisations with the aim of speeding discovery and development of novel compounds. Peter Warner, senior programme officer in discovery and translational sciences at the foundation, explained the advantage of these programmes: “Expertise lies in many sectors: academia, research institutes, pharmaceutical companies and biotechnology. Through these collaborative networks, we have the opportunity to access a broad cross-section of experts and resources.”
Five years ago the foundation launched the Tuberculosis Drug Accelerator. TB kills one person every 25 seconds and 650,000 of the 12 million active cases are drug-resistant. Currently, lengthy treatment regimen is required due to the development of granulomas and cavities in patients’ lungs where TB bacteria can grow. To address the high drop-out rate, the accelerator aims to reduce the current treatment from six months to one month. “The focus is on finding compounds which can penetrate these lesions,” Dr Warner explained. As members of the accelerator programme, many large pharmaceutical companies and research institutions provide access to their compound libraries. “So far, three million compounds have been screened,” said Dr Warner, “and we have 28 promising projects in the hit-to-lead phase.” Another accelerator programme, the Macrofilaricide Drug Accelerator, aims to eliminate river blindness by finding an oral treatment that kills or sterilises the adult parasitic worms that cause the disease in seven days or less. Current drugs are only able to kill juvenile worms and consequently 18 million people are currently infected with the disease. “Through the accelerator, we have been able to select and support the best [projects], trying to understand how the compounds work in animal models,” Dr Warner explained. “We currently have five pre-clinical candidates.”
The fact that much of the disease burden is found in the developing world is also taken into account. “This mismatch between disease burden and available resources in lowincome countries is having a big impact on how we approach formulations and delivery of the drugs we develop,” said Susan Herschenson, the foundation’s deputy director of chemistry, manufacturing and controls. To compensate for the lack of trained health care providers and weak supply chains, “products should be simple, have a long-lasting dosage and be robust enough for the last mile”, she said. Such considerations have led to some breakthroughs. “We invest in a wide spectrum of drug delivery technologies, from increasing availability and reducing cost for already existing formats, to transitioning known drugs into simpler-touse devices,” explained Dr Herschenson. Novel formats include the vaginal ring: a 15-year contraceptive implant which can be turned on and off by the patient to allow for pregnancies.
Another exciting breakthrough is in the area of long-acting oral delivery. “Currently the field is trying to reduce the required frequency from multiple times a day to once a day. But what if we could extend that to a week or a month?” A long-acting starfish-shaped device, currently in development with Lyndra to administer doxycycline, can be taken in a large capsule and springs open in the stomach. Its arms, composed of a polymer drug matrix, deliver drugs one by one over the treatment period, and it is then eliminated from the system. (See Figure 1.)
Human challenge models
A world free of malaria is a big priority for the foundation. But, despite good progress in the past 10 years, this disease still has the second largest global burden of death and disability, after pneumonia, with mortality rates highest in the under-fives. Given the difficulty of developing new antimalarial agents due to the “tremendously agile and adaptive parasite, its complex life cycle and the lack of profit incentive, the foundation aims to mitigate this effort and expense by amassing all the data,” said Steven Kern, deputy director of quantitative sciences. “Probably the most important part of this process is the creation of the human challenge model,” he said. In the new model, volunteers are infected with malaria parasites in order to assess drug efficacy. “Armed with data on the rate of decline of parasitaemia as a result of an effective drug concentration, developers can then design phase IIa trials with a very good idea of what the effective dose is going to be. This will limit the number of people having to take part in trials and the number treated with an ineffective dose,” Dr Kern explained. “We are now in the process of gathering the data generated for eight to 10 compounds which have been tested through this paradigm and aim to create a full computational model of the disease,” said Dr Kern, “incorporating the biological lifecycle of the parasite, the pharmacokinetics of the drug, the pharmacodynamics from the in vitro data, and clinical pharmacogenomic data from the human challenge model.” The computational model will be fully accessible to anyone who wants to develop an antimalarial drug. Dr Kern hopes this will help pharmaceutical companies to predict more effectively whether their compounds could offer something beneficial beyond the existing spectrum of available drugs, and hence make data-driven investments.
Registration as a decelerator
A significant factor in the aim to achieve the greatest impact in the shortest period of time is regulation. “Unfortunately, even in high-income countries, registration of a new drug can happen long before patient access,” said Murray Lumpkin, deputy director of integrated development and lead for global regulatory systems initiatives. “We have even heard of products taking four to seven years to get through the multiple stages of registration.” The foundation has investigated the cause of the delays and found that “in some cases people were submitting applications to different countries one by one, to spread the administration and resource burden”, said Dr Lumpkin. The foundation has identified key challenges for clinical trials in different low- and middle-income countries, including both disparate application requirements and duplication of efforts across separate reviews. In order to streamline the process, it has created a comprehensive database of the complex regulatory requirements for each country. The foundation is also working with the African Vaccines Regulatory Forum (AVAREF) towards “a vision of regulatory harmonisation” for five African regions covering the continent and aims to halve registration time by 2018. The work of the Bill & Melinda Gates Foundation demonstrates how collaborative efforts are bringing us closer to medicines that will erase significant portions of the global disease burden. “We’ve been trying to bring this end-to-end thinking to global health, all the way from thinking about formulation earlier and more often during discovery, to how we utilise the totality of data to make decisions, and the tremendous effort needed to strengthen the regulatory systems,” Dr Hartman said. The foundation’s slogan is “All lives have equal value — we are impatient optimists working to reduce inequity”. It look like this impatience is paying off.