Graeme Bilbe, Research & Development Director, DNDi
Addressing the lack of patient-adapted treatments for those suffering from neglected diseases is no easy task. DNDi’s initial short-term strategies were designed to quickly provide improved treatments through new formulations or combinations of existing drugs, and/or improved treatment regimens. Six new treatments have been delivered since 2003.
The first of these were fixed-dose combinations of individually available antimalarial drugs, ASAQ and ASMQ – both transferred earlier this year to the Medicines for Malaria Venture – which are affordable, easy to administer, and able to withstand tropical conditions: each tablet contains a combination of two drugs given for 3 days. The mainstay treatment for Chagas disease, benznidazole, had no specific paediatric dosage form, so with partners we developed a child-adapted dosage form. NECT, for sleeping sickness (human African trypanosomiasis, HAT), has replaced the arsenic-based melarsoprol treatment – a drug so toxic it killed 1 in 20 patients. However, NECT still requires twice-daily injections of eflornithine over 7 days plus 10 days oral nifurtimox and needs to be administered by trained staff, with patients obliged to stay in hospital during the treatment period. Similarly, the combination of SSG&PM for visceral leishmaniasis in East Africa is better adapted to patients’ needs, but not ideal.
While all of these treatments were much-needed improvements, entirely new, effective, oral treatments, simple and safe enough to be administered at the primary healthcare level, are desperately needed. Discovering and developing such new chemical entities, or NCEs, has been the key challenge for DNDi in carrying out its long-term strategy, set out 12 years ago, and has led us to embark on various new pathways and partnership models to achieve our goals. While today’s pipeline for the most neglected diseases contains a significant number of NCEs in development, we have to continue exploring new ways to ensure the pipeline is systematically filled and replenished to ultimately ensure real breakthroughs in disease treatment.
The most advanced NCEs are for sleeping sickness, and have come from compound mining and the biotechnology industry
The goal is to develop one or two oral-only treatments, which will cure both the early (stage 1) and advanced, brain-form (stage 2) HAT. Fexinidazole came out of early compound-mining efforts involving massive literature research of pharmacological data on abandoned compounds, and testing of identified candidates for effectiveness in killing kinetoplastid parasites. Today, fexinidazole is in clinical development with Sanofi. Recruitment into the pivotal study to assess the efficacy and safety of oral fexinidazole in adults with stage 2 T.b. gambiense HAT was completed last year and patient follow-up is ongoing. Two complimentary studies began recruiting early in 2015 in children over 6 years of age, and in adults with early stage 2 or stage 1 HAT. In addition, further evidence on safety and effectiveness will be gathered from a larger group of patients in a Phase IIIb trial.
The second compound, SCYX-7158, is potentially a single-dose oral treatment. SCYX-7158 emerged from an optimization programme of an earlier compound identified through screening a library of benzoxaboroles from Anacor Pharmaceuticals. The improved SCYX-7158 is the first NCE to have come out of our lead optimization efforts and enter clinical development. It has completed evaluation in healthy human volunteers and preparations are underway for a trial in stage 2 T.b. gambiense HAT patients in early 2016.
Backup candidates have been developed in case of need, and support is given to other players in the field, notably the Novartis Institute for Tropical Diseases.
Filling the development pipeline for leishmaniasis and Chagas disease has proved to be a greater challenge, requiring multiple approaches
The development of treatments for the other kinetoplastid diseases has been more problematic, with studies highlighting the regional differences in response to treatments for visceral leishmaniasis (VL), and the lack of translation of drugs against Chagas disease from laboratory to patient. We are focusing on these diseases in multiple partnerships aimed at identifying NCEs with different mechanisms of action. In a long-term effort to tap into the diversity of compounds and therefore increase our ability to take drugs into testing in man, compound libraries from a variety of sources have been screened to identify ‘starting points’ for subsequent lead optimization, and identification of improved drug candidates. The earliest fruit of such approaches are for leismaniasis, including DNDI0690, a nitroimidazole class compound. In addition, a number of pre-clinical candidates is under investigation from an oxaborole-containing lead series, and other candidates from the aminopyrazole class, originally from Pfizer. The aminopyrazole class optimization work is in collaboration with Takeda through the GHIT fund. These and other new classes, like the pyrolopyrimidine class, are in optimization and illustrate the success of the long-term approach and the need for continued investment into accessing and screening novel compound libraries.
There are also two NCEs in development for cutaneous leishmaniasis (CL). Liposomal amphotericin B is effective in treating visceral leishmaniasis, but has some tolerability issues when taken systemically. A topical cream containing 3% amphotericin B, Anfoleish, is being developed as a short-term solution for cutaneous leishmaniasis, and is undergoing clinical trials in patients. In the longer term, CpG-D35 an adjunct therapy for CL and PKDL (post kala-azar dermal leishmaniasis) chemotherapies is being evaluated. It aims to stimulate the body’s immune response following chemotherapy.
The approach for filarial diseases is specific, based on drug repurposing and focused screening
There is a need for a safe, patient-adapted macrofilaricide to kill the adult worms that cause onchocerciasis and lymphatic filariasis. Drugs used in mass drug administration programmes kill the juvenile worms, but adults remain alive and can continue to reproduce and exacerbate disease. By screening small, focused, animal health compound libraries, we are more likely to identify effective compounds. Emodepside is very effective against filarial worms, and we are working in partnership with Bayer AG to develop a treatment for onchocerciasis. Alternative compounds are under evaluation with other organizations. Furthermore, we are screening so-called ‘repurposing libraries’, which contain approved drugs that may be useful in other disease areas – although high risk, if successful, this strategy can really speed up the drug development process, and thus reach patients faster.
Moving from bilateral to multilateral approaches can increase chances of high quality drug hits, engage cross-company research capacity, and reduce time and cost of early screening
Our approaches so far have been largely bilateral, but we are now exploring new multilateral ways of working with partners in order to increase research capacity whilst keeping costs at a minimum. Earlier this year DNDi launched its NTD Drug Booster. With funding from GHIT, the Booster aims to reduce the time and expense of screening millions of compounds for VL and Chagas. Four partners have joined the collaboration to date – Eisai Co Ltd, Shionogi & Co Ltd, Takeda Pharmaceutical Ltd, and AstraZeneca plc – and it is hoped that others will join in the future. Six initial ‘seed’ compounds have been issued so far. Screening results from our partners at the Institut Pasteur Korea on the first three have confirmed an improved action of these compounds to kill the parasite. In turn, these compounds will be resubmitted to the Booster for further analysis and refinement as part of the compound optimization process.
Open source drug discovery may tap into new potential, whilst building capacity and motivating young researchers in both endemic and non-endemic countries. A crowd-sourcing project is being planned, which will involve undergraduate medicinal chemistry students worldwide in an effort to optimize a drug candidate for one of our neglected diseases.
With the ongoing close collaboration with our partners and sustained engagement of funding partners, we continue to learn from the scientific approaches we have implemented to date, and will keep exploring new pathways to tackle the very specific and complex challenges of our target diseases. Today, with an increasingly diverse menu of approaches, we aim to deliver a new generation of treatments – safe, effective and easy enough to administer in the patients’ own environment – and look forward to the day when these deadly diseases see major R&D breakthroughs.
Graeme Bilbe, Research & Development Director, DNDi