Origins
Despite the major progress achieved in medicine during the past 50 years, many tropical diseases affecting the poorest are still neglected. More than a billion people [6] – more than a seventh of the world's population – are infected with one of the 20 diseases listed by the World Health Organization (WHO) as neglected tropical diseases. [7] Although neglected tropical diseases can be fatal, there is a lack of modern, safe and effective medications to treat these illnesses. [8]
Evidence of the lack of new drugs for diseases that cause high mortality and morbidity among people living in poor areas has been published in the scientific literature. One publication reported that only 1.1% of new drugs were approved specifically for neglected diseases over a period of 25 years (1975 to 1999) despite the fact that these diseases represented 11.4% of the global burden. [9] Another indicated that this trend remained the same between 2000 and 2011 with only 1.2% of the new chemical entities brought to market indicated for neglected diseases. [10]
DNDi was created in 2003 to develop new treatments for neglected diseases. The organization was set up by key research and health institutions, notably from the public sector in neglected-disease-endemic countries – the Oswaldo Cruz Foundation from Brazil, the Indian Council of Medical Research, the Kenya Medical Research Institute, the Ministry of Health of Malaysia and France's Pasteur Institute, with seed funding from Médecins Sans Frontières' (MSF) 1999 Nobel Peace Prize. The WHO Special Programme for Research and Training in Tropical Diseases (TDR) acts as a permanent observer to the initiative. [11]
DNDi's founder Bernard Pécoul led the organization from 2003 until 2022. [12]
From 2022 until now, the organization has a new director, a Chilean doctor called Luis Pizarro.
Non-profit drug development model
As people with neglected diseases do not represent a lucrative market for pharmaceutical companies, incentives to invest in research and development are lacking for these diseases. [13] [14]
Alternatives to profit-driven drug development emerged in the early 2000s to meet the needs of these neglected patients. Product development partnerships (PDPs), also called public-private partnerships (PPPs) aim to implement and accelerate research and development (R&D) into health tools (diagnostics, vaccines, drugs) for diseases that are neglected, by enabling new collaborations between private industry, academia, and the public sector. [15] Examples of PDPs include the International AIDS Vaccine Initiative, MMV, the Global Alliance for TB Drug Development (TB Alliance), and DNDi. [16]
PDPs act as 'conductors of a virtual orchestra', [17] leveraging partners' specific assets, capacities, and expertise to implement projects at all stages of the R&D process, integrating capabilities from academia; public-sector research institutions, particularly in neglected disease-endemic countries; pharmaceutical and biotechnology companies; non-governmental organizations including other PDPs; and governments worldwide. [18]
To overcome the lack of commercial research into drug development, PDPs can apply "delinkage" principles that aim to separate the cost of research and development from the price of products. This allows the incentive for investing in a particular disease to be independent of the price at which any developed products will be sold. [19]
Key achievements
DNDi has built a large drug pipeline for neglected diseases with both improvements on existing drugs and entirely new chemical entities. To date, their 13 key achievements are
Treatments delivered to date:
ASAQ, fixed-dose combination for malaria, 2007
Launched in 2007, this antimalarial product is a fixed-dose combination of artesunate/amodiaquine (ASAQ). The result of a partnership between DNDi and French pharmaceutical company Sanofi, ASAQ, which is produced in Morocco, is affordable (available for only $0.05 for children, $1 for adults), is administered in a simple regimen (1 or 2 tablets per day for three days), meets the latest WHO guidelines for malaria treatment in Africa and was granted "pre-qualified" status in 2008. [20] Although developed without a patent, ASAQ is included in the WHO Model List of Essential Medicines and Essential Medicines List for Children, is registered in 32 African countries, India, Ecuador, and in Colombia, and more than 437 million treatments have been distributed. [21] [22] [23] [24]
A technology transfer agreement has been signed with industrial partner Zenufa in Tanzania in order to provide an additional source of ASAQ. ASAQ was handed over to the MMV Access and Product Management Team in May 2015. [25]
ASMQ, fixed-dose combination for malaria, 2008
The second antimalarial treatment developed by DNDi is a fixed-dose combination of artesunate and mefloquine launched in 2008. It was developed by an international collaboration within the FACT Project Consortium. It has a simple and adapted regimen, a three-year shelf-ife and a very high compliance rate. ASMQ is produced in Brazil by Farmanguinhos [ pt ]/Fiocruz and thanks to a South–South technology transfer, it is now also produced by Cipla. The latter was granted "pre-qualified" status by the WHO in 2012 and included on the WHO Model List of Essential Medicines and Essential Medicines List for Children in 2013. [26] By 2015 it was registered in Brazil, India, Malaysia, Myanmar, Tanzania, Vietnam, Niger, Burkina Faso, Thailand and Cambodia. By the end of 2015 more than one million treatments had been distributed. ASMQ was handed over to the MMV Access and Product Management Team in May 2015. [27]
SSG&PM, combination treatment for visceral leishmaniasis, 2010
SSG&PM, [29] a sodium stibogluconate plus paromomycin combination therapy, is a shorter-course, cost-efficient treatment option against visceral leishmaniasis (VL) in East Africa available since 2010. It is the result of a six-year partnership between DNDi, the Leishmaniasis East Africa Platform (LEAP), the National Control Programmes of Kenya, Sudan, Ethiopia, and Uganda, Médecins Sans Frontières (MSF) and the WHO. [30] It was recommended by the WHO Expert Committee on the Control of Leishmaniasis in 2010 as the first-line treatment in East Africa, and more than 10,000 patients have been treated. Sudan, Ethiopia, South Sudan and Somalia have released revised guidelines recommending SSG&PM as the first-line treatment for VL. [31]
Combination treatments for visceral leishmaniasis in Asia, 2011
Single dose amphotericin B and paromomycin/miltefosine/amphotericin B combinations were recommended by the WHO Expert Committee on the Control of Leishmaniasis (2010). [32] These treatments are less toxic than previous mainstay treatments, useful in areas of antimonial resistance, are shorter course and their cost is comparable with previous treatments. In 2010, a study investigating the three possible 2-drug combinations of amphotericin B, miltefosine and paromomycin was completed in India. All three combination treatments were shown to be highly efficacious (> 97.5% cure rate). A WHO Expert committee recommended these treatments to be used preferentially to current established monotherapy treatments for VL in South Asia. DNDi is working with TDR and WHO to facilitate their introduction and support VL elimination strategies. [33] DNDi conducted more studies, including a pilot project in the Bihar State of India (2012–2015) that demonstrated the safety and effectiveness of combination therapies based on amphotericin B, miltefosine, and paromomycin at the primary healthcare level, and single dose amphotericin B at the hospital level. Based on the study results, the Indian National Roadmap for Kala-Azar Elimination in August 2014 recommended use of single dose amphotericin B as a first option treatment for the treatment of VL patients, with paromomycin and miltefosine as a second option at all levels; [34] a policy also reflected in Bangladesh and Nepal. This removal of miltefosine monotherapy is an important policy change. This project has been a collaboration with a consortium of partners. [35]
Paediatric benznidazole for Chagas disease, 2011
This is the only paediatric dosage treatment for Chagas disease, launched in 2011 through a collaboration between DNDi and Laboratório Farmacêutico do Estado de Pernambuco (LAFEPE). In November 2013, the Mundo Sano Foundation and DNDi signed a collaboration agreement to deliver a second source of the treatment in partnership with ELEA. The paediatric dosage form of benznidazole is designed for infants and young children under two years of age (20 kg body weight) infected congenitally. Thanks to its age-adapted, easy-to-use, affordable, and non-patented tablet, the new treatment contributes to improved dosing accuracy, safety, and adherence to treatment. The paediatric dosage form of benznidazole was granted registration by Brazil's National Health Surveillance Agency in 2011, and further endemic countries are targeted for obtaining registration. It was included on the WHO Essential Medicines List for Children in July 2013. [36]
Superbooster therapy for children living with HIV and tuberculosis, 2016
Among the many challenges of treating children co-infected with both tuberculosis (TB) and HIV is the fact that a key TB drug negates the effectiveness of ritonavir, one of the main antiretrovirals to treat HIV. A DNDi-sponsored study [37] at five hospitals in South Africa demonstrated the effectiveness of 'super-boosting' or adding extra ritonavir to a child's treatment regimen. WHO has since strengthened recommendations to use super-boosting in TB/HIV co-infected children. [38]
Fexinidazole, 2018
Fexinidazole is the first entirely oral treatment for sleeping sickness (or human African trypanosomiase) due to Trypanosoma bruceigambiense. It was developed in partnership by DNDi, Sanofi, and others. The clinical trials enrolled 749 patients from the Democratic Republic of the Congo and the Central African Republic. Results published in The Lancet showed high efficacy and safety for both stages of the disease. Fexinidazole is administered as oral tablets for 10 days. [39]
In November 2018, the European Medicines Agency adopted a positive scientific opinion of fexinidazole. [40] [41] [42] In December 2018, fexinidazole was approved in the Democratic Republic of the Congo. [43]
Other project:
Global Antibiotic Research & Development Partnership
In 2016, the WHO and DNDi collaborated to launch the Global Antibiotic Research & Development Partnership (GARDP), a not-for-profit research and development organization that addresses global public health needs by developing and delivering new or improved antibiotic treatments, while endeavouring to ensure their sustainable access. In 2018, GARDP was organized as an independent legal entity. [44]
Ravidasvir, 2021
Access to affordable hepatitis C treatment with highly efficacious direct-acting antivirals (DAAs) remains extremely limited in many low- and middle-income countries. [45] In 2016, DNDi signed agreements with US biopharmaceutical company Presidio Pharmaceuticals, developer of the DAA drug candidate ravidasvir, and its licensing partner, the Egyptian generic manufacturer Pharco Pharmaceuticals, to enable testing of a new combination treatment optimised for public health use: ravidasvir + sofosbuvir. [46] A Phase II/III study in Malaysia and Thailand, co-sponsored by the Malaysian and Thai Ministries of Health and co-financed by the MSF Transformational Investment Capacity (TIC) initiative, showed that 12 weeks after the end of treatment, 97% of participants were cured. Patients with multiple risk factors were cured, and no unexpected safety signals were detected. [47] In June 2021, Malaysia granted a conditional registration for ravidasvir. [48]
New treatments for HIV/VL, 2022
Leishmania-HIV coinfection has been reported from 35 endemic countries [http://www.who.int/news-room/fact-sheets/detail/leishmaniasis]. People co-infected with HIV and visceral leishmaniasis have poor response to treatment, higher risk of death, and often experience multiple relapse episodes. [49] Based on the results of two studies, in June 2022 WHO released new treatment guidelines for the treatment of people co-infected with visceral leishmaniasis and HIV, recommending a combination of liposomal amphotericin B with miltefosine. [50]
Leishmaniasis in Latin America, 2022
Previously, first-line treatment recommendations for visceral leishmaniasis in Brazil included the use of meglumine antimoniate, which has serious limitations due to toxicity, parenteral administration, and the need for hospitalization. [51] Results of a trial in partnership with the University of Brasilia and the Oswaldo Cruz Foundation of Brazil showed that due to lower toxicity and acceptable efficacy, liposomal amphotericin B would be a more suitable first-line treatment for visceral leishmaniasis than standard treatment. [52] [53] In June 2022, the Pan American Health Organization (PAHO) published new guidelines for the treatment of leishmaniasis in the Americas, which recommend liposomal amphotericin B for the treatment of visceral leishmaniasis instead of pentavalent antimonials. [54]
4-in-1 for paediatric HIV, 2022
This '4-in-1' fixed-dose combination combines the protease inhibitors lopinavir and ritonavir with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine and abacavir for the treatment of paediatric HIV. [55] The 4-in-1 is a significant improvement over currently available lopinavir-based regimens, [56] because it is formulated as a granule-filled capsule, which is heat-stable, taste-masked, solid, and does not contain alcohol or inappropriate solvents. It was developed for infants and young children weighing from 3 to 25 kg, in partnership with Cipla Limited. It can be administered by opening the capsules and sprinkling the granules on soft food, water, or milk. [57] The South African Health Products Regulatory Authority (SAHPRA) approved the 4-in-1 in June 2022. [58]
Awards
In 2013, DNDi won the BBVA Foundation Frontiers of Knowledge Award in the Development Cooperation category [59] for developing and delivering new treatments for poverty-related diseases including Chagas disease, sleeping sickness, malaria and leishmaniasis. [60]
DNDi received the Carlos Slim Health Award in 2013. [61] Created in 2008 by the Carlos Slim Foundation, the aim of the award is to distinguish the people and institutions who are committed to improving the levels of health among the population of Latin America and the Caribbean. [62]
In 2013, The Rockefeller Foundation asked the global community to nominate organizations and individuals who were making a difference for poor and vulnerable populations through innovation. [63] From those nominations, and the votes of individuals around the world, The Rockefeller Foundation selected three winners of the 2013 Next Century Innovators Award. [64] DNDi was one of the awardees. [65]
On December 11, 2015, DNDi won the national FINEP Award for Innovation. [66] The award was in recognition of an innovative R&D model that has delivered a new antimalarial drug developed in Brazil. [67]
DNDi received the prize for innovation in 2017 [68] and the 'cuvée 2018 de la Vigne des Nations' in 2018, [69] both from the Canton of Geneva.
The publication Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial published November 4, 2017 in The Lancet [70] was one of the two winners of the 2018 edition of the Anne Maurer-Cecchini Award. [71]
A short film about fexinidazole, a new treatment for sleeping sickness, was awarded the Grand Prix at the inaugural World Health Organization 'Health for All' film festival in 2020. [72] 'A doctor's dream' was produced by DNDi with Scholars and Gentlemen, a production company from South Africa.
In 2023 the organization was awarded the Princess of Asturias Award in the category of "International Cooperation". [73]
African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species Trypanosoma brucei. Humans are infected by two types, Trypanosoma brucei gambiense (TbG) and Trypanosoma brucei rhodesiense (TbR). TbG causes over 92% of reported cases. Both are usually transmitted by the bite of an infected tsetse fly and are most common in rural areas.
Leishmaniasis is a wide array of clinical manifestations caused by protozoal parasites of the Trypanosomatida genus Leishmania. It is generally spread through the bite of phlebotomine sandflies, Phlebotomus and Lutzomyia, and occurs most frequently in the tropics and sub-tropics of Africa, Asia, the Americas, and southern Europe. The disease can present in three main ways: cutaneous, mucocutaneous, or visceral. The cutaneous form presents with skin ulcers, while the mucocutaneous form presents with ulcers of the skin, mouth, and nose. The visceral form starts with skin ulcers and later presents with fever, low red blood cell count, and enlarged spleen and liver.
James Jude Orbinski is a Canadian physician, humanitarian activist, author and leading scholar in global health. Orbinski was the 2016-17 Fulbright visiting professor at the University of California, Irvine, and as of September 1, 2017, he is professor and inaugural director of the Dahdaleh Institute of Global Health Research at York University in Toronto, Ontario, Canada. He was previously the CIGI Chair in Global Health Governance at the Balsillie School of International Affairs and Wilfrid Laurier University (2012-2017), Chair of Global Health at the Dalla Lana School of Public Health (2010-2012) and full professor at the Faculty of Medicine, University of Toronto (2003-2012), where he was the founding Saul Rae Fellow at Massey College. Orbinski's current research interests focus on the health impacts of climate change, medical humanitarianism, intervention strategies around emerging and re-emerging infectious diseases, and global health governance.
Tropical medicine is an interdisciplinary branch of medicine that deals with health issues that occur uniquely, are more widespread, or are more difficult to control in tropical and subtropical regions.
Paromomycin is an antimicrobial used to treat a number of parasitic infections including amebiasis, giardiasis, leishmaniasis, and tapeworm infection. It is a first-line treatment for amebiasis or giardiasis during pregnancy. Otherwise, it is generally a second line treatment option. It is taken by mouth, applied to the skin, or by injection into a muscle.
Visceral leishmaniasis (VL), also known as kala-azar or "black fever", is the most severe form of leishmaniasis and, without proper diagnosis and treatment, is associated with high fatality. Leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania.
The European and Developing Countries Clinical Trials Partnership (EDCTP) is a partnership between the European Union (EU), Norway, Switzerland and developing countries and other donors, as well as the pharmaceutical industry, to enable clinical trials and the development of new medicines and vaccines against HIV/AIDS, tuberculosis, and malaria. The need for global action against these diseases in order to promote poverty reduction has been recognised by the United Nations, the G8, and the African Union, and the program envisioned the provision of €600 million for the period 2003–2007 in order to translate medical research results into clinical applications relevant to the needs of developing countries.
Sodium stibogluconate, sold under the brand name Pentostam among others, is a medication used to treat leishmaniasis. This includes leishmaniasis of the cutaneous, visceral, and mucosal types. Some combination of miltefosine, paramycin and liposomal amphotericin B, however, may be recommended due to issues with resistance. It is given by injection.
Neglected tropical diseases (NTDs) are a diverse group of tropical infections that are common in low-income populations in developing regions of Africa, Asia, and the Americas. They are caused by a variety of pathogens, such as viruses, bacteria, protozoa, and parasitic worms (helminths). These diseases are contrasted with the "big three" infectious diseases, which generally receive greater treatment and research funding. In sub-Saharan Africa, the effect of neglected tropical diseases as a group is comparable to that of malaria and tuberculosis. NTD co-infection can also make HIV/AIDS and tuberculosis more deadly.
Miltefosine, sold under the trade name Impavido among others, is a medication mainly used to treat leishmaniasis and free-living amoeba infections such as Naegleria fowleri and Balamuthia mandrillaris. This includes the three forms of leishmaniasis: cutaneous, visceral and mucosal. It may be used with liposomal amphotericin B or paromomycin. It is taken by mouth.
Leishmania donovani is a species of intracellular parasites belonging to the genus Leishmania, a group of haemoflagellate kinetoplastids that cause the disease leishmaniasis. It is a human blood parasite responsible for visceral leishmaniasis or kala-azar, the most severe form of leishmaniasis. It infects the mononuclear phagocyte system including spleen, liver and bone marrow. Infection is transmitted by species of sandfly belonging to the genus Phlebotomus in Old World and Lutzomyia in New World. The species complex it represents is prevalent throughout tropical and temperate regions including Africa, China, India, Nepal, southern Europe, Russia and South America. The species complex is responsible for thousands of deaths every year and has spread to 88 countries, with 350 million people at constant risk of infection and 0.5 million new cases in a year.
FIND is a global health non-profit based in Geneva, Switzerland. FIND functions as a product development partnership, engaging in active collaboration with over 150 partners to facilitate the development, evaluation, and implementation of diagnostic tests for poverty-related diseases. The organisation's Geneva headquarters are in Campus Biotech. Country offices are located in New Delhi, India; Cape Town, South Africa; and Hanoi, Viet Nam.
Bernard Pécoul is the founder and former executive director of the Geneva-based Drugs for Neglected Diseases initiative (DNDi) from 2003 until 2022. Prior to his involvement with the DNDi, Pécoul was executive director for Médecins Sans Frontières's campaign for Access to Essential Medicines, executive director of MSF-France, co-founder of the centre for epidemiological research Epicentre, and a MSF field physician in Africa, Latin America, and Asia. He is an outspoken patient advocate and proponent of increased research and development of treatments and innovation for neglected diseases.
Fexinidazole is a medication used to treat African trypanosomiasis caused by Trypanosoma brucei gambiense. It is effective against both first and second stage disease. Also a potential new treatment for Chagas disease, a neglected tropical disease that affects millions of people worldwide. It is taken by mouth.
The London Declaration on Neglected Tropical Diseases was a collaborative disease eradication programme launched on 30 January 2012 in London. It was inspired by the World Health Organization roadmap to eradicate or prevent transmission for neglected tropical diseases by the year 2020. Officials from WHO, the World Bank, the Bill & Melinda Gates Foundation, the world's 13 leading pharmaceutical companies, and government representatives from US, UK, United Arab Emirates, Bangladesh, Brazil, Mozambique and Tanzania participated in a joint meeting at the Royal College of Physicians to launch this project. The meeting was spearheaded by Margaret Chan, Director-General of WHO, and Bill Gates, Co-Chair of the Bill & Melinda Gates Foundation.
Victor Kande Betu Kumeso is a Congolese physician who is an expert in African trypanosomiasis. He works at the Programme National de Lutte contre la Trypanosomiase Humaine Africaine at the University of Kinshasa.
Kala azar in India refers to the special circumstances of the disease kala azar as it exists in India. Kala azar is a major health problem in India with an estimated 146,700 new cases per year as of 2012. In the disease a parasite causes sickness after migrating to internal organs such as the liver, spleen and bone marrow. If left untreated the disease almost always results in the death. Signs and symptoms include fever, weight loss, fatigue, anemia, and substantial swelling of the liver and spleen.
Nilima Arun Kshirsagar FACCP, FRCP, FNAMS FNAS is an Indian clinical pharmacologist who developed and patented liposomal amphotericin B and its drug delivery system in 1993. She is the former dean of King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College. She is the national chairperson in clinical pharmacology at Indian Council of Medical Research (ICMR) and president of the South Asian chapter of the American college of clinical pharmacology. She is a Member of the WHO Committees on Product development and Drug statistics Methodology.
The WHO model list of essential in vitro diagnostics, or WHO list of essential diagnostic tests (EDL) is a World Health Organization (WHO) priority list of medical tests that provides guidance for individual countries on which tests to use and which not to. It was first published in 2018, then revised in 2019, and a third edition was published in 2020.
The Kigali Declaration on Neglected Tropical Diseases is a global health project that aims to mobilise political and financial resources for the control and eradication of infectious diseases, the so-called neglected tropical diseases due to different parasitic infections. Launched by the Uniting to Combat Neglected Tropical Diseases on 27 January 2022, it was the culmination and join commitment declared at the Kigali Summit on Malaria and Neglected Tropical Diseases (NTDs) hosted by the Government of Rwanda at its capital city Kigali on 23 June 2022.
