Drugs for Neglected Diseases Initiative

The logo of the Drugs for Neglected Diseases Initiative.

The Drugs for Neglected Diseases Initiative (DNDI) is a collaborative, patients’ needs-driven, non-profit drug research and development (R&D) organization that is developing new treatments for neglected diseases, notably leishmaniasis, sleeping sickness (human African trypanosomiasis, HAT), Chagas disease,^[1] malaria, paediatric HIV,^[2] and specific helminth infections. DNDi`s malaria activities were transferred to Medicines for Malaria Venture (MMV) in 2015.

Led by its Executive Director Bernard Pécoul,^[3] DNDi’s headquarters are in Geneva, Switzerland, with offices in Kenya, India, Brazil, Malaysia, Japan, the Democratic Republic of Congo, and an affiliate in the USA.

Origins

Despite the major progress achieved in medicine during the past 50 years, many tropical diseases affecting the poorest are still neglected. More than 1.4 billion people^[4] —close to one sixth of the world’s population— are infected with one of the 17 diseases listed by the World Health Organization (WHO) as neglected tropical diseases (NTDs).^[5] Although NTDs can be fatal, there is a lack of modern, safe and effective medications to treat these diseases.

Scientific publications brought the evidence that there was a lack of news drugs for diseases that cause high mortality and morbidity among people living in poor areas. One showed 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.^[6] Another indicated that this trend remained the same between 2000 and 2011 with only 1.2% of the new chemical entities brought to market were indicated for neglected diseases.^[7]

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 Institut -Pasteur, with seed funding from Médecins Sans Frontières/Doctors Without Borders (MSF)’s 1999 Nobel Peace Prize . The WHO Special Programme for Research and Training in Tropical Diseases (TDR) acts as a permanent observer to the initiative.

Non-profit drug development model

As people suffering from neglected diseases do not represent a lucrative market for pharmaceutical companies, the incentives to invest in research and development are lacking for these diseases.^[8][9]

Alternatives to profit-driven drug development emerged in the years 2000 to provide an answer to the needs of these neglected patients. Product development partnerships (PDPs), also called public-private partnerships (PPPs) aim to implement and accelerate the 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.^[10] Examples of PDPs include the International AIDS Vaccine Initiative, the Medicines for Malaria Venture, or the Global Alliance for TB Drug Development and DNDi.

PDPs acts as ‘conductors of a virtual orchestra’,^[11] 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.

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.^[12]

Key Achievements

To date, DNDi has delivered six new treatments and built a large drug pipeline for neglected diseases with both improvements on existing drugs and entirely new chemical entities (NCEs).^[13]

Treatments delivered to date:

ASAQ, a fixed-dose combination for Malaria, 2007

Launched in 2007, this antimalarial product is a fixed-dose combination of artesunate/amodiaquine (ASAQ). It is the result of a partnership between DNDi and Sanofi. Produced in Morocco, this product is cheap^[14] (available at only $.05 for children, $1 for adults), administered in a simple regimen (1 or 2 tablets per day for 3 days), meets the latest WHO guidelines for malaria treatment in Africa and was granted "pre-qualified" status in 2008. It is included in the WHO Essential Medicines List and Essential Medicines List for Children.

ASAQ was developed with no patent.^[15] ASAQ is registered in 32 African countries, in India, Ecuador and in Colombia, and included in the . More than 437 million treatments had been distributed.^[16][17] More than 437 million treatments had been distributed. 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.

ASMQ, a 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. Developed by an international collaboration within the FACT Project Consortium. It has a simple and adapted regimen, a 3-year shelf life and a very high compliance rate. ASMQ is produced in Brazil by Farmanguinhos/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 in the WHO Essential Medicines List and Essential Medicines List for Children in 2013. 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.

NECT, an improved treatment for Sleeping Sickness, 2009

NECT, a combination therapy of nifurtimox and eflornithine, is the first new, improved treatment option in 25 years for stage 2 (advanced stage) human African trypanosomiasis (HAT) also known as sleeping sickness. It is the result of a six-year partnership between NGOs, governments, pharmaceutical companies, and the WHO. It was launched in 2009 and included in the WHO Essential Medicines List and WHO Essential Medicines List for Children in 2009 and 2013 respectively. It requires shorter hospitalization than previous treatment, and is much safer than previously widely used arsenic-based Melarsoprol that killed about 5% of patients. NECT is now used to treat 100% of the patients infected with HAT stage 2 in all 13 endemic countries.

SSG&PM, a combination treatment for Visceral Leishmaniasis, 2010

SSG&PM,^[18] 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.^[19] 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.

Combination treatments for Visceral Leishmaniasis in Asia, 2011

Single dose AmBisome® & paromomycin/miltefosine/AmBisome® combinations were recommended by the WHO Expert Committee on the Control of Leishmaniasis (2010). 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 (AmBisome), 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.^[20] 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 AmBisome®, miltefosine and paromomycin at the primary healthcare level, and single dose AmBisome® 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 AmBisome® as a first option treatment for the treatment of VL patients, with paromycin and miltefosine as a second option at all levels; 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 the National (Vector Borne) Disease Control Programmes of India and Bangladesh, MSF, TDR, OneWorld Health/PATH, Bihar State Health Society and the Indian Council for Medical Research.

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 LAFEPE (Laboratório Farmacêutico do Estado de Pernambuco). 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 (producers of Abarax®). The paediatric dosage form of benznidazole is designed for infants and young children under 2 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 (ANVISA) 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

Awards

In 2003, DNDi won the BBVA Foundation Frontiers of Knowledge Award in the Development Cooperation category^[21] for developing and delivering new treatments for poverty-related diseases including Chagas disease, sleeping sickness, malaria and leishmaniasis.

DNDi received the Carlos Slim Health Award in 2013. 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.

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.^[22] From those nominations - and the votes of individuals around the world - The Rockefeller Foundation selected three winners of the 2013 Next Century Innovators Award. DNDi was one of the awardees.^[23]

On December 11, 2015, DNDi won the national FINEP Award for Innovation.^[24] The award was in recognition of an innovative R&D model that has delivered a new antimalarial drug developed in Brazil.^[25]

Regional Clinical Trial Platforms

DNDi works with partners in disease-endemic countries to strengthen existing clinical research capacity and build new capacity where necessary. DNDi helped in setting up and works with four regional disease-specific platforms in Africa and Latin America. The Leishmaniasis East Africa Platform (LEAP) on leishmaniasis. The HAT Platform on sleeping sickness, or human African trypanosomiasis. The Chagas Clinical Research Platform (CCRP). The RedeLeish Network on leishmaniasis in Latin America.

Their mission is to define patient needs, taking into consideration the local conditions, bring together key regional actors in the field of health, reinforce clinical capacities in endemic regions, address infrastructural requirements where necessary and provide on-site training.^[26]

Long-term Objective

DNDi plans to develop 16-18 new treatments by 2023.^[27]

See also

• The Neglected Diseases
• Fexinidazole
• Artemisinin
• Quinine

References

External links and publications

• dndi.org, Drugs for Neglected Diseases Initiative
• , WHO, Tropical Disease Research
• International Labour Organization
• European Bioinformatics Institute
• European Medicines Agency
• Food and Drug Administration
• Structural Genomics Consortium