Annual Report 2017
2017 Annual Report

Responding to
Neglected Patients’ Needs
Through Innovation

READ
LEADERSHIP
MESSAGE
CLOSE

Message

from the Chair of the Board and the Executive Director

  • Dr Marie-Paule Kieny

    Chair of the Board of Directors

  • Dr Bernard Pécoul

    Executive Director

DNDi will soon be marking the 15 years since its founding, an anniversary which comes at an exciting time in DNDi’s growth since 2003.


Our pipeline is maturing, and significant scientific milestones are on the cusp of being reached.


We have already delivered seven treatments for five diseases. This illustrates the wisdom of having invested early on, not only in long-term projects to discover and develop new chemical entities (NCEs), but also in short-term projects that would have a more immediate impact on improving clinical care for patients.


Our investments in drug discovery are beginning to bear fruit. DNDi’s portfolio currently includes more than 20 new chemical entities (NCEs) that are adapted to the needs of patients. Some will contribute to supporting the control or sustainable elimination of several neglected tropical diseases, including:

  • Sleeping sickness: Fexinidazole, DNDi’s first NCE, which is in the last stages of regulatory review, submitted by our industrial partner Sanofi. If successful, ‘fexi’ would be the first all-oral treatment for sleeping sickness.
  • Leishmaniasis: Novel drugs, based on four NCEs in early discovery research and six in pre-clinical development.

Engaging with partners

  • Contributed to Grupo Insud’s successful registration of the first treatment to be approved in the US for Chagas disease; the sale of Insud’s priority review voucher will go towards increasing access to treatment for neglected patients.
  • Worked with Insud’s non-profit partner Fundación Mundo Sano, to create a new Chagas access framework and put an end to the unacceptable situation where only 1% of people today have access to diagnosis and treatment.
  • Forged alliances with Pharco Pharmaceuticals, the Ministries of Health of Malaysia and Thailand, Doctors Without Borders (MSF), and the Foundation for Innovative New Diagnostics (FIND) to assess new approaches to hepatitis C diagnosis and treatment, including through clinical trials that showed ravidasvir is as safe and effective as the very best of existing treatments.

The need for political leadership

A comprehensive approach to meeting global health needs requires strong political leadership and national commitment. We saw strong examples of this in 2017, including:

  • The landmark decision of the Malaysian government to issue a “government use” licence enabling access to more affordable versions of an expensive and patented medicine to treat the more than 400,000 people living with hepatitis C in Malaysia – and beyond.
  • The ambitious programme on universal health coverage from the WHO Director-General, Dr Tedros, highly relevant for NTDs and antimicrobial resistance.
  • The pledge of the G20 Ministers of Health Summit under Germany’s presidency to invigorate research and development efforts to find new, urgently needed drugs.

Nearly 15 years ago, the founding partners of DNDi refused to accept as a given that neglected populations must continue to be forgotten by medical innovation.


On behalf of DNDi, we express our sincere gratitude to our many partners, our funders and donors, and our staff, who have made our collective successes possible.
Thank you!

2017 in numbers

 

666,917

PEOPLE

screened for sleeping sickness by 10 mobile teams in DR Congo and treated for a variety of diseases

OVER

2,500

PATIENTS

enrolled in the clinical studies completed in 2017

 

685

PEOPLE

trained to support clinical research, from Good Clinical Practice to the use of new diagnostic technologies and processes

44

R&D PROJECTS UNDERWAY

covering every stage of the R&D process

12

 

new R&D partnerships

869

PEOPLE

working on DNDi projects in partner organizations

170,407

COMPOUNDS SCREENED

to look for promising “hits” as potential drug candidates

3+2

 

3 COMPOUNDS advanced to pre- clinical stage, and 2 CANDIDATES advanced to clinical development

21

CLINICAL TRIALS

in progress in 7 disease areas at 52 sites in 15 countries

2

TECHNOLOGY TRANSFERS

in Malaysia and in Latin America – for the manufacture and supply of hepatitis C treatments

€ 6

MILLION

Value of in-kind contributions from partners

CLOSE MORE

DNDi R&D portfolio

December 2017

Key R&D achievements in 2017

CLICK ON THE ICONS TO DISCOVER MORE

MALARIA

  • RESEARCH

  • TRANSLATION

  • DEVELOPMENT

  • IMPLEMENTATION

RESEARCH

TRANSLATION

DEVELOPMENT

IMPLEMENTATION

ASAQ ASMQ
New Chemical Entity (NCE)
2017 Disease and project updates (pdf)
June 2018 portfolio

2017 achievements
from DNDi regional offices

TAP ON PINS TO DISCOVER MORE
India DNDI INDIA IN 2017 Japan DNDI JAPAN IN 2017 South-East Asia DNDI SOUTH-EAST ASIA IN 2017 Africa DNDI AFRICA IN 2017 DR Congo DNDI DR CONGO IN 2017 South Africa DNDI SOUTH AFRICA IN 2017 Latin America DNDI LATIN AMERICA IN 2017 North America DNDI NORTH AMERICA IN 2017 Switzerland DNDI HEADQUARTERS SWITZERLAND IN 2017
DNDi Headquarters - Switzerland
  • Strategic leadership and coordination of research and development, from drug discovery through clinical development and registration
  • Administrative and support departments, including finance, human resources, IT, policy advocacy, communications, and fundraising
  • About half of all DNDi staff
  • Re-organization process started in 2017 to ensure structure keeps pace with evolution of DNDi portfolio.
DNDi North America in 2017
  • Approval by the U.S. Food and Drug Administration (FDA) of Chemo Group’s (now InSud Pharma) benznidazole for children with Chagas disease in close collaboration with Exeltis, Mundo Sano, and DNDi
  • A DNDi-supported survey of almost 5,000 Latin American-born residents of Los Angeles County found that 1.24% tested positive for Chagas disease
  • Advocacy at the UN High-Level Political Forum on Sustainable Development in New York and continued support for global health R&D in Washington, DC in a changing political environment
  • A campaign to raise funds for African sleeping sickness secures over USD 500,000 in new private contributions that will help put the disease on the path to sustainable elimination
DNDi Latin America in 2017
  • Completion of recruitment in the clinical study of new regimens of benznidazole monotherapy and in combination with fosravuconazole in Bolivia for the treatment of Chagas disease
  • Start of a Phase II clinical study in Spain to test short courses of fexinidazole for Chagas disease
  • Implementation of a new, simplified diagnostic algorithm and treatment for all patients with Chagas disease, including chronic patients, as part of the pilot Chagas Access Programme in Colombia
  • Start of a clinical study on cutaneous leishmaniasis combining thermotherapy with miltefosine in Colombia and Peru
DNDi South Africa in 2017
  • Opening of a new DNDi-GARDP joint liaison office in Cape Town
  • Collaboration agreement with South African Medical Research Council
DNDi DR Congo in 2017
  • Support completion of fexinidazole clinical studies in adults (stage 1 and 2) and children with sleeping sickness
  • Start of Phase IIIb study in seven clinical sites in DR Congo to generate information on fexinidazole in special population groups in in- and out-patients
  • Start of Phase II/III study in nine clinical sites in DR Congo to test acoziborole as a single-dose treatment in patients with stage 1 or 2 sleeping sickness
DNDi Africa in 2017
  • Support for the first-ever clinical trial in eumycetoma, studying the efficacy of the anti-fungal drug fosravuconazole at the Mycetoma Research Centre, Sudan
  • Preliminary evaluation of the paediatric HIV ‘LIVING’ study: high levels of viral suppression in infants and young children after 48 weeks of treatment
  • Initiation of the first site for the miltefosine/paromomycin clinical trial in Sudan for visceral leishmaniasis (VL) in Eastern Africa
  • Community meetings in Amudat, Uganda, and Kacheliba and West Pokot, Kenya to share findings of the miltefosine dosing clinical trial in children with primary VL
  • Stakeholders’ meeting in Addis Ababa, Ethiopia on clinical trial for HIV/VL coinfected patients
  • ISO 9001:2008 certification (quality management systems) received for Nairobi office
DNDi South-East Asia in 2017
  • After completion of patient recruitment in the sofosbuvir/ ravidasvir clinical study for hepatitis C in Malaysia, start of recruitment in Thailand
  • Approval by Malaysia of a “government use” licence to secure access to more affordable treatments for hepatitis C
  • Agreement signed between pharmaceutical companies Pharmaniaga (Malaysia) and Pharco Pharmaceuticals (Egypt), and DNDi to supply affordable hepatitis C treatment in Malaysia
DNDi Japan in 2017
  • NTD Drug Discovery Booster presented with Japanese pharmaceutical partners at the Annual Meeting of the Pharmaceutical Society of Japan
  • Official side event on NTDs at the Universal Health Coverage Forum in partnership with Uniting to Combat NTDs, Nagasaki and St Luke’s International Universities
  • Renewed support of GHIT Fund to projects on leishmaniasis, Chagas disease, and eumycetoma
DNDi India in 2017
  • Support of Indian National Kala-azar Elimination Programme in building capacity to diagnose kala-azar and post-kala-azar dermal leishmaniasis (PKDL)
  • Study to determine prevalence of PKDL in previously treated leishmaniasis patients
  • Technical partner in an MSF study on kala-azar-HIV co-infection in Bihar, testing treatments with AmBisome monotherapy and AmBisome-miltefosine combination
  • Start of a clinical trial for PKDL, testing AmBisome monotherapy and AmBisome-miltefosine combination
  • Expansion of the Open Source Network project with an additional Indian university
GARDP Rapid progress in first year

The WHO-DNDi joint initiative GARDP progressed its programmes in 2017, addressing antimicrobial resistance in neonatal sepsis, in sexually-transmitted infections, and through a ‘memory recovery and exploratory’ programme.

MORE INFO

The Disease that Strikes Back

Could a form of leishmaniasis challenge elimination efforts in India?

READ THE STORY

7 new treatments delivered, recommended & implemented since 2007

PAEDIATRIC HIV

2016

VISCERAL LEISHMANIASIS IN ASIA

2011

CHAGAS DISEASE

2011

VISCERAL LEISHMANIASIS IN EAST AFRICA

2010

HUMAN AFRICAN TRYPANOSOMIASIS (HAT)

2009

MALARIA

2008

MALARIA

2007

SUPERBOOSTER THERAPY

PAEDIATRIC HIV

Partnership with Cipla

2016
  • More effective treatment for children co-infected with HIV and tuberculosis (TB)
  • “Super-boosting” the dose of ritonavir, an antiretroviral used to treat HIV in children, counteracts negative interactions between common TB drug rifampicin and HIV therapy
  • WHO revised its guidelines to recommend “superboosting” of ritonavir when treating co-infected children (2016)

NEW VL TREATMENTS ASIA

VISCERAL LEISHMANIASIS IN ASIA

Partnerships with kala-azar actors in South Asia including the MoH, research institutes, NGOs, and WHO-TDR

2011
  • Better combination therapies for South Asia to replace treatments with severe side effects and growing drug resistance
  • Recommended by the WHO Expert Committee on the Control of Leishmaniases (2010) as safe and effective treatments for VL in Asia (AmBisome single or multiple dose, and all combinations tested in DNDi’s clinical trial)
  • Policy change supported for the control and elimination of kala-azar in highly endemic countries (India, Bangladesh, Nepal)

PAEDIATRIC BENZNIDAZOLE

CHAGAS DISEASE

Partnership with LAFEPE (Brazil) to develop the first paediatric treatment for Chagas (2011) and with Elea/FMS (early 2018)

2011
  • Child-adapted dose of 12.5 mg per tablet twice daily for 60 days (children were previously treated with fractioned tablets designed for adults)
  • WHO Essential Medicines List (children)
  • Collaboration with Fundación Mundo Sano (FMS) and Laboratorio ELEA PHOENIX, Argentina to develop a second source
  • Registered in Brazil (2011) and in Argentina (2018)

SSG&PM

VISCERAL LEISHMANIASIS IN EAST AFRICA

Partnership with the Leishmaniasis East Africa Platform (LEAP), national control programmes, MSF, and WHO

2010
  • Intramuscular injection once per day for 17 days (instead of 30 days previously)
  • Recommended by the WHO Expert Committee on the Control of Leishmaniases (2010) as safe and effective treatment for VL in East Africa
  • Included in national treatment guidelines of Ethiopia, Kenya, South Sudan, Sudan, and Uganda

NECT

HUMAN AFRICAN TRYPANOSOMIASIS (HAT)

Partnership with MSF, Epicentre, national control programmes, and WHO

2009
  • First new treatment for HAT in over 25 years, replacing complex and toxic melarsoprol treatment that killed 5% of those treated
  • 14 intravenous infusions of eflornithine over 7 days + oral nifurtimox 3 times/day for 10 days
  • WHO Essential Medicines Lists (adults and children)
  • First-line treatment in the 13 endemic countries in sub-Saharan Africa
  • Free supply from WHO via drug donations by Sanofi and Bayer to endemic countries

ASMQ*

MALARIA

Partnership with Farmanguinhos/Fiocruz (Brazil)

2008
  • Once daily fixed-dose artemisinin-based combination for 3 days, in 4 dosage forms
  • WHO prequalified (2012) and WHO Essential Medicines Lists (adults and children)
  • Registered in 11 countries in Asia, Latin America, and Africa
  • South-South technology transfer to Cipla (India)

*Projects handed over to Medicines for Malaria Venture in 2015

ASAQ*

MALARIA

Partnership with Sanofi

2007
  • Once daily fixed-dose artemisinin-based combination for 3 days, in 4 dosage forms
  • WHO prequalified (2008) and WHO Essential Medicines Lists (adults and children)
  • Registered in 32 African countries, plus India, Ecuador, and Colombia
  • 500 million treatments delivered since 2007
  • Technology transfer to Zenufa (Tanzania)

* Projects handed over to Medicines for Malaria Venture in 2015

Drug discovery and translational research

Open approaches and increased efficiency for new chemical entities

DNDi works through collaborations in all phases of drug research and development. In the very earliest stages of drug discovery, from molecule screening through to lead selection and optimization, this collaborative work takes place through key partnerships and drug discovery consortia that DNDi has gradually put in place over the last 15 years. Consortia are working on hit-to-lead and lead optimization activities for visceral leishmaniasis and Chagas disease with partners in the US, Canada, Europe, China, India, Japan, Korea, Australia, and finally Brazil where DNDi’s first early-stage research programme, Lead Optimization Latin America (LOLA), was launched in a neglected disease-endemic country.

NTD Drug Discovery Booster: speeding up drug discovery & cutting costs

  • 2 new partners in 2017 - 8 partners total
  • Millions of compounds screened for leishmaniasis and Chagas disease through a simultaneous search process across the pharmaceutical companies
  • 12 hit series identified, 4 of these investigated for proof of principle
READ MORE

Open Synthesis Network: crowdsourcing compound synthesis

  • 6 new partners in 2017 - 12 partner universities total
  • Master's and undergraduate students synthesizing compounds for leishmaniasis and Chagas disease
  • Partners in Brazil, India, Switzerland, UK, and USA
READ MORE

Unprecedented leishmaniasis portfolio: Towards new-generation treatments

  • New chemical classes with different mechanisms of action against Leishmania parasites
  • 6 compounds in pre-clinical development
  • 2 compounds ready to enter clinical development in 2018
  • 1 new combination for cutaneous leishmaniasis in Proof of concept study
READ MORE
READ MORE

Mycetoma Clinical
Trial Begins

WATCH FILM

2017 clinical activities:
21 trials, 4,000+ participants

Clinical trial data transparency

DNDi recognizes the scientific importance and the ethical imperative of sharing data collected through its clinical trials for health research, and is a signatory to the WHO Joint Statement on Public Disclosure of Results from Clinical Trials.

Reset Map

DISEASES

  • Human African trypanosomiasis
  • Leishmaniasis
  • Chagas disease
  • Filarial disease
  • Mycetoma
  • Paediatric HIV
  • Hepatitis C

PHASES

  • PHASE I
  • PHASE II a/PoC
  • PHASE IIb/III
  • PHASE IV

STORIES

  • HIV: Introducing oral pellets for children living with HIV
  • Sleeping sickness: A study for the Congolese run by the Congolese
  • Hepatitis C: Enabling public health impact

DISEASES

  • Human African trypanosomiasis
  • Leishmaniasis
  • Chagas disease
  • Filarial disease
  • Mycetoma
  • Paediatric HIV
  • Hepatitis C

Click on the diseases to see related sites

Filarial diseases
  • Emodepside single ascending dose for onchocersiasis (UK)
  • Safety, tolerability, and PK of multiple ascending doses of emodepside (UK)
  • Relative bioavailability study of emodepside immediate release tablets and solution (UK)
HAT
  • Acoziborole pivotal study in adults with stage 1 and stage 2 HAT (DR Congo)
Mycetoma
  • Fosravuconazole proof-of-concept for eumycetoma patients (Sudan)
Cutaneous leishmaniasis
  • Thermotherapy & miltefosine combination proof-of-concept (Colombia, Peru)
PKDL
  • Short-course regimens for treatment of PKDL (Sudan)
  • Short-course regimens for treatment of PKDL (India, Bangladesh)
Chagas disease
  • Benznidazole new doses, improved treatment, and therapeutic associations (Bolivia)
  • Fexinidazole proof-of-concept (Spain)
HAT
  • Study of fexinidazole in special population groups, in in- and out-patients (DR Congo)
  • Fexinidazole pivotal study (DR Congo)
  • Fexinidazole study in adults with early-stage 1 + stage 2 HAT (DR Congo)
  • Fexinidazole study in children with both stage 1 + 2 HAT (DR Congo)
Hepatitis C
  • Ravidasvir/sofosbuvir combination therapy (Malaysia, Thailand)
Paediatric HIV
  • Lopinavir/ritonavir pellets with dual NRTIs implementation study in infants and young children (Kenya, Uganda, Tanzania)
Visceral leishmaniasis
  • Miltefosine/paromomycin Phase III trial for treatment of primary visceral leishmaniasis (VL) patients in Eastern Africa (Ethiopia, Kenya, Sudan, Uganda)
PKDL
  • Infectivity study of PKDL patients (Bangladesh)
HIV-VL
  • New treatments for HIV-VL co-infection (MSF study sponsored by DNDi) (India)
  • New treatments for HIV-VL co-infection (MSF study sponsored by DNDi) (Ethiopia)
PKDL
  • Follow-up study of PKDL patients (India)
Clinical trial data transparency

DNDi recognizes the importance of sharing data collected through its clinical trials for health research, and the ethical imperative to contribute to increasing scientific knowledge. As such, in May 2017, DNDi signed on to the WHO Joint Statement on Public Disclosure of Results from Clinical Trials and committed itself to WHO’s standards on clinical trial transparency, including registering all clinical trials in a publicly available register, promptly reporting trial results 12 months after completion of the trial, and publishing findings in open access journals.

HIV: Introducing oral pellets for children living with HIV

Since 2015, DNDi has been running the “LIVING” study in Kenya, Uganda, and Tanzania for an improved “2-in-1” oral pellet formulation, with 819 children enrolled by the end of 2017. Interim results show the 2-in-1 formulation is effective and well-tolerated by children, and highly acceptable to caregivers. By introducing the 2-in-1 oral pellets, which are an interim solution to replace bitter-tasting syrups, DNDi is paving the way for the more rapid introduction of a “4-in-1” fixed dose combination, on track to be delivered in 2019.

Sleeping sickness: A study for the Congolese run by the Congolese

More than 200 people in the Democratic Republic of the Congo (DR Congo) have been actively engaged in DNDi’s five-year clinical development effort for fexinidazole. This unprecedented effort generated data enabling Sanofi to submit a regulatory dossier to the European Medicines Agency. All data were collected by local health staff at nine clinical sites (DR Congo and Central African Republic), with 10 mobile teams from the Congolese National Sleeping Sickness Control Programme screening over 2 million people in remote villages – and more than 660,000 people in 2017 alone. All data (biological, quality assessment, follow-up) were collected and managed by Congolese partners.

Hepatitis C: Enabling public health impact

DNDi conducted the STORM-C-1 open label trial to assess the efficacy, safety, tolerance, and pharmacokinetics of the drug candidate ravidasvir combined with sofosbuvir for the treatment of hepatitis C virus (HCV) in Malaysia. Interim results showed that 12 weeks after completing treatment, 97% of the 301 patients enrolled were cured.

PHASES

  • PHASE I
  • PHASE II a/PoC
  • PHASE IIb/III
  • PHASE IV

STORIES

  • HIV: Introducing oral pellets for children living with HIV
  • Sleeping sickness: A study for the Congolese run by the Congolese
  • Hepatitis C: Enabling public health impact

Challenges of Conducting Clinical Trials in Remote Areas

WATCH FILM

Strengthening capacities

Disease-specific research platforms and networks are central to DNDi’s commitment to strengthen existing research capacity in endemic countries and to support programme sustainability.

As we work with endemic-country partners to conduct clinical trials, central to DNDi’s mission and vision is the idea of strengthening existing clinical research capacities to ensure the sustainability of our work, and increasing endemic countries’ ability to respond to their own research needs.


The disease-specific research platforms and networks created by DNDi and partners form a central part of this objective. To date, platforms or networks have been established for leishmaniasis in both East Africa and Latin America, for Chagas disease, and for human African trypanosomiasis. A filarial clinical research network is also beign set up, and efforts are underway to develop a network of researchers working in paediatric HIV.

MORE

685 PEOPLE TRAINED IN 2017

People trained 1,200 1,000 800 600 400 200 0 2010 95 59 2012 85 131 100 2013 132 106 134 2014 226 235 275 2015 482 99 517 2016 262 270 96 2017 31 120 373 161 2011 62 70 108 +9%

Platforms & Networks

TAP ON PINS TO DISCOVER MORE
Reset Map

Chagas Clinical Research Platform (CCRP)

Founded in 2009 in Uberaba, Brazil

424 members from over 150 institutions

  • 7 clinical trial sites were active: 3 in Bolivia for the Phase II proof-of-concept BENDITA trial (to assess safety and tolerability of benznidazole with reduced doses and treatment duration, and in combination with fosravuconazole) and 4 in Spain for the Phase II proof-of-concept study of fexinidazole to treat Chagas.
  • 161 people trained at 4 workshops/technical meetings in Colombia, Brazil, and the US.
  • Discussions promoted by the Chagas Platform in Brazil are supporting the ongoing changes of the Brazilian national guidelines for the treatment of Chagas disease.

7

CLINICAL SITES*

161

PEOPLE TRAINED

*Sites belonging to platform/network members and used for DNDi studies

Over 150 institutions including: Pan American Health Organization (PAHO); Department of Neglected Tropical Diseases, WHO; Ministries of Health and National Control Programmes of high-burden endemic countries (Argentina, Bolivia, Brazil, Mexico, Paraguay, Honduras); MSF; International Federation of People Affected by Chagas Disease and patient associations. ARGENTINA: Hospital de Niños Ricardo Gutiérrez; Instituto Nacional de Parasitología Dr M. Fatala Chabén; Hospital de Niños de Jujuy; Hospital Público Materno Infantil – Salta; Centro de Chagas y Patologia Regional, Santiago del Estero; Consejo Nacional de Investigaciones Científi cas y Técnicas; Fundación Mundo Sano, ELEA. BRAZIL: Instituto Oswaldo Cruz; Instituto de Pesquisa Evandro Chagas–Fiocruz; Centro de Pesquisas René Rachou–Fiocruz; LAFEPE. BOLIVIA: Universidad Mayor de San Simón; Platform of Integral Care for Patients with Chagas Disease; Collective of Applied Studies and Social Development. COLOMBIA: Centro de Investigaciones en Microbiología y Parasitología Tropical, Universidad de los Andes; Centro Internacional de Entrenamiento e Investigaciones Médicas; Programa de Estudio y Control de Enfermedades Tropicales, Universidad de Antioquia (PECET); Red Chagas Colombia. FRANCE: Institut de Recherche pour le Développement. GERMANY: Bayer HealthCare. JAPAN: Eisai Co., Ltd. MEXICO: Instituto Carlos Slim de la Salud; Instituto Nacional de Salud Pública. SPAIN: ISGlobal and Barcelona Centre for International Health Research; Hospital Clinic Barcelona; Instituto de Parasitología y Biomedicina López Neyra; Consejo Superior de Investigaciones Científicas; Instituto Catalán de la Salud. SWITZERLAND: DNDi; Geneva University Hospitals. UK: The Global Health Network. USA: Merck; Sabin Vaccine Institute.

RedeLEISH

Founded in 2014 in Rio de Janeiro, Brazil

139 members, from 62 institutions

  • Launch of a manifesto, signed by 143 investigators and civil society representatives, for mucocutaneous leishmaniasis to raise the awareness of the scientific community and policy makers of the urgent need for more research for this very neglected form of leishmaniasis.
  • Co-organization of the ‘Brazilian Patients Forum against Infectious and Neglected Diseases’ during the 53rd Brazilian Congress of Tropical Medicine (MedTrop).
  • In coordination with TDR/WHO, supported efforts on the harmonization of criteria for clinical trials in cutaneous leishmaniasis and conducted a systematic review to assess therapeutic response and relapse rates.

BOLIVIA: Fundación Nacional de Dermatología (FUNDERMA), Universidad Mayor de San Simon. BRAZIL: Plataforma de Pesquisa Clínica – FIOCRUZ RJ, Centro de Pesquisa Gonçalo Moniz-FIOCRUZ BA; Universidade Federal da Bahia (UFBA); Universidade Federal do Piauí (UFPI); Centro de Pesquisa René Rachou-FIOCRUZ BH; Instituto Nacional de Infectologia – FIOCRUZ RJ; Fundação de Medicina Tropical Heitor Vieira Dourado; Ministério da Saúde ; Instituto Evandro Chagas; Universidade do Estado do Pará (UEPA); Instituto Nacional de Pesquisa da Amazônia (INPA); Secretaria Municipal de Saúde Unidade Referência em Atenção Primária Dra Claudia Vitorino; Universidade de Brasília – Núcleo de Medicina Tropical (UnB); Universidade Federal de Mato Grosso/Hospital Universitário Júlio Müller; Universidade de São Paulo (USP); Universidade Federal do Pará (UFPA); Universidade do Rio de Janeiro (UFRJ); Universidade Federal do Ceará (UFC), Universidade de Pernambuco (UFPE), Laboratório do Estado de Pernambuco (LAFEPE), Universidade Federal de Santa Catarina (UFSC). COLOMBIA: Centro Dermatológico Federico Lleras Acosta; Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM); Instituto Colombiano de Medicina Tropical; Instituto Nacional de Salud (INS); Programa de Estudios y Control de Enfermedades Tropicales (PECET), Ministerio de la Salud. GUATEMALA: Universidad del Valle. MEXICO: Universidad Nacional Autónoma de México. PANAMA: Instituto Conmemorativo Gorgas de Estudios de la Salud. PERU: Department of Parasitology, Public Health Training Program - U.S. Naval Medical Research Unit No. 6; Universidad Peruana Cayetano Heredia. SWITZERLAND: DNDi; FIND. VENEZUELA: Instituto Medico la Floresta. WHO. PAHO.

HAT Platform

Founded in 2005 in Kinshasa, DR Congo

120 members from over 20 institutions

  • 11 clinical trial sites were active and 2 in rehabilitation to conduct the Phase II/III study of acoziborole and the Phase IIIb study of fexinidazole. 10 mobile teams supported the screening of patients.
  • Training activities increased, with 373 people trained (vs 262 in 2016) to address all aspects of ongoing clinical activities, including: training of investigators, nurses, and lab technicians; waste management; and training on diagnostic tools.
  • Prepare for policy change and the development of national sleeping sickness treatment guidelines with fexinidazole in DR Congo.

11

CLINICAL SITES*

373

PEOPLE TRAINED

*Sites belonging to platform/network members and used for DNDi studies

National sleeping sickness control programmes, research institutions, and national laboratories of public health of the most affected endemic countries: Angola, Central African Republic, Chad, Democratic Republic of Congo, Guinea, Republic of Congo, South Sudan, Sudan, Uganda; Centre interdisciplinaire de Bioéthique pour l’Afrique Francophone (CIBAF); Drugs for Neglected Diseases initiative (DNDi), Switzerland; Eastern Africa Network for Trypanosomosis (EANETT); Foundation for Innovative New Diagnostics (FIND), Switzerland; Institut de Recherche pour le Développement (IRD), France; Institut National de Recherche Biomédicale (INRB), DR Congo; Institut Pasteur Bangui, CAR; Institute of Tropical Medicine-Antwerp, Belgium; INZI Project, University of Edinburgh, UK; Juba University, South Sudan; Kenya Agricultural Research Institute – Trypanosomiasis Research Centre (KARI-TRC), Kenya; Médecins Sans Frontières (MSF); Swiss Tropical and Public Health Institute (Swiss TPH), Switzerland; Tropical Medicine Research Institute (TMRI), Sudan; University of Makerere, Uganda; WHO Department of Neglected Tropical Diseases, as observer.

Leishmaniasis East Africa Platform (LEAP)

Founded in 2014 in Rio de Janeiro, Brazil

139 members, from 62 institutions

  • 5 clinical trial sites were active and 1 under construction in Ethiopia, Kenya, Uganda, and Sudan.
  • Outside of the clinical trials, 1,084 people were treated and 2,898 were screened.
  • 120 people were trained, including investigators, lab technicians, nurses, and pharmacists on Good Clinical Practice and protocols. Others received training on how to better communicate on their projects. Financial support for seven long-term trainings (Master’s degrees or diplomas) was also provided.
  • Following the dissemination of the HIV/VL study results, support for the development of a new policy by WHO.

5

CLINICAL SITES*

120

PEOPLE TRAINED

*Sites belonging to platform/network members and used for DNDi studies

Center for Clinical Research, Kenya Medical Research Institute, Kenya; Ministry of Health, Kenya; Institute of Endemic Diseases, University of Khartoum, Sudan; Federal Ministry of Health, Sudan; Addis Ababa University, Ethiopia; Gondar University, Ethiopia; Federal Bureau of Health, Ethiopia; Makerere University, Uganda; Ministry of Health, Uganda; MSF; London School of Hygiene & Tropical Medicine, UK; WHO; DNDi, Switzerland; FIND, Switzerland.

Access - Transitioning from registration to implementation

Ending the Neglect of Chagas in Colombia

SEE STORY

Hepatitis C: A public health approach for access

Despite availability of effective and safe treatment options for hepatitis C virus (HCV), access to treatment is out of reach for millions due to high prices. DNDi has partnered with a range of stakeholders who share the common goal of increasing access to affordable HCV treatment, including: Pharco (Egypt) in the development of ravidasvir; the Malaysian Ministry of Health, which is taking a public health approach to treating HCV; and industrial partners Pharmaniaga (Malaysia) and Insud/Elea (Argentina), to secure a much more affordable price of USD 300-500 per treatment course.
Results suggest that the ravidasvir/sofosbuvir combination is comparable to the best treatments available today, with a radical difference: price. But to use this drug combination, countries would also need access to affordable sofosbuvir. In September 2017, Malaysia issued a “government use” licence to source generic sofosbuvir, a move which has allowed it to accelerate access to affordable HCV treatment in its public hospitals.


Fexinidazole: Using the regulatory process to pave the way for access

In December 2017, a few months after the conclusion of large-scale DNDi clinical trials, our industrial partner Sanofi submitted the registration dossier for fexinidazole as the first all-oral treatment for sleeping sickness. In a promising move for access, a submission was made to the European Medicines Agency under what is known as Article 58.

If fexinidazole is registered in late 2018, regulatory approval will only be the first step. Translation into national policy and treatment guidelines will be needed as well as community awareness efforts and treatment knowledge for health providers.

HIV: Preparing for the 4-in-1 by encouraging uptake of the 2-in-1

DNDi is working with Indian manufacturer Cipla to develop a “4-in-1”, a solid first-line fixed-dose combination combining four antiretrovirals (abacavir, lamivudine, lopinavir, and ritonavir), as granules contained in a capsule. Caregivers will be able to open the capsules and give the granules to children with soft food, breast milk, or milk and water. These granules will not require refrigeration, and they will be taste-masked and easy to dose across various weight bands. Submission for US FDA registration will be pursued in late 2018.

Policy, fundraising & communications

 

6

NATIONAL TREATMENT POLICIES

or guidelines revised to reflect the use of DNDi-delivered treatment, and 4 policy changes in progress

EUR

83.4

MILLION

Multi-year funds secured for DNDi and GARDP in 2017

22

PEER-REVIEWED SCIENTIFIC PUBLICATIONS

on DNDi’s research, of which 87% were open access publications

Policy

WHO Director General Dr Tedros has declared universal health coverage (UHC) to be the priority for his mandate. This has important implications for NTDs, which are diseases of poverty affecting most countries. Delivering quality UHC depends on the availability of and access to safe, effective, and affordable medicines, underscoring the continued need for R&D for NTDs as a key component of the UHC agenda. NTD programmes provide entry points to some of the world’s hardest-to-reach communities, and many policymakers have identified the ability to address NTDs as a “litmus test” for UHC.

The Berlin Declaration that followed the first-ever G20 Health Ministers meeting in May 2017 cautioned that success in the fight against AMR cannot be achieved with current treatments. It recognized the importance of ‘reactivating the R&D pipeline through incentive mechanisms that avoid the reliance on high price/volume combinations’ to ensure sustainable access. It called for ‘broadening the voluntary financial support’ for initiatives, including GARDP, which ‘reinvigorate R&D in science and industry for antimicrobials’.

2017 was marked by the Malaysian government’s decision to reaffirm its strong commitment to providing access to treatments for hepatitis C by issuing a “government use” licence enabling access to more affordable versions of sofosbuvir, an expensive and patented treatment for hepatitis C. This is a landmark decision for the more than 400,000 people living with hepatitis C in Malaysia.

Fundraising

Funds raised in 2017 for the neglected disease portfolio include increased support for the sleeping sickness programme from the Bill & Melinda Gates Foundation, as well as from private donors primarily from the US, through the HAT campaign launched last year, but also in Europe. Other noteworthy contributions include the first grant from the GHIT Fund secured for mycetoma, and from the European and Developing Countries Clinical Trials Partnership for a visceral leishmaniasis clinical trial in four African countries. In addition, the first grant entirely dedicated to DNDi’s HCV programme was received from the Médecins Sans Frontières/Doctors Without Borders (MSF) Transformational Investment Capacity.

In May, the G20 Health Ministers cautioned that success in the fight against antimicrobial resistance (AMR) cannot be achieved with the current treatments. The Declaration welcomed and sought to build on initiatives such as GARDP, to ‘reinvigorate research and development in science and industry for antimicrobials.’ The German Federal Ministry of Health and Ministry of Education and Research then hosted a pledging conference for GARDP in September 2017. A total of EUR 56 M was pledged by Germany, Luxembourg, Monaco, the Netherlands, South Africa, Switzerland, the United Kingdom, and the Wellcome Trust for the development of new and improved treatments to fight antibiotic resistance and contribute to ensuring healthy lives and well-being for all. Of this total, EUR 5.5 M was received in 2017.

Since 2003, DNDi’s cumulative income reached EUR 491 M, against a target of EUR 650 M by 2023. By the end of 2017, GARDP had EUR 64 M in commitments and pledges, almost 25% of the EUR 270 M total funding required to deliver GARDP’s objectives by 2023.

More on DNDi donors

Communications

In 2017, DNDi joined forces with the WHO Collaborating Centre for Leishmaniasis at the Instituto de Salud Carlos III, Madrid, to co-organize the 6th World Congress on leishmaniasis. The event attracted 1,500 scientific experts, health decision-makers, WHO, government representatives of endemic countries, and all major organizations involved in the fight against leishmaniasis. Among the outputs from the conference were a PLOS special collection dedicated to leishmaniasis; the ‘100 students’ initiative programme allowing students and young scientists from esourcelimited settings to attend, and supporting professional development of a new generation of scientists; and the launch of a manifesto to raise awareness of the urgent need for more research on mucocutaneous leishmaniasis, a very neglected form of leishmaniasis.

In 2017, DNDi staff members authored or co-authored 22 peer-reviewed publications. Of these, nine had a lead author or co-author from an endemic country, and 18 were published in an open access journal, in keeping with DNDi's commitment to open access.

Here is the full list of DNDi 2017 scientific publications Here is the list of GARDP 2017 publications

In recognition of its innovative and collaborative model, DNDi was awarded the Innovation Prize 2017 by the Geneva Chamber of Commerce, Industry and Services, the Department of Security and Economy, and the Office for the Promotion of Industries and Technologies.

Read more in the full report

A word of thanks

DNDi would like to thank all its donors worldwide for their loyal commitment and collaboration since 2003. To date, DNDi has delivered seven new treatments and aims to bring 16-18 treatments to patients living with neglected diseases by 2023. DNDi is grateful for the support received from all donors who contributed toward the advancement of its mission and goals. Listed are supporters who have given a cumulative contribution of more than USD or EUR 10,000, as well as collaborative funding partners.

READ MORE

Photo credits: Benoit Marquet-DNDi; Kishore Pandit-DNDi; Felipe Abondano-DNDi; Neil Brandvold-DNDi; Bobby Tan-DNDi; Scholars and Gentlemen/DNDi.

HUMAN AFRICAN TRYPANOSOMIASIS / SLEEPING SICKNESS

Key R&D achievements in 2017
A regulatory dossier is submitted by Sanofi to the European Medicines Agency for fexinidazole as the first all-oral treatment for sleeping sickness, following results from the Phase II/III study which proved “fexi” to be safe and effective. The introduction of fexinidazole would be revolutionary as it would end the need for invasive lumbar punctures to stage patients and for systematic hospitalization.

DNDi aims to deliver:

  • Safe, effective, and orally administered drugs to replace current first-line HAT treatments, and to simplify current case management
  • The goal is to develop two drugs effective for both stage-1 and 2, and both subspecies of the parasite
MORE ON THE DISEASE

LEISHMANIASIS

Key R&D achievements in 2017
DNDi and partners build up an unprecedented portfolio of 10 chemical classes, including four lead series, four pre-clinical candidates, and two clinical candidates to progress to Phase I, with the ultimate aim of developing two entirely new treatment combinations for both visceral and cutaneous leishmaniasis, in all regions. Meanwhile, studies begin in South Asia, Latin America, and East Africa to test new regimens for post-kala-azar dermal leishmaniasis, cutaneous leishmaniasis, and visceral leishmaniasis. And the results of a trial showing the efficacy of a potential new firstline regimen for HIV/VL co-infection are presented in Ethiopia.

DNDi aims to deliver:

  • An oral, safe, effective, low-cost, and short-course treatment for VL
  • A new treatment for PKDL that is shorter and better tolerated than current options
  • A new treatment regimen for people co-infected with HIV and VL
  • A safe, effective, and shorter treatment for CL
MORE ON THE DISEASE

CHAGAS DISEASE

Key R&D achievements in 2017
Insud’s benznidazole is registered in the US, supported by DNDi. This is the first drug approved by the FDA to treat Chagas disease. Insud is granted a priority review voucher – 50% of revenue derived from its sale will support access to Chagas treatment, notably through the new Chagas Disease Regional Access Framework developed by DNDi and Fundación Mundo Sano. The search for better treatment options goes on, with recruitment completed in the Phase II study of new regimens of benznidazole, and benznidazole in combination with fosravuconazole in Bolivia, and a study launching in Spain to evaluate short-course fexinidazole regimens.

DNDi aims to deliver:

  • Alternative regimens of existing drugs (lower doses, shorter treatment duration, and combinations):
    • A new benznidazole monotherapy
    • A new benznidazole and fosravuconazole combination therapy
    • A new fexinidazole monotherapy
  • A safe and effective new drug treatment for chronic Chagas patients, ideally also effective for acute Chagas patients, including children, and safe to use during pregnancy
  • An early test of cure and/or markers of therapeutic response
MORE ON THE DISEASE

FILARIAL DISEASES

Key R&D achievements in 2017
DNDi continues to build a diverse portfolio of potential macrofilaricides (drugs that kill adult filarial worms) in order to provide a needed cure for patients. Phase I studies in healthy volunteers begin for both Bayer’s emodepside, which targets adult worms, and AbbVie’s antibiotic TylAMac, which targets the endosymbiotic bacteria (Wolbachia) that live in some filarial worms and are essential for the worms’ survival.

DNDi aims to deliver:

  • A new oral, short-course macrofilaricide treatment, with potential application to treat both onchocerciasis and lymphatic filariasis, and allow for treatment in regions co-endemic for Loa loa
MORE ON THE DISEASE

MYCETOMA

Key R&D achievements in 2017
Patients are enrolled in Sudan in the first- ever double-blind, randomized clinical trial for eumycetoma (the fungal version of mycetoma), assessing fosravuconazole as a potential new treatment for this extremely neglected and disfiguring disease.

DNDi aims to deliver:

  • A new, safe, effective, and affordable treatment for patients with eumycetoma
MORE ON THE DISEASE

PAEDIATRIC HIV

Key R&D achievements in 2017
A first-line “4-in-1” fixed-dose combination of abacavir, lamivudine, lopinavir, and ritonavir granules is on track to be submitted for US FDA registration in late 2018 to radically improve treatment options for young children living with HIV. In the meantime, results from the LIVING study show that “2-in-1” lopinavir/ritonavir pellets improve treatment outcomes for children, and are well adopted by caregivers.

DNDi aims to deliver:

  • Develop an improved, first-line, child-friendly “4- in-1” therapy for infants and young children – a lopinavir/ritonavir-based, fixed-dose formulation in combination with two nucleoside reverse transcriptase inhibitors
  • Introduce lopinavir/ritonavir pellets until better- adapted 4-in-1 products are available
MORE ON THE DISEASE

HEPATITIS C

Key R&D achievements in 2017
Treatment is completed by all 301 patients in a Phase II/III trial combining ravidasvir and sofosbuvir in Malaysia and Thailand, with 97% cured overall and high cure rates for the hardest-to-treat (cirrhotic) patients. This means the combination is equivalent to the best therapies in use today, raising hope for alternative affordable options for countries unable to access generic treatments.

DNDi aims to deliver:

  • A safe, effective, and easy-to-use direct-acting antiviral regimen in an affordable combination, paving the way for a public health approach to HCV treatment
MORE ON THE DISEASE
/

HUMAN AFRICAN TRYPANOSOMIASIS / SLEEPING SICKNESS

RESEARCH
SCYX-1330682 & SCYX-1608210

OBJECTIVE: Maintain back-up candidate oxaboroles to replace the drug candidate acoziborole, if needed.
To ensure future development options if needed, DNDi continues to provide support and advice to researchers working on the discovery of new candidates for HAT, and maintains two back-up candidates from the oxaborole class, both having demonstrated cure for stage-2 of the disease in a murine model.

DEVELOPMENT
Acoziborole (SCYX-7158)

OBJECTIVE: Develop and register acoziborole as a new, single-dose, oral treatment for the treatment of stage-2 HAT caused by T.b. gambiense (g-HAT), that is also safe and effective for stage-1 HAT
Following its identification as a hit compound in the Anacor chemical library, acoziborole became DNDi’s first new chemical entity resulting from its own lead optimization programme to enter clinical development. A Phase I study was completed in 2015 and determined the therapeutic dose at 960 mg, to be administered as a single dose of three tablets, with a favourable safety profile. A pivotal Phase II/III trial started in the last quarter of 2016 in seven clinical sites in the Democratic Republic of Congo (DR Congo).
In 2017, recruitment continued in the DR Congo with the inclusion of 76 patients (out of a target of 210) at eight clinical sites, including new sites in Bandundu and Kinshasa (Roi Baudouin Hospital), in addition to Katanda, Isangi, Dipumba, N’gandajika, Masi Manimba, and Kwamouth. One site (Bolobo) was closed in December 2017. Three more sites will open in 2018, including one in Guinea. The submission of a regulatory dossier to the European Medicines Agency under Article 58 is planned for 2021.


Fexinidazole: On the regulatory pathway with the European Medicines Agency

OBJECTIVE: Develop and register fexinidazole as a new all- oral treatment for the treatment of stage-1 and stage-2 HAT caused by T.b. gambiense (g-HAT) in adults and children
In the 1970s, Hoechst (now part of Sanofi) initiated but did not pursue the pre-clinical development of fexinidazole, an anti-parasitic drug. In 2005, the compound was identified by DNDi as showing activity against the parasite that causes sleeping sickness. Pre-clinical studies began in 2007. In 2009, DNDi and Sanofi concluded a collaboration agreement for the development, manufacturing, and distribution of fexinidazole, with DNDi responsible for pre-clinical, clinical, and pharmaceutical development, and Sanofi responsible for the industrial development, registration, production, and distribution of the drug. Phase I studies began in 2010, and a Phase II/III pivotal clinical study started in 2012, led by the National HAT Control Programme (PNLTHA) of the Democratic Republic of Congo (DR Congo) and supervised by DNDi.
Between 2012 and 2016, the open label randomized pivotal Phase II/III clinical trial compared the efficacy and safety of fexinidazole – a 10-day all-oral treatment – with today’s first- line treatment, nifurtimox-eflornithine combination therapy (NECT) – 14 intravenous infusions of eflornithine over seven days together with three times a day oral nifurtimox for ten days and requiring hospitalization – in meningo-encephalitic (stage-2) g-HAT patients. 394 patients were recruited across 10 sites in the DR Congo and Central African Republic.
Results confirmed a treatment success rate of 91.2% for fexinidazole, versus 97.6% for NECT, 18 months after the end of treatment. The results show that fexinidazole is effective within a predetermined acceptability margin, set following a survey with practitioners, based on the significant advantages of having a first-line treatment that is oral. There were no major differences in safety. The results were published in The Lancet1 and presented at the European Congress on Tropical Medicine and International Health in October 2017.
Two additional complementary cohorts with fexinidazole were completed in 2016, one including 230 adult patients with stage-1 and early stage-2 disease, and another including 125 children between six and 14 years, both at sites in the DR Congo. Follow-up of these patients was completed in 2017, with results to be published in 2018.
In January 2018, DNDi’s industrial partner Sanofi submitted a regulatory dossier to the European Medicines Agency (EMA) under Article 58 for the treatment of T.b. gambiense HAT (stages-1 and 2) in adults and children above the age of six and above 20kg. By involving the WHO and regulators from the DR Congo and Uganda in the EMA process, the use of Article 58 will enable faster in-country implementation of fexinidazole.
A further Phase IIIb trial to obtain more information about special populations not included in previous fexinidazole studies (including pregnant and lactating women, and patients with poor nutritional status or chronic diseases) started in 2016 and is ongoing at seven sites in the DR Congo, of which two were newly opened in 2017. Patients are treated either in hospital or at home, based on pre-determined clinical and social criteria, thereby also providing preliminary information about treatment compliance and final effectiveness in ambulatory patients. Three additional sites will be opened in 2018, including one in Guinea.

1Mesu, Victor Kande Betu Ku et al. Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. The Lancet, Volume 391, Issue 10116, 144-154. November 2017.

Main R&D Partners

Advinus Therapeutics Ltd, India; Aesica, UK; Amatsi Aquitaine (formerly Bertin Pharma), France; Aptuit, Italy; Avista Pharma (formerly SCYNEXIS), USA; Biotrial, France; Cardiabase, France; CBCO, DR Congo; Creapharm, France; Eurofins-Optimed, France; HAT Platform; Institut de Recherche pour le Développement, France; Institut National de Recherche Biomédicale, DR Congo; Institute of Tropical Medicine Antwerp, Belgium; Laboratory of Microbiology, Parasitology, and Hygiene, University of Antwerp, Belgium; Luxembourg Institute of Health, Luxembourg; Médecins Sans Frontières; National Control Programmes of the Democratic Republic of Congo, the Central African Republic, and of Guinea; Pace University, USA; Patheon, UK; Pfizer Inc., USA; Pfizer Inc. (formerly Anacor Pharmaceuticals Inc.), USA; PhinC, France; RCTs, France; Sanofi, France; SGS, Belgium; SGS, France; Swiss Tropical and Public Health Institute, Switzerland; Theradis Pharma, France; WHO-NTD (Neglected Tropical Diseases department).

READ MORE ON THE DNDi WEBSITE
/

CHAGAS DISEASE

RESEARCH
Screening

OBJECTIVE: Use high throughput screening to identify novel hit series for Chagas disease from synthetic compound collections accessed from partners or acquired from commercial suppliers, and expand screening activities to natural products that are a promising source of novel active series
More than 20 novel series were identified in 2017 and are currently being progressed.


Chagas H2L

OBJECTIVE: Identify new lead series from ongoing hit-to- lead activities by taking advantage of optimization consortia and screening platforms for Chagas disease
A new discovery cascade was implemented in 2017, comprising new in vitro and in vivo models. If promising activity is demonstrated, the identified series will then be advanced to full lead optimization programmes.


Booster H2L

OBJECTIVE: Speed up the process and cut the cost of finding new treatments for Chagas disease by bringing together pharmaceutical companies in a multilateral, simultaneous, and non-competitive search process
The Drug Discovery Booster was launched in 2015 to circumvent early-stage commercial barriers between pharmaceutical participants, allowing DNDi to search millions of unique compounds simultaneously in the hunt for new treatment leads.
In 2017, two new companies - AbbVie and Merck - joined the Drug Discovery Booster, which included already Takeda, Eisai, Shionogi, AstraZeneca, and Celgene, bringing the total to seven participants.
To date, 32 iterations of the booster have been launched around 16 distinct seed compounds. Ten hit series have been identified, four of which will enter into proof-of-concept in vivo efficacy studies by Q1 2018.


Daiichi-Sankyo LH2L/CH2L

OBJECTIVE: Identify at least one – possibly two – progressable lead series meeting DNDi lead stage criteria for visceral leishmaniasis and/or Chagas disease
Three T. cruzi active series with marginal activity against Leishmania were identified from a high-throughput screening of 40,000 members of the Daiichi Sankyo Pharma Space Library. Current medicinal chemistry efforts of this hit-to-lead collaboration focus on one series that was confirmed as the most promising chemotype in terms of activity and selectivity profile. To date, over 100 analogs to this series have been synthesized and tested for T. cruzi and Leishmania activities at Institut Pasteur Korea, leading to the identification of four preferred molecules nominated to proceed with pharmacokinetics studies. This project was initiated in April 2017 for a duration of 18 months.


TRANSLATION
Chagas C205 series

OBJECTIVE: Optimize leads issued from the hit-to-lead 205 series, and identify pre-clinical candidates with the potential to fulfill the target product profile for Chagas disease
Following curative activity in vivo observed for several lead compounds of the 205 series, work in 2017 concentrated on better understanding the necessary parameters for obtaining cure in animals, in particular by testing different regimens and doses while exploring further optimization. Further characterization of this series is ongoing, and compounds are being profiled for candidate nomination. More than 400 compounds have been synthesized by this programme to date


Biomarkers

OBJECTIVE: Identify and evaluate new biological markers of therapeutic efficacy in chronic Chagas disease
The only measurable treatment outcome currently available is the disappearance of anti-Chagas antibodies. In adults, this can take several decades. Pre-clinical studies started in 2016 and were ongoing in 2017 to identify and validate potential biological markers of therapeutic response in Chagas patients. In addition, through the Ibero-American network NHEPACHA, DNDi is fostering work on testing four biomarkers to assess the response to Chagas treatment.


New benznidazole regimens

OBJECTIVE: Evaluate new therapeutic regimens of benznidazole – the standard treatment for Chagas disease – as monotherapy or in combination with fosravuconazole – for the treatment of adult patients with chronic Chagas disease
Benznidazole, the standard treatment for Chagas, has sustained efficacy until 12 months post-therapy, but it is associated with side effects that can result in treatment discontinuation. The proof-of-concept “BENDITA” study was developed based on results from two previous clinical trials conducted by DNDi. A proof-of-concept trial carried out in 2013 showed that fosravuconazole (previously known as E1224), an azole-class antifungal drug discovered by the Japanese pharmaceutical company Eisai, was safe and effective at clearing the parasite, but its efficacy was not sustained. A Phase I drug-drug interaction study, undertaken in 2014 in 28 healthy human volunteers in Buenos Aires, Argentina, assessed the safety and pharmacokinetic interactions of fosravuconazole and benznidazole administered separately and in combination
The “BENDITA” study aims to improve safety, tolerability, and compliance whilst maintaining or increasing efficacy compared to current regimens for chronic indeterminate Chagas disease patients. The trial used different doses, dosing frequency, and treatment duration of benznidazole as monotherapy or in combination with fosravuconazole. The trial has been conducted in three sites in Bolivia, with recruitment completed in July 2017. The primary efficacy parameter is sustained parasitological response at six months. The final assessment will include 12 months of follow-up, with final results available in early 2019.


Fexinidazole

OBJECTIVE: Evaluate efficacy and safety of short-course and low-dose regimens of fexinidazole in adults with chronic Chagas disease
A Phase II proof-of-concept study of fexinidazole initiated in 2014 in Bolivia was interrupted due to safety and tolerability issues. Analyses of key outcomes demonstrated high efficacy findings at the lowest dose tested for all treatment durations, with safety concerns about treatment at high doses tested for more than 14 days. Acceptable safety and tolerability were found at low doses and short treatment durations.
From this conclusion, a new Phase II proof-of-concept study using shorter and lower-dose treatment regimens started in October 2017 at four sites in Spain (three in Barcelona, one in Valencia) with a fifth site to be opened in Madrid. The target conclusion date is mid-2019. This is the first time DNDi conducts a clinical trial for Chagas disease outside Bolivia and Latin America.


Main R&D Partners

AbbVie, USA; Astellas Pharma Inc., Japan; AstraZeneca, Sweden and UK; Barcelona Centre for International Health Research (CRESIB), Spain; Barcelona Centre for International Health Research, Spain; Barcelona Institute for Global Health (ISGlobal), Spain; Bayer, Germany; Bioascent, UK; Bioaster, France; Brazilian Biosciences National Laboratory, Brazil; Bristol-Myers Squibb, USA; Broad Institute of M.I.T and Harvard, USA; Celgene Corporation, USA; Centre for Drug Candidate Optimisation, Monash University, Australia; Centro de Chagas y Patologia Regional, Hospital Independencia, Argentina; Centro National de Pesquisa em Energia e Materiais, LN Bio, Brazil; Collective of Applied Studies and Social Development, Bolivia; Daiichi Sankyo Company, Limited, Japan; Daiichi Sankyo RD Novare Co., Ltd., Japan; Dr Mario Fatala Chaben National Institute of Parasitology, Argentina; Drug Discovery Unit, University of Dundee, UK; EI du Pont de Nemours, USA; Eisai Co., Ltd., Japan; Epichem, Australia; Eurofins, France; FP Clinical Pharma – Ethel Feleder, Argentina; GlaxoSmithKline, Spain and UK; Griffith Institute for Drug Discovery (GRIDD), Griffith University, Australia; Hospital Clínic de Barcelona, Spain; Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; Hospital General de l’Hospitalet Consorci Sanitari Integral, Barcelona, Spain; Infectious Diseases Data Observatory, University of Oxford, UK; Institut Pasteur Korea, South Korea; Institute of Microbial Chemistry, Japan; Instituto de Física, Universidade de São Paulo, Brazil; Instituto de Química, Universidade Estadual de Campinas, Brazil; Instituto Nacional de Parasitologia Dr Fatala Cháben, Argentina; Johnson & Johnson, USA; Kitasato Institute for Life Sciences, Japan; Laboratorio ELEA PHOENIX, Argentina; Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Belgium; LAT Research, Argentina; London School of Hygiene & Tropical Medicine, UK; Luxembourg Institute of Health, Luxembourg; McGill University, Canada; Médecins Sans Frontières; Medicines for Malaria Venture, Switzerland; Merck KGaA, Germany; Merck, USA; Mundo Sano Foundation, Argentina; National Council of Scientific and Technological Research (INGEBI-CONICET), Argentina; NHEPACHA network; Northwick Park Institute for Medical Research, UK; Novartis, Switzerland and USA; Nucleus of Pharmaceutical and Cosmetics Development, Brazil; Pfizer Inc., USA; Pfizer Inc. (formerly Anacor Pharmaceuticals Inc.), USA; PhinC, France; Platform of Integral Care for Patients with Chagas Disease, Spain/Bolivia; Sandexis, UK; Sanofi Merial, USA; Sanofi, France; Sequella Inc, USA; Shionogi & Co., Ltd., Japan; Swiss Tropical and Public Health Institute, Switzerland; Takeda Pharmaceutical Company Limited, Japan; TB Alliance, USA; TCG Life Sciences, India; Texas Biomedical Research, USA; Unidad de Enfermedades Infecciosas, Seccion de Salud Internacional y Consejo al Viajero, Valencia, Spain; Universidad Autónoma Juan Misael Saracho, Bolivia; Universidad Mayor de San Simon, Bolivia; Universidad San Martin, Argentina; University Hospitals of Geneva, Switzerland; University of Cape Town, South Africa; University of Georgia Research Foundation, USA; University of Texas at El Paso, USA; Vall d’Hebron University Hospital, Spain; Walter Reed Army Institute of Research, USA; WHO-TDR (Special Programme for Research and Training in Tropical Diseases); WuXi AppTech, China; Zoetis (formerly Pfizer Animal Health), USA

READ MORE ON THE DNDi WEBSITE
/

LEISHMANIASIS

RESEARCH
Screening

OBJECTIVE: Use high throughput screening to identify novel hit series for leishmaniasis from synthetic compound collections accessed from partners or acquired from commercial suppliers, and expand screening activities to natural products that are a promising source of novel active series
More than 20 novel series were identified in 2017 and are now being progressed.


Leish H2L

OBJECTIVE: Identify new lead series from current ongoing hit-to-lead activities by taking advantage of the optimization consortia and screening platforms for leishmaniasis
The process of hit-to-lead optimization is ongoing with multiple series from several pharmaceutical companies and with hits from libraries purchased from commercial vendors and screened by DNDi to be advanced if promising activity can be shown in pre-clinical models.


Booster H2L

OBJECTIVE: Speed up the process and cut the cost of finding new treatments for leishmaniasis by bringing together pharmaceutical companies in a multilateral, simultaneous, and non-competitive search process
The Drug Discovery Booster was launched in 2015 to circumvent early-stage commercial barriers between pharmaceutical participants, allowing DNDi to search millions of unique compounds simultaneously in the hunt for new treatment leads.
In 2017, two new companies - AbbVie and Merck - signed on to the Drug Discovery Booster, joining Takeda, Eisai, Shionogi, AstraZeneca, and Celgene.
To date, 32 iterations of the booster have been launched around 16 distinct seed compounds. Ten hit series have been identified, four of which will enter into proof-of-concept in vivo efficacy studies by Q1 2018.


Daiichi-Sankyo LH2L (leishmaniasis hit-to-lead)

OBJECTIVE: Identify at least one – possibly two – progressable lead series meeting DNDi lead stage criteria for visceral leishmaniasis
Current hit-to-lead efforts of the series identified from the Daiichi Sankyo Pharma Space Library focus on Chagas disease (see p. 52), but the project team submits any newly synthesized molecules to a Leishmania cross screen to assess potential.


DNDI-5421 & DNDI-5610

OBJECTIVE: Maintain back-up candidate oxaboroles that could replace the drug candidate DNDI-6148, if needed
These two compounds from the oxaborole class serve as back-ups to DNDI-6148. Their further development is currently on hold and will only recommence should problems be encountered with the development of DNDI-6148.


Aminopyrazoles

OBJECTIVE: Select a pre-clinical candidate from the aminopyrazole series for the treatment of leishmaniasis
DNDI-5561 was nominated as a new pre-clinical candidate from the aminopyrazole series in October 2017. Four back-up compounds are well advanced and offer similar profiles to DNDI-5561. Additional studies, including preliminary toxicology assessments, are being planned to further understand the safety profiles of these compounds and to identify the best back-up to DNDI-5561. DNDi developed this aminopyrazole series from a high- throughput screening hit from a Pfizer compound library.


CGH VL series 1

OBJECTIVE: Select a pre-clinical candidate from the Celgene Global Health VL series for the treatment of VL
DNDi’s collaboration with Celgene Global Health continues to explore the potential of this series to deliver a pre- clinical candidate. Compounds with much improved physical properties, including improved aqueous solubility, were identified in 2017.


Leish L205 series

OBJECTIVE: Progress a compound from the 205 series towards candidate selection and nomination for further pre- clinical development for VL
Following proof-of-principle with the 205 series for VL, compounds from this series have shown a 100% parasite load reduction in liver and spleen in a VL murine model. Further characterization of this series is ongoing. Over 400 compounds have been synthesized to date in this lead optimization programme for Chagas disease and leishmaniasis.

TRANSLATION
DNDI-0690 nitroimidazole

OBJECTIVE: Progress DNDI-0690, a nitroimidazole compound, through clinical development for the treatment of leishmaniasis
DNDI-0690, a nitroimidazooxazine for the treatment of VL and possibly CL, was selected for pre-clinical development in September 2015. A full pre-clinical toxicology and safety studies package was completed in 2017, and the decision to progress to a Phase I single ascending dose study in healthy volunteers is anticipated in early 2018.


DNDI-6148

OBJECTIVE: Progress DNDI-6148, an oxaborole compound, through clinical development for the treatment of leishmaniasis
DNDi and Anacor have been working together over the last few years to identify oxaborole compounds, initially for the HAT programme, but this work has now expanded to include both leishmaniasis and Chagas disease. DNDI- 6148 has emerged as a promising lead candidate for VL and CL, and by the end of 2015, studies including exploratory toxicology necessary for possible progression to pre-clinical development had been successfully completed. In January 2016, DNDI-6148 was nominated as a pre-clinical candidate for the treatment of VL and possibly CL.
The pre-clinical toxicology package was completed in 2017, and the decision was made to progress to Phase I single ascending dose in healthy volunteers in parallel with additional toxicological investigations.


DNDI-5561

OBJECTIVE: Progress DNDI-5561, a selected aminopyrazole compound, to Phase I clinical studies for the treatment of VL
This project is the continuation of the optimization of the aminopyrazole series for VL. With the funding of the Japanese GHIT Fund, DNDi and partner Takeda worked with the objective of delivering an anti-parasitic aminopyrazole drug, as well as back-up candidates. DNDI-5561 is the front- running second-generation aminopyrazole.
Following positive results from efficacy and safety studies, DNDI-5561 was selected as a pre-clinical candidate in October 2017.


GSK3186899 / DDD853651 & GSK3494245 / DDD1305143

OBJECTIVE: Progress pre-clinical development of compounds for leishmaniasis
In April 2017, DNDi and GSK entered into an agreement for the pre-clinical development of two compounds for leishmaniasis which were discovered by GSK in collaboration with the Drug Discovery Unit (DDU) at the University of Dundee, following some co-funding by the Wellcome Trust.


CpG-D35 for CL

OBJECTIVE: Demonstrate the suitability of CpG-D35, an immunomodulator to stimulate the innate immune system to fight the parasitic infection responsible for CL, as an adjunct to drug therapy, for progression to Phase 1 clinical studies
CpG-D35 is being developed as a combination therapy for the treatment of complicated CL and PKDL in partnership with GeneDesign. Leishmania parasites are able to persist in host cells by evading or exploiting immune mechanisms. Modulating the immune response with CpG oligonucleotides may improve the effectiveness of chemotherapies.
In 2017, final results of the pre-clinical in vivo efficacy study showed an improved outcome for CpG-D35, either alone or in combination with pentavalent antimony (glucantime). These results supported the completion of the pre-clinical package and initiation of the preparation of clinical supplies for a Phase I study.


New CL combination therapies

OBJECTIVE: Further explore opportunities to maximize existing approved treatment approaches for CL when used in combination
When administrated alone, current CL treatments (antimonials, miltefosine, and thermotherapy) have well-established safety and efficacy profiles which are not satisfactory. Using a combination of therapeutic approaches may reduce efficacy rates, reduce treatment duration, and reduce the rate of adverse events. A combination of one single application of thermotherapy at 50°C for 30 seconds with a three-week course of oral miltefosine is being tested in a Phase II study in Colombia and Peru to gain information about safety and efficacy.
In 2017, recruitment of patients continued in Peru with the inclusion of 41 patients, and the study started in Colombia with the inclusion of 21 patients (out of a target of 130 patients). An interim analysis is planned in early 2018 once 65 patients have completed the Day 90 follow-up visit.


DEVELOPMENT
New treatments for HIV/VL

OBJECTIVE: Identify and deliver a safe and highly effective treatment for VL in HIV co-infected patients that will improve long-term survival
Patients with VL and HIV co-infection are very difficult to manage. They have a high rate of treatment failure, a higher risk of death, and multiple episodes of relapse.
In 2014, a randomized non-comparative Phase III study testing both AmBisome monotherapy (regimen currently recommended by WHO) and a combination of AmBisome and miltefosine was initiated at two sites in Ethiopia for the treatment of HIV/VL co-infection. After 59 patients had been enrolled, recruitment was interrupted, as efficacy at the end of treatment was lower than expected. Patients who had not achieved cure at the end of treatment were given a second cycle of the same treatment and efficacy was measured again at the end of this second cycle.
Despite an initial disappointing result, the efficacy of the AmBisome and miltefosine combination used within a strategy of prolonged treatment for patients difficult to cure, gave promising results.
In 2017, results were presented to the Ethiopian authorities and WHO, to promote the implementation of the combination of AmBisome and miltefosine as first-line treatment for HIV/VL co-infected patients, using the strategy of one or two treatment cycles. A scientific paper will be published in 2018 to open discussion with other stakeholders to support new recommendations for treating HIV/VL co-infection.
In India, DNDi is the technical partner with the Rajendra Memorial Research Institute (RMRI) in a study sponsored by MSF and launched in the state of Bihar in 2017. This Phase III study will test AmBisome monotherapy and AmBisome in combination with miltefosine in 150 patients. Recruitment is expected to be completed by early 2018. Results will inform the national road map of kala-azar elimination in India.


New treatments for PKDL

OBJECTIVE: Determine the safety and efficacy of two treatment regimens for patients with PKDL
PKDL is present mainly in two regions. In East Africa, the disease affects approximately 55% of patients previously treated for VL, a few months after VL therapy, and self-heals in 80% of cases within six months. Due to the nature of the disease and toxicity of the currently available treatments, only certain patients are targeted for treatment. In South Asia, where PKDL occurs in around 5-15% of treated VL cases many months or even years after VL therapy, the recommendation is to treat all patients.
Early treatment of PKDL patients has a benefit for the individual, but could also be a critical element of any VL public health and elimination strategy, as PKDL patients are believed to constitute a potential reservoir of infection for VL.
In late 2017, recruitment started for a Phase II study in Asia to test both AmBisome monotherapy and a combination of AmBisome and miltefosine, with six patients enrolled in clinical sites in India (RMRI in Patna and KAMRC in Muzzafarpur), while a clinical site in Bangladesh is preparing for initiation. The target recruitment of 110 patients is expected to be completed by January 2019.
A Phase II study to test both AmBisome in combination with miltefosine, and paromomycin in combination with miltefosine is under preparation in Sudan. Target recruitment will be 110 patients over two years.
A PKDL infectivity study – studying the ability of a pathogen to establish a horizontal infection, that is not from parent to child – in Bangladesh completed the recruitment of 65 patients and results are under analysis. In Sudan, the preparation of an insectarium for infectivity studies continues.


New VL treatments in Latin America

OBJECTIVE: Assess the efficacy and safety of amphotericin B deoxycholate, AmBisome, and AmBisome combined with glucantime, as compared to the first-line treatment, glucantime, for the treatment of VL patients in Brazil, supporting the Brazilian Ministry of Health and its partners
The Brazilian Ministry of Health is reviewing its treatment policy with regard to the adoption of AmBisome as first-line treatment for VL following the presentation of previous trial results to the Ministry in 2016.


Miltefosine/paromomycin combination for Africa

OBJECTIVE: Assess the safety and efficacy of a miltefosine/ paromomycin combination compared to the current standard VL treatment
A Phase III study to compare two different durations (14 and 28 days) of combination regimens of miltefosine and paromomycin with the current standard VL treatment - sodium stibogluconate (SSG), and paromomycin - in both paediatric and adult patients has begun in East Africa - replacing the toxic SSG with oral miltefosine treatment in a combination.
In 2017, the study protocol went through a joint review facilitated by WHO-AVAREF (African Vaccine Regulatory Forum), with representatives from AVAREF, the National Ethic Committees, and regulatory authorities from Ethiopia, Kenya, Sudan, and Uganda. A clinical site was initiated in Dooka, Sudan in December 2017 and the first patient recruited in January 2018. Clinical sites in Kenya (Kacheliba) and Ethiopia (Gondar) are about to be initiated, followed by additional sites in Uganda and Kenya.


Main R&D Partners

AbbVie, USA; Accelera, Italy; Academic Medical Center in Amsterdam, The Netherlands; Addis Ababa University, Ethiopia; Advinus Therapeutics Ltd, India; Amatsi Aquitaine (formerly Bertin Pharma), France; Amudat Hospital, Uganda; Aptuit, Italy; Astellas Pharma Inc., Japan; AstraZeneca, Sweden and UK; Auckland University, New Zealand; BaseCon, Denmark; Bayer, Germany; Bioascent, UK; BioAster, France; Brasilia University, Brasilia, Brazil; Bristol-Myers Squibb, USA; Celgene Corporation, USA; Centre for Drug Candidate Optimisation, Monash University, Australia; Centro National de Pesquisa em Energia e Materiais (CNPEM), LN Bio, Brazil; Charles River Laboratories (Wil Research), France and Netherlands; Crystallise!, Switzerland; Daiichi Sankyo Company, Limited, Japan; Daiichi Sankyo RD Novare Co., Ltd, Japan; Drug Discovery Unit, University of Dundee, UK; EI du Pont de Nemours, USA; Eisai Co., Ltd., Japan; Epichem, Australia; Eurofins Cerep, France; Eurofins Panlabs Thailand, Thailand; Eurofins Panlabs, USA; Eurofins-Optimed, France; Foundation for Innovative New Diagnostics, Switzerland; GeneDesign Inc., Japan; Gilead Sciences, USA; GlaxoSmithKline, Spain and UK; Gondar University Hospital, Ethiopia; Griffith Institute for Drug Discovery, Griffith University, Australia; Hospital Sao José de Doencas Infecciosas, Fortaleza; Hypha Discovery Ltd, UK; Institut Pasteur Korea, South Korea; Institute of Endemic Disease, Khartoum University, Sudan; Institute of Medical Sciences, Banaras Hindu University, India; Institute of Microbial Chemistry, Japan; Institute of Tropical Medicine Antwerp, Belgium; Instituto de Física, Universidade de São Paulo, Brazil; Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru; Instituto de Química, Universidade Estadual de Campinas, Brazil; Instituto de Salud Carlos III, Spain; International Centre for Diarrhoeal Disease Research, Bangladesh; Johnson & Johnson, USA; Kacheliba District Hospital, Kenya; Kala Azar Medical Research Centre, India; Kenya Medical Research Institute, Kenya; Kitasato Institute for Life Sciences, Japan; Laboratory of Microbiology Parasitology and Hygiene, University of Antwerp, Belgium; Lambda Therapeutic Research Ltd., India; LEAP Platform; London School of Hygiene & Tropical Medicine, UK; Makerere University, Uganda; Médecins Sans Frontières, Spain; Médecins Sans Frontières, The Netherlands; Medicines for Malaria Venture, Switzerland; Merck KGaA, Germany; Merck, USA; Ministry of Health, Neglected Tropical Disease Directorate, Ethiopia; Ministry of Health, Neglected Tropical Diseases Unit, Leishmaniasis Programme, Kenya; Ministry of Health, Neglected Tropical Diseases Unit, Leishmaniasis Programme, Sudan; Ministry of Health, Leishmaniasis Control Programme, Uganda; Montes Claros State University, Montes Claros, Brazil; Nagasaki University, Japan; National Institute of Pathology, India; National Institutes of Health, USA; Netherlands Cancer Institute, The Netherlands; Northwick Park Institute for Medical Research, UK; Novartis, Switzerland and USA; Ohio State University, USA; Osaka University, Japan; Paediatric Hospital Joao Paulo II – FHEMIG, Belo Horizonte, Brazil; Pfizer Inc., USA; Pfizer Inc. (formerly Anacor Pharmaceuticals Inc.), USA; Piaui Federal University, Teresina, Brazil; Programa de Estudio y Control de Enfermedades Tropicales, Universidad de Antioquia, Medellin, Colombia; Programa Nacional de Leishmaniasis, Colombia; Rajendra Memorial Research Institute of Medical Sciences, India; Rene Rachou Research Center– Fiocruz-MG, Belo Horizonte, Brazil; Research Foundation of The Netherlands Cancer Institute, The Netherlands; Sandexis, UK; Sanofi Merial, USA; Sanofi, France; Sanofi-Aventis, France; Sara Pharm, Romania; Scynexis, USA; Sequella Inc, USA; Sergipe Federal University, Aracaju, Brazil; Shionogi & Co., Ltd., Japan; SK Hospital, Mymensingh, Bangladesh; Swiss Tropical and Public Health Institute, Switzerland; Syngene, India; Takeda Pharmaceutical Company Limited, Japan; TB Alliance, USA; TCG Lifesciences, India; The Broad Institute of M.I.T and Harvard, USA; Thermosurgery Technologies Inc, USA; UBC, Switzerland; Universidade Estadual do Rio de Janeiro, RJ, Brazil; University of Cape Town, South Africa; University of Gedaref, Sudan; University of Gondar, Ethiopia; US Food and Drug Administration, USA; Walter Reed Army Institute of Research, USA; WHO-NTD (Neglected Tropical Diseases department); WHO-TDR (Special Programme for Research and Training in Tropical Diseases); WuXi AppTech, China; Zoetis (formerly Pfizer Animal Health), USA

READ MORE ON THE DNDi WEBSITE
/

MYCETOMA

DEVELOPMENT
Fosravuconazole

OBJECTIVE: Study the efficacy of fosravuconazole as a potential new, safe, and affordable treatment for patients with eumycetoma
Fosravuconazole (formerly known as E1224 in DNDi’s portfolio), an orally bioavailable azole developed by the Japanese pharmaceutical company Eisai, is under development for Chagas disease by DNDi (see p. 53). It could also be an effective and affordable treatment for eumycetoma. Its pharmacokinetic properties are favourable and its toxicity is low.
After receiving regulatory and ethical approval in March 2017, the Mycetoma Research Centre, a WHO Collaborating Centre, began recruiting patients into the first-ever double-blind, randomized Phase II/III clinical trial for eumycetoma. The clinical trial, which plans to recruit 138 patients, evaluates the efficacy of the anti-fungal fosravuconazole in moderate lesions in comparison with the current treatment, itraconazole.
The primary objective of this single-centre study conducted in Sudan is to demonstrate the superiority of fosravuconazole over itraconazole after 12 months’ treatment. By the end of 2017, 20 patients had been enrolled into the trial, a pace of enrolment that was slower than anticipated. In 2018, a satellite site will be established to screen more patients and refer them for treatment and care.

Main R&D Partners

Eisai Co., Ltd., Japan; Erasmus Medical Center, The Netherlands; Free University Amsterdam, The Netherlands; Institute of Endemic Diseases, Khartoum University, Sudan; Mycetoma Research Centre, Soba University Hospital, Khartoum, Sudan; Radboud University Medical Center, Nijmegen, The Netherlands

READ MORE ON THE DNDi WEBSITE
/

FILARIAL DISEASES

RESEARCH
Screening

OBJECTIVE: Identify new drug candidates, by accessing and evaluating registered drugs, pre-clinical and clinical candidates, focused sets and libraries with known anthelminthic activity from animal and human health companies
In 2017, well-characterized libraries of compounds that had been extensively optimized for other indications were provided to DNDi by several pharmaceutical companies for screening. Early screening of 530 compounds has been completed with Salvensis, Merck Sharp & and Dohme, University of Carolina, AbbVie, and others. From this initial screen, a full lead optimization programme has been undertaken in collaboration with Celgene with further exploration of identified hits (505 compounds). This effort will continue through 2018, with the aim of delivering a pre- clinical candidate for filarial diseases.


Macro-filaricide 3

OBJECTIVE: Develop a third macrofilaricide candidate for filarial diseases
Following a drug repurposing strategy, screening of compounds against Onchocerca gutturosa and Onchocerca lienalis identified several candidates from compound libraries provided by pharmaceutical companies. These compound collections are well-characterized chemical series which have been extensively optimized for use in other indications. Although the project was quite successful, none of the identified candidates had a drug profile with utility for filarial diseases.
Screening of compounds from several more companies yielded further candidates. These companies are conducting a hit-to-lead and lead optimization programme, which aims to develop a drug candidate for filarial indications. DNDi has contributed to this effort by providing biological resources, expertise, and the target product profile to select the best candidates.
In 2017, candidates from four distinct chemical series were evaluated through the lead optimization effort conducted in collaboration with Celgene while others were evaluated through the Macrofilaricide Drug Accelerator (MAC DA) led by the Bill & Melinda Gates Foundation as part of efforts to develop a third microfilaricide candidate for development.


TRANSLATION
Oxfendazole

OBJECTIVE: Develop a macrofilaricide for filarial disease
Oxfendazole is currently under development for treatment of neurocysticercosis and trichuriasis. Taking advantage of pre-clinical work already available in the public domain, DNDi is exploring the possibility of repurposing oxfendazole as a macrofilaricidal treatment for filarial indications.


ABBV-4083 (TylAMac)

OBJECTIVE: Develop ABBV-4083 as an anti-Wolbachia therapy and assess its macrofilaricidal efficacy
ABBV-4083 is a derivative of Tylosin, a veterinary antibiotic that targets the worm-symbiont Wolbachia. The compound is currently in early clinical development by AbbVie for the treatment of filarial diseases. ABBV-4083 is orally available, induces a robust anti-Wolbachia effect in several in vivo models, demonstrates clear superiority over doxycycline, and is effective after a shorter dosing regimen. Preliminary safety and toxicology profiling of this compound suggests a favourable safety profile.
Toxicology studies were completed in 2017, and an oral formulation was developed. In December, AbbVie began the first human trial of ABBV-4083 to test the drug’s safety in healthy volunteers and assist in the selection of doses for future trials. This Phase I study, conducted at at AbbVie’s Clinical Pharmacology Research Unit in Chicago, US is expected to be completed in 2018.


Emodepside

OBJECTIVE: Develop emodepside as a new macrofilaricidal treatment for patients suffering from onchocerciasis
Originating from the Japanese pharmaceutical company Astellas, emodepside has been developed and is currently commercialized by Bayer Animal Health as an anti-helminthic veterinary drug for cats and dogs. DNDi has a collaboration agreement with Bayer to jointly develop emodepside for the treatment of onchocerciasis in humans. DNDi is responsible for clinical development, and Bayer for pre-clinical, pharmaceutical development, manufacturing, registration, and supply of the drug at the lowest sustainable price.
Emodepside entered into Phase I studies in 2016, which continued throughout 2017 with 116 healthy volunteers recruited by the end of the year. The single ascending dose study was completed and the multiple ascending dose study will be completed in 2018.


Main R&D Partners

AbbVie, USA; AWOL, UK; Analytical Services International, UK; Bayer, Germany; Bonn University Hospital, Institute of Medical Microbiology, Immunology and Parasitology, Germany; Celgene Corporation, USA; Hammersmith Medicines Research, UK; Imperial College, UK; Institut Bouisson Bertrand, France; Liverpool School of Tropical Medicine, UK; Mahidol University, Thailand; Merck, USA; National Museum of Natural History, France; Niche Science and Technology, UK; Northwick Park Institute for Medical Research, UK; Salvensis, UK; University of Carolina, USA; University of Health and Allied Sciences, Ghana; University of Washington, USA;

READ MORE ON THE DNDi WEBSITE
RESEARCH
MISSING CONTENT

MISSING CONTENT MISSING CONTENT

Main R&D Partners

MISSING CONTENT

READ MORE ON THE DNDi WEBSITE
/

PAEDIATRIC HIV

TRANSLATION
A “4-in-1”: Towards a substantially improved treatment option for children

OBJECTIVE: Following the work that led to the registration of a “2-in-1” lopinavir/ritonavir (LPV/r) fixed-dose combination, develop and register a solid, taste-masked, first-line LPV/r-based fixed-dose formulation with two nucleoside reverse transcriptase inhibitors (NRTIs), lamivudine and abacavir
Together with Cipla Ltd. and with the support of Unitaid, DNDi has developed a solid first-line 4-in-1 fixed-dose combination (abacavir/lamivudine/lopinavir/ritonavir) using the World Health Organization-recommended treatment regimen for infants and young children.
The 4-in-1 formulation, in the form of a capsule containing solid taste-masked granules, will be a great improvement over the current high-alcohol content LPV/r syrup and will not require refrigeration. It will be adequately dosed based on a child’s weight, according to weight bands. In addition, caregivers will no longer have to worry about whether their children can swallow a capsule, as the granules within the capsule can easily be mixed with soft food or breast milk.
Preliminary pharmacokinetic studies in healthy human volunteers were conducted in 2017 with a final 4-in-1 formulation. Bioequivalence studies in healthy human volunteers will be performed in 2018, enabling regulatory filing. Safety, acceptability, and efficacy data on this new formulation will also be generated in sub-Saharan Africa to provide evidence for worldwide scale-up. The objective is to submit the 4-in-1 dossier for registration in late 2018.

DEVELOPMENT
LPV/r pellets + dual NRTI

OBJECTIVE: Evaluate the effectiveness of LPV/r pellets in addition to AZT/3TC (or ABC/3TC) paediatric fixed-dose combination tablets in an implementation study in HIV-infected infants and young children who cannot swallow pills
Up until 2015, the only available version of LPV/r was a bitter-tasting syrup that requires refrigeration and contains 40% alcohol. In June of that year, the U.S. Food and Drug Administration approved an oral pellet formulation of LPV/r, developed by the Indian generic pharmaceutical company Cipla Ltd., which can be administered to young children with food and does not require refrigeration.
In September 2015, and with the support of Unitaid, DNDi launched the LIVING Study to provide early access to and demonstrate the effectiveness, safety, and acceptability of this new “2-in-1” LPV/r pellet formulation with more than 800 patients across Kenya. The study was expanded to additional sites in Uganda, and then to Tanzania in LPV/r pellets + dual NRTI 2017. This study tested the use of these pellets in the field in combination with a class of ARVs known as nucleoside reverse transcriptase inhibitors (NRTIs), namely zidovudine/ lamivudine (AZT/3TC) or abacavir/lamivudine (ABC/3TC). The study is intended to demonstrate the effectiveness, safety, and acceptability of LPV/r oral pellets in the field and pave the way for the 4-in-1. This study marks the first time that these pellets are being used in real-life settings and the findings will undoubtedly help programmes worldwide scale up treatment for HIV-infected children.
As of the end of 2017, 818 paediatric patients had been enrolled at 12 sites. Interim results were presented at the end of 2017 at the ICASA conference, showing that oral “2- in-1” pellets are effective, well tolerated, and well accepted by caregivers and children. Based on experience gained from introducing the 2-in-1, DNDi will work with health ministries, donors, and other HIV stakeholders to ensure that children will have access to the 4-in-1 when it is available.


Main R&D Partners

AbbVie, USA; Associated Medical Sciences/PHPT International Research Unit, Thailand; Baylor College of Medicine Children’s Foundation, Uganda; Centre for Disease Control and Prevention/President’s Emergency Plan for AIDS Relief, USA; Children of God Relief Institute-Lea Toto Project/Nyumbani, Nairobi, Kenya; Cipla Ltd., India; Clinton Health Access Initiative, USA; Department of Health, South Africa; Epicentre, Uganda; Gertrude’s Children’s Hospital, Kenya; Ifakara Health institute, Tanzania; Institute of Tropical Medicine, Antwerp; Joint Clinical Research Centre, Fort Portal, Uganda; Joint Clinical Research Centre, Gulu, Uganda; Joint Clinical Research Centre, Kampala, Uganda; Kenya Medical Research Institute/FACES Project/St Lumumba Health Centre, Kisumu, Kenya; Kenyatta National Hospital, Kenya; Management and Development for Health, Tanzania; Mbagathi District Hospital, Kenya; Médecins Sans Frontières; Medical Research Council, UK; Ministry of Health, Kenya; Moi Teaching and Referral Hospital, Kenya; Necker Institute, France; Swiss Tropical and Public Health Institute, Switzerland; University of Nairobi, Kenya; various academic partners in South Africa, Kenya, Uganda, and Tanzania

READ MORE ON THE DNDi WEBSITE
/

HEPATITIS C

DEVELOPMENT
Ravidasvir/sofosbuvir: Towards a pan-genotypic, simple, and affordable treatment

OBJECTIVE: Conduct Phase II/III clinical trials to evaluate the efficacy of a ravidasvir + sofosbuvir combination
More than one million people are estimated to be chronically infected with HCV in Thailand and 400,000 in Malaysia, where genotypes 1, 3, and 6 are most common. Both countries were initially excluded from all global voluntary licensing agreements with drug companies.
In 2016, DNDi launched the “STORM-C-1” open label trial at eight sites in Malaysia and Thailand to assess the efficacy, safety, tolerability, pharmacokinetics, and acceptability of 12- and 24- week regimens combining the drug candidate ravidasvir with sofosbuvir in people living with the hepatitis C virus (HCV).
In stage one of this study, 301 chronically infected adults were treated with the ravidasvir/sofosbuvir combination for 12 weeks for patients without cirrhosis of the liver, and for 24 weeks for those with compensated cirrhosis.
Initial results published in April 2018 showed that after 12 weeks of treatment, 97% of those enrolled were cured (95% CI: 94.4- 98.6). Cure rates were very high, even for the hardest-to-treat patients. Importantly, patients combining several risk factors were cured, and no unexpected safety signals were detected.
To further establish the pan-genotypic profile of ravidasvir, further data will be collected in Malaysia and Thailand, and other trials are envisioned in other parts of the world (for genotypes 2 and 5) and Ukraine (for vulnerable patient groups, including injecting drug users). Registration of ravidasvir will be pursued in Malaysia and other middle-income countries, including in Latin America.
DNDi‘s HCV programme includes work with Médecins Sans Frontières to develop and implement simpler models of care in specific target populations, as well as in large-scale treatment cohorts in Cambodia and Ukraine. The objective is to demonstrate that the challenges posed by HCV can be addressed through a public health approach.

Main R&D Partners

Associated Medical Sciences/PHPT International Research Unit, Thailand; Clinical Research Malaysia, Ministry of Health, Malaysia; Doppel Farmaceutici, Italy; Hospitals of Geneva, Switzerland; Hospital Kuala Lumpur, Malaysia; Insud Pharma/Elea, Argentina; Médecins Sans Frontières, Ukraine; Ministry of Health, Thailand; Ministry of Industry, Science and Technology, Thailand; Mundo Sano Foundation, Argentina; Pharco Pharmaceuticals Inc, Egypt; Pharmaniaga, Malaysia; Presidio Pharmaceuticals, USA

READ MORE ON THE DNDi WEBSITE

PUBLIC INSTITUTIONAL SUPPORT

PRIVATE SUPPORT

We use cookies to improve your experience with our website. By continuing to browse our website, you are agreeing to our use of cookies. However, you can change your cookie settings at any time in your browser. Read Cookie Policy. Close