1553 DNDI portfolio 2011 v17 - gov.uk...2011 R&D PORTFOLIO A Needs-Driven Collaborative R&D Model for Neglected Diseases SUPPORT DNDi Thanks to our donors, DNDi has successfully secured

2011 R&D PORTFOLIO

A Needs-Driven Collaborative R&D Model for Neglected Diseases

SUPPORT DNDiThanks to our donors, DNDi has successfully secured over EUR 170 million as per July 2011 of the EUR 400 million required to achieve the objectives of building a robust pipeline and delivering 11 to 13 new treatments by 2018. Support from public and private donors is vital to DNDi’s efforts. In the coming years, more is needed to make new tools available.

Join DNDi in fi ghting these poverty-related diseases by supporting our efforts to produce new medicines that address patient needs.

Contact the DNDi fundraising team for more information: +41 (0)22 906 92 30 or [email protected]

> Public Institutional Donors• Department for International Development (DFID) / United Kingdom

• Dutch Ministry of Foreign Affairs (DGIS) / The Netherlands

• European Union – Framework Programme 5, 6, and 7

• European and Developing Countries Clinical Trials Partnerships

(EDCTP) with co-funding from Member States / International

• French Development Agency (AFD) / France

• Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ) on

behalf of the Government of the Federal Republic of Germany /

Germany

• The Global Fund to Fight AIDS, Tuberculosis and Malaria (AMFm) /

International

• Ministry of Foreign and European Affairs (MAEE) / France

• National Institutes of Health (NIH), National Institute of Allergy and

Infectious Diseases (NIAID) / United States of America

• Region of Tuscany / Italy

• Republic and Canton of Geneva / Switzerland

• Spanish Agency of International Cooperation for Development

(AECID) / Spain

• Swiss Agency for Development and Cooperation (SDC) / Switzerland

> Private Donors• Médecins Sans Frontières (Doctors without Borders) / International

• The Bill & Melinda Gates Foundation / United States of America

• Medicor Foundation / Liechtenstein

• The Peter and Carmen Lucia Buck Foundation / United States

of America

• Fondation André & Cyprien / Switzerland

• Fondation ARPE / Switzerland

• Fondation de bienfaisance de la banque Pictet / Switzerland

• Fondation Pro Victimis / Switzerland

• Starr International Foundation / Switzerland

• The Sasakawa Peace Foundation / Japan

• Other private foundations who would like to remain anonymous

• Numerous individual donors

• Alice DAUTRY, Institut Pasteur, France

• Abul FAIZ, Patient representative; Sir Salimullah Medical College, Bangladesh

• Unni KARUNAKARA, Médecins Sans Frontières (MSF), Switzerland

• Datuk Mohd Ismail MERICAN, Ministry of Health, Malaysia

• Carlos MOREL, Oswaldo Cruz Foundation (Fiocruz), Brazil

• Bennett SHAPIRO, PureTech Ventures, formerly with Merck & Co., USA

Board of Directors

Scientifi c Advisory Committee

Founding Partners

• Paulina TINDANA, Patient representative; Navrongo Health Research Centre, Ghana

• Els TORREELE, Open Society Foundations, USA

• Position vacant for Kenya Medical Research Institute (KEMRI), Kenya

• Position vacant for Indian Council of Medical Research (ICMR), India

• Robert G. RIDLEY, WHO-TDR (Permanent Observer of Board), Switzerland

• Indian Council of Medical Research (ICMR), India

• Institut Pasteur, France

• Kenya Medical Research Institute (KEMRI), Kenya

• Malaysian Ministry of Health, Malaysia

• Paul HERRLING, Novartis International AG, Switzerland

• Dale KEMPF, Abbott, USA

• Nor Shahidah KHAIRULLAH, Infectious Diseases Research Center, Malaysia

• Shiv Dayal SETH, Indian Council of Medical Research (ICMR), India

• Faustino TORRICO, Universidad Mayor de San Simon, Cochabamba, Bolivia

• Mervyn TURNER, formerly with Merck & Co., USA

• Muriel VRAY, Institut Pasteur, France

• Krisantha WEERASURIYA, World Health Organization (WHO), India

• Médecins Sans Frontières (MSF), International

• Oswaldo Cruz Foundation (Fiocruz), Brazil

• WHO-TDR as permanent observer15 Chemin Louis-Dunant, 1202 Geneva, Switzerland Tel: +41 (0) 22 906 9230; Fax: +41 (0) 22 906 [email protected]; www.dndi.org

The Drugs for Neglected Diseases initiative (DNDi) is a patient-needs driven, not-for-profi t research and development (R&D) organization that develops safe, effective, and affordable medicines for neglected diseases that affl ict millions of the world’s poorest people. DNDi focuses on developing new treatments for the most neglected patients suffering from diseases such as sleeping sickness (or human African trypanosomiasis), leishmaniasis, Chagas disease, malaria, and more recently paediatric HIV and helminth infections.

DNDi ’s primary objective is to:> Deliver 11 to 13 new treatments by 2018 for these neglected diseases and to establish

a strong R&D portfolio that addresses patients’ treatment needs.

In doing this, DNDi will also:

> Use and strengthen capacities in disease-endemic countries via project implementation

> Raise awareness about the need to develop new drugs for neglected diseases and advocate

for increased public responsibility.

Quartier Socimat

La Gombe, Kinshasa

Democratic Republic of the CongoTel: +243 81 011 81 31

Affi liate

DNDi NORTH AMERICA40 Wall Street, 24th Floor

New York, NY 10005

USATel: +1 646 616 8680

www.dndina.org

Regional Offi ces

DNDi AFRICA c/o Centre for Clinical ResearchKenya Medical Research Institute

PO Box 20778

KNH 00202 Nairobi

KenyaTel: +254 20 273 0076

DNDi LATIN AMERICAJardim Botânico–Rio de Janeiro

Rua Santa Heloisa 5

Rio de Janeiro, RJ 22460-080

BrazilTel: +55 21 2215 2941

www.dndi.org.br

DNDi INDIAc/o Indian Council of Medical

Research 2nd Campus – Room No 3, 1st Floor

TB Association Building

3, Red Cross Road

New Delhi 110-001

IndiaTel: +91 11 2373 1635

DNDi JAPAN3-1-4 Nishi-Shinjuku

Shinjuku-ku Tokyo 160-0023

JapanTel: +81 3 6304 5588

www.dndijapan.org

DNDi MALAYSIAc/o Centre for Drug Research

University Sains Malaysia11800 Minden – Pulau Pinang

MalaysiaTel: +60 4 657 9022

Project Support

Offi ce

DNDi DRCc/o Bureau de la Représentation de l’Institut Tropical et de Santé Publique Suisse11 avenue Mpeti

TO DATE DNDi HAS BEEN SUPPORTED BY:

Chair: Marcel TANNER, Swiss Tropical and Public Health Institute (Swiss TPH), SwitzerlandSecretary: Reto BRUN, Swiss Tropical and Public Health Institute (Swiss TPH), SwitzerlandTreasurer: Bruce MAHIN, independent, formerly with Médecins Sans Frontières (MSF), Switzerland

Chair: Pierre-Étienne BOST, formerly with Institut Pasteur, France

• Khirana BHATT, University of Nairobi, Kenya

• Chris BRUENGER, IDEC Inc., Japan

• François CHAPPUIS, Geneva University Hospitals / Médecins Sans Frontières (MSF), Switzerland

• J Carl CRAFT, formerly with Medicines for Malaria Venture (MMV), Switzerland

• Simon CROFT, London School of Hygiene and Tropical Medicine (LSHTM), UK

• Federico GOMEZ DE LAS HERAS , formerly with GlaxoSmithKline (GSK), Spain

• Chitar Mal GUPTA, Central Drug Research Institute (CDRI), India

• Maria das Graças HENRIQUES, Farmanguinhos/Fiocruz, Brazil

TARGET 2003-2018:

EUR 400 million

TO DATE: EUR 170 million

DiscoveryRLO LS

Pre-clinicalClinicalImplementation I

Exploratory

HAT LO Consortium • Scynexis• Pace Univ.

VL LOConsortium• Advinus• CDRI

Chagas LOConsortium• CDCO• Epichem• Murdoch

Univ.• FUOP

HAT: Human African TrypanosomiasisVL: Visceral Leishmaniasis

Nitroimidazole backup (HAT)

Oxaborole SCYX7158 (HAT)

Alternative formulations ofAmphotericin B (VL)

Exploratory

Nitroimidazole (VL)

Drug combination (Chagas)

K777 (Chagas)

Flubendazole Macrofilaricide (Helminth)

Fexinidazole (HAT) Discovery Activities

• Compound mining• Chemical classes• Target-based• Screening

Major Collaborators• Sources for hit and lead compounds: GSK, Anacor, Merck, Pfizer, Novartis (GNF, NITD), TB Alliance, …• Screening Resources: Eskitis, Institut Pasteur Korea, Univ. Scynexis, Univ. Dundee, …• Reference screening centres: LSHTM, Swiss Tropical & Public Health Institute, University of Antwerp

New VL treatments – Bangladesh

New VL treatments – Africa

New VL treatments –Latin America

Benznidazole Paediatric dosage form (Chagas)

Azoles E1224 & Biomarker (Chagas)

Paediatric HIV(exploratory)

ASMQ (Malaria)

Fixed-DoseArtesunate/Mefloquine

ASAQ (Malaria)

Fixed-DoseArtesunate/

Amodiaquine

NECT (Stage 2 HAT)Nifurtimox -Eflornithine

Co-administration

SSG&PM(VL in Africa)

co-administration

New VL treatments in Asia

(SD AmBisome®, PM+M / A®+M / PM+A®)

Portfolio expansion in 2011Since its inception in 2003, DNDi has built the most robust portfolio ever developed for kinetoplastid diseases (sleeping sickness, leishmaniasis, Chagas disease). True to its mission of responding to the unmet needs of neglected patients, DNDi, while maintaining a full commitment to kinetoplastid diseases, has expanded its portfolio in 2011 to include two new disease areas: paediatric HIV and

helminth infections, with a specifi c focus on fi lariasis. DNDi will conclude its malaria activities, including technology transfer and sustained access activities, by 2014.

DNDi Portfolio

ASMQ (Fixed-dose combination of artesunate + mefl oquine)

NEW VL TREATMENTS IN ASIA

• Produced by Farmanguinhos (Brazil) • Simple and adapted regimen for

children and adults • South - South technology transfer

from Farmanguinhos to Cipla, India

• Large four-arm implementation study with health authorities at state, national, and regional levels, in collaboration with TDR and iOWH

• Recommended by the WHO Expert Committee on the Control of Leishmaniases (March 2010)

• High effi cacy and good safety profi le• Field-adapted

2008

2011 NECT (Nifurtimox-efl ornithine combination therapy)

• Six-year partnership between DNDi, MSF, governments, pharmaceutical companies, and WHO

• The fi rst-line treatment covering more than 60% of all stage 2 patients (in 2010)

• Available in 10 African countries (covering 97% of reported HAT cases)

2009SSG&PM(Sodium stibogluconate & paromomycin combination therapy)

• Partnership between DNDi, the Leishmaniasis East Africa Platform (LEAP), national control programmes of Kenya, Sudan, Ethiopia, and Uganda, MSF, and WHO

• Recommended by the WHO Expert Committee on the Control of Leishmaniases for East Africa (March 2010)

• Approved and implemented in Sudan in 2010

2010

malaria

sleeping sickness

stage 2VLVL

TREATMENTS

DELIVERED

DNDi has made

new treatments

available each year

since 2007

ASAQ (Fixed-dose combination of artesunate + amodiaquine)

• Innovative partnership with Sanofi • 80 million treatments distributed

(end 2010)• Registered in 30 sub-Saharan

countries + India• Simple regimen: 1 or 2 tablets once

a day for 3 days • Being transferred to African industrial

partner (Zenufa)

2007

malaria

(SD AmBisome® / PM+M / A®+M / PM+A®)

A research capacity strengthening network of clinicians, national

control programme representatives, and scientists from the

African countries most affected by sleeping sickness (Angola,

Central African Republic, Chad, Democratic Republic of the Congo,

Republic of Congo, Uganda, Sudan) as well as international

institutions.

> HAT Platform

> Leishmaniasis East Africa Platform (LEAP)

> Chagas Clinical Research Platform (CCRP)

DNDi works closely with partners in disease-endemic countries to strengthen clinical research capacity. This support of research and implementation programmes is vital to ensuring sustainable access to the treatments delivered. Three platforms bring together scientists, research organizations, international organizations, NGOs, and national programmes for the three kinetoplastid diseases in DNDi’s portfolio.

STRENGTHENING CAPACITIES

IN ENDEMIC COUNTRIES

Main Partners:

National Control Programmes of most affected endemic countries;

Swiss Tropical and Public Health Institute (Swiss TPH), Switzerland;

Institute of Tropical Medicine in Antwerp (ITM), Belgium; Institut

National de Recherche Biomédicale (INRB), DRC; Centers for

Disease Control and Prevention (CDC), USA; Kenya Agricultural

Research Institute – Trypanosomiasis Research Centre (KARI-TRC),

Kenya; MSF/Epicentre; Foundation for Innovative New Diagnostics

(FIND); TDR; Regional networks such as Eastern Africa Network for

Trypanosomosis (EANETT), Pan African Bioethics Initiative (PABIN),

the African Malaria Network Trust (AMANET). In collaboration

with WHO.

A research capacity strengthening network of health agencies

and scientists from the four African countries most affected by

visceral leishmaniasis (Ethiopia, Kenya, Sudan, Uganda) as well

as international experts. The LEAP Platform has established seven

trial sites and trained principle investigators, lab technicians, and

monitors.

Main Partners:

Center for Clinical Research, Kenya; Medical Research Institute,

Kenya; Ministry of Health, Kenya; Institute of Endemic Diseases

(IEND), 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; Médecins Sans Frontières;

i+ solutions; Institute for OneWorld Health (iOWH); AMC/KIT/

University of Slotervaart, The Netherlands; London School of

Hygiene and Tropical Medicine (LSHTM), UK. In collaboration

with WHO.

A network of health agencies and scientists in the Americas and

around the world that aims at capacity strengthening, expanding

community participation, and improving evaluation and delivery of

new treatments across the region. The CCRP held its fi rst meeting

in March 2010 in Buenos Aires, Argentina, with representatives of

the following organizations:

Ministries of Health and National Control Programmes of high

burden endemic countries (Argentina, Bolivia, Brazil, Mexico);

Hospital de Niños Ricardo Gutiérrez, Argentina; Instituto Nacional

de Parasitología Dr. M Fatala Chabén, Argentina; Hospital de Niños

de Jujuy, Argentina; Hospital Público Materno Infantil – Salta,

Argentina; Centro de Chagas y Patologia Regional, Santiago del

Estero, Argentina; Consejo Nacional de Investigaciones Científi cas

y Técnicas (CONICET), Argentina; Instituto Oswaldo Cruz, Brazil;

Instituto de Pesquisa Evandro Chagas – Fiocruz, Brazil; Centro

de Pesquisas René Rachou – Fiocruz, Brazil; Universidad Mayor

de San Simon – Platform of Integral Care for Patients with

Chagas Disease, Bolivia; CRESIB – Hospital Clinic Barcelona,

Spain; Médecins Sans Frontières; Institut de Recherche pour le

Développement, France; Eisai, Japan. Department for the Control

of Neglected Tropical Diseases, WHO; PAHO.

Sudan

Uganda

Angola

Republic of

the Congo

Democratic

Republic

of the Congo

Chad

Central African

Republic

Sudan

Kenya Uganda

Ethiopia

Mexico

Bolivia

Brazil

Argentina

2011 R&D PORTFOLIO













Germany


International







(AECID) / Spain






of America















Board of Directors


Founding Partners




















• WHO-TDR as permanent observer 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland Tel: +41 (0) 22 906 9230; Fax: +41 (0) 22 906 [email protected]; www.dndi.org








Quartier Socimat

La Gombe, Kinshasa


Affi liate


New York, NY 10005

USATel: +1 646 616 8680

www.dndina.org

Regional Offi ces


PO Box 20778

KNH 00202 Nairobi

KenyaTel: +254 20 273 0076


Rua Santa Heloisa 5


BrazilTel: +55 21 2215 2941

www.dndi.org.br




3, Red Cross Road

New Delhi 110-001

IndiaTel: +91 11 2373 1635



JapanTel: +81 3 6304 5588

www.dndijapan.org




Project Support

Offi ce













TARGET 2003-2018:

EUR 400 million


DiscoveryR LOLS

Pre-clinical Clinical ImplementationI

Exploratory




Univ.• FUOP





Exploratory

Nitroimidazole (VL)


K777 (Chagas)


Fexinidazole (HAT)Discovery Activities









ASMQ (Malaria)


ASAQ (Malaria)


Amodiaquine


Co-administration


co-administration





DNDi Portfolio









2008

2011NECT (Nifurtimox-efl ornithine combination therapy)




2009 SSG&PM(Sodium stibogluconate & paromomycin combination therapy)




2010

malaria

sleeping sickness

stage 2 VL VL

TREATMENTS

DELIVERED

DNDi has made

new treatments

available each year

since 2007






partner (Zenufa)

2007

malaria







institutions.

> HAT Platform






Main Partners:











with WHO.






monitors.

Main Partners:










with WHO.






















Sudan

Uganda

Angola

Republic of

the Congo

Democratic

Republic

of the Congo

Chad

Central African

Republic

Sudan

KenyaUganda

Ethiopia

Mexico

Bolivia

Brazil

Argentina

2011 R&D PORTFOLIO













Germany


International







(AECID) / Spain






of America















Board of Directors


Founding Partners




















• WHO-TDR as permanent observer 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland Tel: +41 (0) 22 906 9230; Fax: +41 (0) 22 906 [email protected]; www.dndi.org








Quartier Socimat

La Gombe, Kinshasa


Affi liate


New York, NY 10005

USATel: +1 646 616 8680

www.dndina.org

Regional Offi ces


PO Box 20778

KNH 00202 Nairobi

KenyaTel: +254 20 273 0076


Rua Santa Heloisa 5


BrazilTel: +55 21 2215 2941

www.dndi.org.br




3, Red Cross Road

New Delhi 110-001

IndiaTel: +91 11 2373 1635



JapanTel: +81 3 6304 5588

www.dndijapan.org




Project Support

Offi ce













TARGET 2003-2018:

EUR 400 million


DiscoveryR LOLS

Pre-clinical Clinical ImplementationI

Exploratory




Univ.• FUOP





Exploratory

Nitroimidazole (VL)


K777 (Chagas)


Fexinidazole (HAT)Discovery Activities









ASMQ (Malaria)


ASAQ (Malaria)


Amodiaquine


Co-administration


co-administration





DNDi Portfolio









2008

2011NECT (Nifurtimox-efl ornithine combination therapy)




2009 SSG&PM(Sodium stibogluconate & paromomycin combination therapy)




2010

malaria

sleeping sickness

stage 2 VL VL

TREATMENTS

DELIVERED

DNDi has made

new treatments

available each year

since 2007






partner (Zenufa)

2007

malaria







institutions.

> HAT Platform






Main Partners:











with WHO.






monitors.

Main Partners:










with WHO.






















Sudan

Uganda

Angola

Republic of

the Congo

Democratic

Republic

of the Congo

Chad

Central African

Republic

Sudan

KenyaUganda

Ethiopia

Mexico

Bolivia

Brazil

Argentina

Discovery

Pre-clinical Development

ClinicalDevelopment

Implementation

Founding Partner

Project Partners

Platform Member Countries

• About 8 million people are infected, mostly across Latin America, where the parasite is transmitted by the so called ‘kissing bugs’

• 12,000 people every year die of Chagas disease• Acute infection kills approximately 1 in 20, primarily children • Chronic symptomatic disease develops in about one-third of the infected patients and most

often involves the heart or the gastrointestinal tract• Chagas disease is a leading cause of cardiomyopathy worldwide

Current Treatments

• Benznidazole or nifurtimox is used for acute & early indeterminate disease stages:– Long treatment period (30-60 days); Dose-dependent toxicity; High rate of patient non-

compliance; No paediatric formulation; No treatment for chronic disease

Chagas disease (American Trypanosomiasis)

Phase I

Fexinidazole (HAT)

Objective: To undertake the clinical development

of fexinidazole, the fi rst orally administered drug

candidate in clinical phase for sleeping sickness.

Fexinidazole entered into Phase I fi rst-in-human

clinical studies in September 2009. Phase II clinical

studies will start in early 2012. DNDi and Sanofi

have signed an agreement for the development,

manufacturing, and distribution of fexinidazole.

Major Partners: Sanofi , France; Swiss TPH,

Switzerland; HAT Platform partners.

Phase II

Azoles E1224 & Biomarkers (Chagas)

Objective: To evaluate E1224, a new generation azole

compound, for the treatment of Chagas disease. DNDi

and Eisai, which discovered and developed E1224,

signed a collaboration and licensing agreement in

2009. E1224 is being advanced into Phase II effi cacy

and safety evaluation in Bolivia. DNDi will evaluate

selected biomarkers for their potential application

in clinical research on Chagas disease (shortening

patient follow-up for test of cure).

Major Partners: Eisai, Japan; Centre de Recerca en

Salut Internacional de Barcelona (CRESIB), Spain;

Platform of Integral Care for Patients with Chagas

Disease, Spain/Bolivia; Universidad Mayor de San

Simon, Bolivia; CONICET, Argentina; Federal University

of Ouro Preto, Brazil; Médecins Sans Frontières

(MSF); Chagas Clinical Research Platform.

Phase III

New VL treatments - Bangladesh

Objective: To identify safe and effective short-

course combination therapies using the existing

drugs, miltefosine, paromomycin, and liposomal

amphotericin B (AmBisome®), to provide simplifi ed

treatment options to facilitate control programmes.

A two-step Phase III trial (fi rst in hospital followed

by treatment in primary healthcare centres) using

the same combinations as in the trial conducted

by DNDi in India (see Implementation) was initiated

in Bangladesh in mid-2010.

Major Partners: GVK Bio, India; International Centre

for Diarrhoeal Disease Research, Bangladesh;

Shaheed Suhrawardy Medical College and Hospital,

Bangladesh; Community Based Medical College,

Bangladesh.

New VL treatments - Africa

This project aims to ensure geographical extension

of all available anti-leishmanial drugs and the

development of new short-course combination

treatments in the East African region. After the

implementation of the fi rst combination treatment in

Sudan and Uganda (SSG&PM), additional clinical trials

are ongoing to identify a second combination therapy

for East Africa:

Miltefosine-AmBisome®

Objective: To evaluate the safety and effi cacy of

miltefosine, in combination therapy with AmBisome®,

and to geographically extend the use of the drugs into

East Africa. Currently DNDi is conducting three Phase

II clinical trials (Kenya and Sudan).

Major Partners: Kenya Medical Research Institute

(KEMRI), Kenya; Institute of Endemic Diseases

(IEND), University of Khartoum, Sudan; Addis Ababa

University, Ethiopia; Gondar University, Ethiopia;

University of Makerere, Uganda; LSHTM, UK; ASK

(AMC, Slotervaart Hospital, KIT), The Netherlands;

Ministries of Health of Ethiopia, Sudan, Kenya,

and Uganda; MSF; i+ solutions, The Netherlands;

Institute for OneWorld Health (iOWH), USA; LEAP

(Leishmaniasis East Africa Platform).

New VL treatments - Latin America

Objective: To assist coordination of the

implementation of a Ministry of Health-sponsored

clinical trial aiming to evaluate the safety and

effi cacy of the 3 treatments currently recommended

for VL in Brazil, as well as one combination arm

of AmBisome® + Glucantime®. The project will be

conducted in different VL reference centres, involving

a total of 600 adults and children.

Major Partners: René Rachou Research Institutition

– FIOCRUZ-MG, Brazil; Paediatric Hospital João

Paulo II – FHEMIG, Brazil; Brasilia University, Brazil;

Montes Claros State University, Brazil; Piauí Federal

University, Brazil; Sergipe Federal University, Brazil;

Tocantins Federal University, Brazil; Leishmaniasis

Control Programme/ Brazilian Ministry of Health,

Brazil.

Paediatric Benznidazole dosage form (Chagas)

Objective: To develop and register a dispersible

paediatric tablet of benznidazole to treat children

with Chagas in endemic countries. Currently,

benznidazole is manually fractioned into pieces for

children. The compliance cannot be guaranteed.

The most appropriate paediatric tablet formulation,

strength, and associated dosing regimen have

been determined through partnership with LAFEPE.

Registration process is ongoing.

Major Partners: LAFEPE, Brazil; Hospital de Niños

Ricardo Gutierrez, Argentina; Centro Nacional de

Diagnóstico e Investigación de Endemo-epidemias,

Argentina; Ministry of Health, Argentina; University

of Liverpool, UK.

Exploratory

Paediatric HIV

Objective: To identify signifi cant gaps in fi rst-line

treatment for children under 3 years of age that

meet the 2010 WHO Recommendations for HIV

infection in infants and children, and to assess

feasibility of minimum 2 to 3 projects.

3

CLINICAL DEVELOPMENT

Nitroimidazole Back-up (HAT)

Objective: In case the clinical development of a

potential drug in development for HAT fails to meet

the expected profi les, DNDi is undertaking the pre-

clinical development of a back-up drug candidate

from the nitroimidazoles proactive screening project.

Partners: TB Alliance, USA; Swiss TPH, Switzerland;

Suwinski, Poland.

Oxaborole SCYX-7158 (HAT)

Objective: To undertake the pre-clinical development

of oxaboroles – a boron-based compound series

originated by Anacor. During the course of the

collaboration, chemists at SCYNEXIS synthesized

several hundreds of new compounds and screened

additional compounds from the Anacor libraries.

One of the optimized compounds, SCYX-7158,

a promising new drug candidate for HAT, will be

advanced into Phase I fi rst-in-human clinical studies

in 2011.

Partners: Anacor, USA; SCYNEXIS, USA; Pace

University, USA; Advinus Therapeutics, India.

Alternative formulations of Amphotericin B (VL)

Objective: To identify an improved formulation of

amphotericin B that shows the most promise in terms

of in vivo effi cacy, safety, heat stability, and cost.

Partners: Polytherics, UK; The School of Pharmacy,

University of London, UK; LSHTM, UK.

2

PRE-CLINICAL DEVELOPMENT

Nitroimidazole (VL)

Objective: To perform all non-clinical activities

(safety studies, chemistry, manufacturing, and control)

on a new chemical entity, originally identifi ed by TB

Alliance. The aim is to fi le an Investigational New Drug

(IND) by the end of 2011.

Partners: Advinus Therapeutics, India; CDRI, India;

LSHTM, UK; University of Auckland, New Zealand; TB

Alliance, USA.

Drug Combination (Chagas)

Objective: To assess the potential of azole +

benznidazole/nifurtimox combinations to reduce

the dose and duration of treatment of Chagas

disease, reduce toxicity, improve effi cacy, and delay

the development of resistance to the individual

component drugs of the combination.

Partners: Federal University of Ouro Preto, Brazil;

Chagas Clinical Research Platform.

K777 (Chagas)

Objective: To collaborate with the University of

California San Francisco in completing the pre-clinical

drug development requirements to allow K777, a new

chemical that has demonstrated the ability to cure

Chagas disease in animal models, to move into Phase I.

Partner: University of California San Francisco (UCSF),

USA.

Flubendazole Macrofi laricide (Helminth)

Objective: To evaluate fl ubendazole as a

macrofi laricide clinical candidate for the treatment

of onchocerciasis and lymphatic fi lariasis in areas

where loiasis is coendemic. This involves formulation

development and safety and effi cacy studies.

Partners: Michigan State University, USA; McGill

University, Canada.

SCREENING PROCESS

> Compound miningExtensive proactive investigation of small series of

compounds, on which some biological tests have

already been performed, to assess them as potential

drug leads against the kinetoplastid parasites

(Chagas, HAT, VL), e.g. nitroimidazoles.

Partners: Sanofi , France; Pfi zer, USA;

GlaxoSmithKline, Tres Cantos, Spain.

> Chemical classesIdentifi cation of promising lead compounds from

different sources, libraries and collaborations with

pharmaceutical and biotech companies or other

PDPs, corresponding to specifi c chemical classes.

Performance of in vitro and in vivo screens of

chemical series to identify new compounds active

against kinetoplastid diseases.

Partners: Sanofi , France; Pfi zer, USA; Global Alliance

for Tuberculosis Drug Development (TB Alliance), USA;

GlaxoSmithKline, Tres Cantos, Spain; Drug Discovery

Unit at the University of Dundee, UK; Merck, USA;

Novartis Institute for Tropical Diseases, Singapore;

UNDP/World Bank/WHO’s Special Programme for

Research and Training in Tropical Diseases (TDR).

> Chemical diversityAccess to chemical diversity is essential to identify

potent and selective hits with acceptable drug-like

characteristics and to identify novel compounds

via high-throughput screening (HTS).

Partners: Pfi zer, USA; Genomics Institute of the

Novartis Research Foundation, USA; Drug Discovery

Unit at the University of Dundee, UK; Pfi zer, USA.

> Target basedScreening compounds and assessing their activity

against a specifi c target known to be essential

for parasite growth.

Partners: Drug Discovery Unit at the University of

Dundee, UK; TI Pharma, The Netherlands.

> ScreeningIdentifi cation of new active compounds via low- to

high-throughput screening assays in dedicated

centres:

• High-throughput screeningHigh-throughput screening of large-size libraries

for Leishmania and T. cruzi (Institut Pasteur Korea),

and T. b. brucei (Eskitis) have been developed and

are used to identify novel hit compounds. Screening

capacity is a key element of DNDi’s discovery strategy

as it enables the screening of large libraries/series

of compounds and therefore a quicker identifi cation

of hits/leads critical to discovery programmes.

Partners: Institut Pasteur Korea (IPK), South Korea;

Eskitis Institute (Griffi th University), Australia.

• Reference Screening CentresThe Swiss Tropical and Public Health Institute (Swiss

TPH), the Laboratory of Microbiology, Parasitology,

and Hygiene (LMPH) of the University of Antwerp, and

the London School of Hygiene & Tropical Medicine

(LSHTM) serve as reference screening centres to

ensure that screening methodologies are comparable,

and that in vitro and in vivo assays at different sites

and with different groups meet the same standard.

The centres also provide expert parasitology advice

that ensures the quality of data and work.

Partners: Swiss TPH, Switzerland; LMPH, University

of Antwerp, Belgium; LSHTM, UK.

LEAD OPTIMIZATION (as of May 2011)

HAT Consortium

Objective: To obtain optimized leads by progressing

‘hits’ with a good safety profi le and activity against

Trypanosoma brucei parasites.

Partners: Anacor, USA; SCYNEXIS, USA; Pace

University, USA; with the support of Swiss TPH,

Switzerland.

VL Consortium



Leishmania parasites.

Partners: Anacor, USA; Advinus Therapeutics, India;

Central Drug and Research Institute (CDRI), India; with

the support of LMPH, University of Antwerp, Belgium.

Chagas Consortium



Trypanosoma cruzi parasites.

Partners: Anacor, USA; Centre for Drug Candidate

Optimisation Monash University, Australia; Epichem,

Australia; Murdoch University, Australia; with the

support of Federal University of Ouro Preto, Brazil.

> SCREENING > LEAD SELECTION > LEAD OPTIMIZATION

Discovery is a three-stage process consisting of compound screening, lead selection, and lead optimization. The objective is to identify drug candidates that meet a predetermined set of criteria to enter the clinical development process. DNDi has entered into a number of partnerships aimed at ensuring that a robust portfolio is built by 2018.

1

DISCOVERY

4

IMPLEMENTATION

ASAQ, Fixed-Dose Artesunate/Amodiaquine Combination Therapy (Malaria)

Objective: To support the implementation of ASAQ;

to contribute to a comprehensive risk management

plan to collect data on tolerability and effectiveness

of ASAQ conducted by Sanofi , Medicines for Malaria

Venture (MMV), with the support of DNDi –

in particular, in Ivory Coast, a 2-year observation

study involving 15,000 patients. A manufacturing

technology transfer to Zenufa in Tanzania is

in development.

Achievements: Over 80 million treatments were

delivered, in collaboration with Sanofi , to 30 African

countries, by the end of 2010. A study completed

in 2009 in Liberia provided additional information

on the safety of ASAQ.

Major Partners since 2003: Sanofi , France; Centre

National de Recherche et de Formation sur le

Paludisme, Burkina Faso; Universiti Sains Malaysia;

Oxford University, UK; Institut de Recherche pour

le Développement, Senegal; Mahidol University,

Thailand; MSF; Epicentre, France; TDR; KEMRI,

Kenya; Indian Council of Medical Research (ICMR);

Zenufa, Tanzania; AEDES, Belgium; National Malaria

Control Programme, Ministry of Health, Burundi;

WHO, Burundi; Ministry of Health, Sierra Leone;

Komfo Anokye Teaching Hospital, Ghana.

ASMQ, Fixed-Dose Artesunate/Mefl oquine Combination Therapy (Malaria)

Objective: To continue pharmaceutical development

and registration of ASMQ in Latin America and

South-East Asia; to assess the potential utility of

ASMQ in Africa, where an effi cacy and safety study

of 940 children under fi ve years started in early

2011 in Tanzania, Kenya, and Burkina Faso.

Achievements: ASMQ was registered in Brazil

in 2008 and is included in Brazilian national

guidelines. A technology transfer took place in 2010

from Farmanguinhos, Brazil to Cipla in India, where

registration dossier has been submitted.

Major Partners since 2003: Farmanguinhos, Brazil;

Shoklo Malaria Research Unit, Thailand; Universiti

Sains Malaysia; Oxford University, UK; TDR; Cipla,

India; ICMR, India; Epicentre, France; Centre

Hospitalier Universitaire Vaudois, Switzerland;

National Institute of Medical Research, Tanzania;

KEMRI, Kenya; Centre National de Recherche et de

Formation sur le Paludisme, Burkina Faso.

NECT-Field – Nifurtimox-Efl ornithine Co-administration Therapy (HAT)

Objective: The Phase IIIb NECT-Field study in

DRC will further document the safety and ease of

use of the combination in real-life fi eld conditions

and in new populations, such as pregnant and

breastfeeding women, and children.

Achievements: Since March 2009 NECT is

included in the WHO Essential Medicines List.

NECT is implemented in 10 countries as fi rst-line

treatment of stage 2 sleeping sickness.

Major Partners: Epicentre, France; MSF; Swiss

TPH, Switzerland; National Trypanosomiasis Control

Programmes of the Republic of Congo and the

Democratic Republic of the Congo (DRC); HAT

Platform partners. With the collaboration of WHO,

drug donation from Sanofi and Bayer.

SSG&PM Paromomycin Combination Therapy (VL in Africa)

Objective: To assess the safety and effi cacy of

paromomycin to treat acute, symptomatic VL in

East Africa, with the goal of registering this drug

in Sudan, Ethiopia, Kenya, and Uganda. To develop

a shorter-course combination therapy, involving

paromomycin and sodium stibogluconate (SSG).

Achievements: The results of the trial showed

that SSG&PM combination therapy is as safe and

effective as the SSG standard monotherapy, with

the advantage of offering a shorter and cheaper

treatment course. After being recommended by

the WHO Expert Committee on the Control of

Leishmaniases as fi rst-line treatment for VL in East

Africa, SSG&PM is now implemented in Sudan.

To be registered in other East African countries.

Major Partners: KEMRI, Kenya; IEND, University of

Khartoum, Sudan; Addis Ababa University, Ethiopia;

Gondar University, Ethiopia; University of Makerere,

Uganda; LSHTM, UK; ASK, The Netherlands;

Ministries of Health of Ethiopia, Sudan, Kenya, and

Uganda; MSF; i+ solutions, The Netherlands; iOWH,

USA; LEAP.

New VL treatments – Asia (SD AmBisome®, PM+M / A®+M / PM+A®)

Achievements: In India, Phase III trial results

have been reported in 2010 for 3 combinations

(miltefosin e & paromomycin, AmBisome® &

miltefosine, AmBisome® & paromomycin – (DNDi

study) and single dose AmBisome® (Kala-Azar

Medical Research Centre study), all of which

showed effi cacy above 95%. Recommended

by the WHO Expert Committee on the Control

of Leishmaniases.

Objective: With TDR and iOWH, and under the

guidance of national vector-borne disease control

programmes, to evaluate new treatment modalities

as successful tools to control and support the

elimination strategies for VL in the most endemic

regions of South Asia.

Major Partners: ICMR, India; Rajendra Memorial

Research Institute of Medical Sciences, India;

Bihar State Health Society, India; National Vector

Borne Disease Control Programme, India; Kala-Azar

Medical Research Centre, India; iOWH, USA; TDR.

DNDi ’s R&D projects link scientists from around the world > MAKING DRUGS

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Photos credits: Anita Khemka-DNDi; João Roberto Ripper-

DNDi; Benoît Marquet-DNDi; Claude Mahoudeau-MSF.

• Number of estimated cases is currently 30,000 • Tsetse fl y, the vector for the trypanosome parasite, is present in 36 countries

in sub-Saharan Africa• The disease occurs in two stages: stage 1 is often not diagnosed and therefore the disease

goes undetected; in stage 2, HAT is fatal without treatment

Current Treatments

• For stage 1, pentamidine injections are used for T. b. gambiense HAT; suramin for T. b. rhodesiense HAT. Both drugs present adverse effects

• For stage 2, three treatments are available:– Melarsoprol: a highly toxic arsenical administered in ten intravenous injections; very painful

and failures are increasingly reported; 5% treatment-related mortality– Efl ornithine: a cancer drug shown to be safe and effective for HAT, but requires complicated

administration (4 infusions/day over 14 days)– NECT (Nifurtimox-Efl ornithine Combination Therapy), developed by DNDi and its partners,

available since September 2009; an improved therapy option, safer than melarsoprol, as well-tolerated and effi cacious as efl ornithine, and easier to administer

Human African Trypanosomiasis (HAT, sleeping sickness)

Leishmaniasis

• 500,000 cases of visceral leishmaniasis (VL) per year, 1.5 million cases of cutaneous leishmaniasis (CL) per year

• VL is the most severe form and fatal if left untreated (approx. 50-60,000 deaths per year)• Transmitted by the sandfl y and occurs in 98 countries on 4 continents• Signifi cant proportion of cases are children

Current Treatments

• Pentavalent antimonials: toxic, 30-day, hospital-based parenteral treatment with increasing treatment failures due to resistance

• Amphotericin B: dose-limiting toxicity, 15–20 day, hospital-based intravenous treatment• Liposomal Amphotericin B: effective, but very expensive; intravenously administered• Miltefosine: expensive and teratogenic• Paromomycin: registered in India (2006). Used in monotherapy, requires 3 weeks of

intramuscular administration• SSG&PM (sodium stibogluconate and paromomycin combination therapy), developed by

DNDi and its partners, implemented since 2010 in Sudan. Shorter-course, cost-effective, and improved therapy

• New treatments for VL in Asia, AmBisome® in single dose and combination therapies

Malaria

• One of the three most deadly diseases in Africa• 50% of world population at risk; endemic in 106 countries• 225 million cases of malaria worldwide each year, with nearly 1 million deaths

Current Treatments

• Several artemisinin-based combination therapies (ACTs) developed since widespread appearance of drug resistance to chloroquine – easy and affordable treatment

• New ACTs, such as the two fi xed-dose combination therapies ASAQ and ASMQ developed by DNDi and its partners, launched in 2007 and 2008, are currently in use

• Despite WHO recommendation of ACTs, implementation is far from optimal

Paediatric HIV

• 2.5 million children (<15 yrs) living with HIV and 370,000 infected in 2009• 700 deaths in children every day, mostly in Africa• Most (>85%) infected children are not treated; one-third of infected infants will have died

by one year of age, and about half will have died by two years of age

Current Treatments

• Complexity of antiretroviral (ARV) drugs• 1st and 2nd line treatments: mostly for adults• Need for a better combination treatment for children under 3 years old which is

consistent with 2010 WHO Recommendations for HIV infection in infants and children

Helminth infections

• Filarial diseases, part of helminth infections, include lymphatic fi lariasis (LF), onchocerciasis, and Loa loa fi lariasis (loiasis)

• 120 million humans estimated to be infected by LF; most infections are asymptomatic • 17 million humans estimated to be infected by onchocerciasis• Loiasis occurs in West Africa; 12-13 million humans estimated to be infected• Patients co-infected with onchocerciasis and loiasis cannot be easily treated with current

drugs due to risk of major adverse effects

Current Treatments

• Drugs used as chemopreventive therapy through mass drug administration (MDA) with repeated dosing on an annual or semiannual basis for up to 15 years

• Two treatments for MDA: ivermectin (onchocerciasis) and DEC+Albendazole (LF)• MDA treatment kills juvenile worms so patients are not cured• Need for a macrofi laricide to reduce the number of MDA treatment cycles and to treat

co-infections

2011 R&D PORTFOLIO













Germany


International







(AECID) / Spain






of America















Board of Directors


Founding Partners




























Quartier Socimat

La Gombe, Kinshasa


Affi liate


New York, NY 10005

USATel: +1 646 616 8680

www.dndina.org

Regional Offi ces


PO Box 20778

KNH 00202 Nairobi

KenyaTel: +254 20 273 0076


Rua Santa Heloisa 5


BrazilTel: +55 21 2215 2941

www.dndi.org.br




3, Red Cross Road

New Delhi 110-001

IndiaTel: +91 11 2373 1635



JapanTel: +81 3 6304 5588

www.dndijapan.org




Project Support

Offi ce













TARGET 2003-2018:

EUR 400 million


DiscoveryRLO LS


Exploratory




Univ.• FUOP





Exploratory

Nitroimidazole (VL)


K777 (Chagas)











ASMQ (Malaria)


ASAQ (Malaria)


Amodiaquine


Co-administration


co-administration





DNDi Portfolio









2008









2010

malaria

sleeping sickness

stage 2VLVL

TREATMENTS

DELIVERED

DNDi has made

new treatments

available each year

since 2007






partner (Zenufa)

2007

malaria







institutions.

> HAT Platform






Main Partners:











with WHO.






monitors.

Main Partners:










with WHO.






















Sudan

Uganda

Angola

Republic of

the Congo

Democratic

Republic

of the Congo

Chad

Central African

Republic

Sudan

Kenya Uganda

Ethiopia

Mexico

Bolivia

Brazil

Argentina

2011 R&D PORTFOLIO













Germany


International







(AECID) / Spain






of America















Board of Directors


Founding Partners




























Quartier Socimat

La Gombe, Kinshasa


Affi liate


New York, NY 10005

USATel: +1 646 616 8680

www.dndina.org

Regional Offi ces


PO Box 20778

KNH 00202 Nairobi

KenyaTel: +254 20 273 0076


Rua Santa Heloisa 5


BrazilTel: +55 21 2215 2941

www.dndi.org.br




3, Red Cross Road

New Delhi 110-001

IndiaTel: +91 11 2373 1635



JapanTel: +81 3 6304 5588

www.dndijapan.org




Project Support

Offi ce













TARGET 2003-2018:

EUR 400 million


DiscoveryRLO LS


Exploratory




Univ.• FUOP





Exploratory

Nitroimidazole (VL)


K777 (Chagas)











ASMQ (Malaria)


ASAQ (Malaria)


Amodiaquine


Co-administration


co-administration





DNDi Portfolio









2008









2010

malaria

sleeping sickness

stage 2VLVL

TREATMENTS

DELIVERED

DNDi has made

new treatments

available each year

since 2007






partner (Zenufa)

2007

malaria







institutions.

> HAT Platform






Main Partners:











with WHO.






monitors.

Main Partners:










with WHO.






















Sudan

Uganda

Angola

Republic of

the Congo

Democratic

Republic

of the Congo

Chad

Central African

Republic

Sudan

Kenya Uganda

Ethiopia

Mexico

Bolivia

Brazil

Argentina

Documents

1553 DNDI portfolio 2011 v17 - gov.uk...2011 R&D PORTFOLIO A Needs-Driven Collaborative R&D Model for Neglected Diseases SUPPORT DNDi Thanks to our donors, DNDi has successfully secured