DNDi’s objective is to deliver 11 to 13 new treatments by 2018 and to maintain a robust pipeline to support long-term objectives. R&D MODEL, STRATEGY & PORTFOLIO

Beginning with the end in mind

Since its inception, DNDi has delivered six new treatments and built a robust pipeline with 12 new chemical entities in pre-clinical and clinical stages. DNDi’s portfolio matured in 2012, with six treatments now registered or available to patients, promising compounds progressing through the clinical pipeline, and new chemical libraries or compounds being screened.

DNDi’s R&D strategy is defi ned by patients’ needs and relies end-product are. These are summarized into Target Product on the combination of long-term goals, through the develop- Profi les (TPPs), taking the target population in need as the ment of new chemical entities (NCEs) to support sustainable starting point, then defi ning the ideal technical attributes of control or elimination of neglected diseases, with short-term effi cacy, safety, and ‘user-friendliness’ (i.e. duration, mode of goals based on the optimization of existing drugs, to address administration, storing conditions), as well as cost. TPPs are more immediate and urgent needs. Building the future of novel developed with input from disease experts, representatives and effective treatments for neglected diseases includes of Ministries of Health and National Control Programmes in progressing promising compounds through the develop- endemic countries, WHO representatives, leading clinicians ment pipeline, establishing collaborations with the pharma- and researchers, as well as health workers, all of whom deal ceutical industry, biotechs, academia, and increasingly with with the realities of the diseases in the fi eld. DNDi’s target other product development partnerships (PDPs), to access diseases call for clear TPPs that are based on epidemiologi- new chemical libraries or compounds using cutting-edge cal data and cater for the needs of specifi c populations – the technologies, such as high-throughput screening (imaging poorest of the poor, both adults and children. technology-based high-content screening assays against intracellular Leishmania and T. cruzi), as well as develop- ing strong lead optimization consortia. DNDi also builds By Keeping the Focus on Patients and their Needs, and consolidates capacity for clinical research in the fi eld, DNDi’s Project Portfolios Balance Long-term by supporting regional platforms for each kinetoplastid dis- and Short/medium-term Projects ease. So far, DNDi has delivered six new treatments for four > Long-term projects – to develop innovative diseases: malaria, sleeping sickness, visceral leishmaniasis, medicines with new chemical entities and Chagas disease. > Medium-term projects – to identify existing The key features of the new drugs/treatments DNDi seeks to pre-clinical or clinical stage compounds suitable develop are at the centre of the organization’s target disease for therapeutic switching, or for further strategies, which defi ne the patient need and desired outcome improvements via improved formulations of each product, taking into account the current research > Short-term projects – to make existing drugs landscape as well as the health systems in endemic coun- available in broader geographic areas and to tries. Because drug development can be a long process, it develop better treatments, including is essential to plan from the outset with the end in sight, i.e. combinations, from existing drugs agreeing on what the key features and attributes of the intended

DNDi Annual Report 2012 13 R&D MODEL, STRATEGY & PORTFOLIO

With the right dose, the right formulation, the right taste, no Malaria: By the end of 2012, more than 180 million ASAQ refrigeration required, a well-designed product and adapted treatments had been distributed in 30 African countries. In packaging, DNDi and partners aim to ensure the best treat- addition, more than 20 million treatments had been ordered ment is delivered to those in need in all endemic countries for the private sector in seven countries in Africa within the at an affordable price; by engaging and seeking early advice Affordable Medicines Facility – malaria (AMFm). ASMQ received from regulatory authorities and the WHO, regulatory and pre-qualifi cation from the WHO and was registered in Malay- fi eld adoption can be greatly facilitated. This implies look- sia and Myanmar. It is now included on the WHO Essential ing for treatments that can be delivered at the village or pri- Medicines Lists for adults and children.(1) mary healthcare level to avoid the long distances that many patients must travel, as well as the time and money required In 2011, DNDi’s portfolio was extended to paediatric HIV and for patients and family members to reach and stay at district fi larial diseases: hospitals (or secondary healthcare level). DNDi’s TPPs are publicly available on the web (www.dndi.org). Paediatric HIV: The added arm to the CHAPAS-2 trial (sponsored by MRC), which aimed to clinically assess the Human African trypanosomiasis (HAT): In 2012, fexini- protease inhibitor lopinavir/ritonavir in the existing sprinkle dazole entered a pivotal Phase II/III study in the Democratic (minitablet) formulation in children between 1-4 years of Republic of the Congo and the Central African Republic. If age (additional CHAPAS-2 cohort), was concluded in 2012. successful, fexinidazole could become the fi rst oral-only treatment for sleeping sickness patients. SCYX-7158, also

an oral drug candidate, entered fi rst-in-human studies in Filarial diseases: Work was undertaken to develop a healthy volunteers. Promising backups are in lead optimi- pre-clinical formulation of fl ubendazole, a potential mac- zation and pre-clinical phases. NECT is now on the national rofilaricide that allows oral absorption, and non-clinical essential medicines lists of 12 countries across Africa and development progressed, notably studies required to fi le an has almost entirely replaced melarsoprol and efl ornithine Investigational New Drug (IND) application. monotherapy as first-line treatment for second stage T. b. gambiense sleeping sickness. It is now included on the WHO Essential Medicines List for children.(1)

Leishmaniasis: Recruitment for the LEAP 0208 study in East Africa, which aims to evaluate the safety and effi cacy of miltefosine alone as well as combination treatments for VL ended in March 2012 – results will be available at the begin- Target Product Profi le (TPP) ning of 2013 and will inform the decision to evaluate one of the combinations in a Phase III trial. SSG&PM is available and implemented in Sudan and Uganda. In 2012, it was added > Indications: Which disease(s)? to Kenya’s national VL guidelines. New drug combination > Population: Which type of patients and where? therapies are available for Asia. Backup compounds are at > Clinical Effi cacy: Does it treat the infection the pre-clinical stage and promising leads are in the lead effectively? optimization phase. > Safety and Tolerability: What level of acceptability for adverse events? Chagas disease: The paediatric dosage form of benznida- zole, registered in Brazil at the end of 2011, is now included > Stability: How long is the shelf-life of the drug(s), on the WHO Essential Medicines List for children.(1) Recruit- and what are the storage conditions? ment for the E1224 Phase II clinical trial concluded in June > Route of Administration: How is it administered 2012 and the fi rst results will be available in the second half to patients? of 2013. In addition, in 2012, DNDi received funding for the > Dosing Frequency and Treatment Duration: fi rst-ever large-scale study involving treatment of non-human How often and how long must it be given? primates (macaques) naturally infected in their outdoor living environment with Trypanosoma cruzi with the aim of identi- > Cost: Will it be affordable to the target fying new biological markers for the evaluation of treatment population? effi cacy in Chagas disease.

(1) As of July 2013: www.who.int/medicines/EMP_Website_notice_EML_July2013.pdf

14 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO

6 new treatments and 12 new chemical entities in the pipeline

Portfolio 2012

Research Translation Development Implementation Screen Hit to Lead Lead Opt. Pre-clinicalPhase IPhase IIa/PoC Phase IIb/III Registration Access

Nitroimidazole Oxaborole Fexinidazole NECT backup SCYX-7158 HAT Nifurtimox-Efl ornithine Combination Therapy Oxaborole backup

Nitroimidazole VL-2098 Fexinidazole New VL treatments SSG&PM backup (VL) for Bangladesh (VL) Sodium Stibogluconate S & Paromomycin C New VL treatments Combination Therapy for Africa for VL in Africa Anfoleish R (CL) E New treatments for New treatments HIV/VL co-infection for VL in India

LEISHMANIASIS for Africa

E N New VL treatments I for Latin America N Fenarimol Azoles Benznidazole G series E1224 Paediatric dosage form Nitroimidazole K777 CHAGAS DISEASE

Biomarkers

Flubendazole

FILARIAL DISEASES Macrofi laricide

Improved PI PI Sprinkles for fi rst-line (CHAPAS-2) treatment Superboosting PAEDIATRIC HIV - TB-HIV

ASAQ FDC Artesunate Amodiaquine Fixed-Dose Combination MALARIA ASMQ FDC Artesunate-Mefl oquine Fixed-Dose Combination

New Chemical Entity (NCE) Fexinidazole (for HAT and VL) = 1 NCE

DNDi Annual Report 2012 15 R&D MODEL, STRATEGY & PORTFOLIO

RESEARCH Increasing efforts to discover new drugs

he earliest stages of drug discovery consist of three series to enter the Hit-to-Lead and LO phases in order to Tphases: sourcing and screening compounds, hit-to-lead bring additional pre-clinical candidates to the DNDi discov- expansion up to lead selection, and lead optimization (LO). ery pipeline. In order to ensure an uninterrupted supply of quality active DNDi’s discovery strategy relies on partnerships with public series to its lead optimization programmes, DNDi screens (e.g. universities and academia) and private partners (phar- libraries from its pharmaceutical, biotech, academic and maceutical and biotechnology companies); lead optimization PDP partners using defi ned selection criteria, then reviews/ activities are carried out by two consortia that work across prioritizes series according to the probability of success. all three kinetoplastid diseases, enabling cross-talk between At the same time, DNDi secures back-up series to address diseases for each compound series being investigated. the attrition rate in optimization programmes.

For 2012, DNDi refocused its early Screening Hit Expansion Lead Optimization Lead to Candidate discovery and LO efforts on the dis- covery and development of novel Reiterative cycles of active lead series for leishmaniasis. medicinal chemistry Pharmaceutical chemistry This was achieved through a signifi - cant increase in the high through- put screening capacity against GPL Toxicology Leishmania parasites in collabo- Parallel assessment of DMPK, Tox, and Potency Drug ration with the University of Dundee, Candidate as well as prioritizing active hit

In 2012, DNDi screened over 150,000 compounds in more than

3T3 cells infected with T. cruzi (DRAQ5 staining, THP1 cells infected with L. donovani-eGFP 420,000 20x Objective) Cytoplasm selection (DAPI staining, 20x Objective) screening assays Over 20 active series have been advanced to the Hit-to Lead and Lead Optimization phases for the three kinetoplastid diseases with priority given to visceral leishmaniasis. THP1 cells infected with L. donovani-eGFP (DAPI THP1 cells infected with L. donovani-eGFP staining, 20x Objective) Cytoplasm selection (DAPI staining, 20x Objective) Infected cells

16 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO

SCREENING (TB Alliance). Access to specifi c sets of compounds (inhibitors of a specifi c target and chemical classes) from DNDi’s phar- Main partners: maceutical partners (e.g. Sanofi , GSK, or MSD) was one of the AbbVie (formerly Abbott), USA; Actelion, Switzerland; Anacor, major focuses of DNDi’s discovery strategy in 2012. USA; Astellas, Japan; AstraZeneca, Sweden; Bayer, Germany; Bristol-Myers Squibb, USA; Celgene, USA; E.I. du Pont de Nemours, USA; Eisai Co., Ltd, Japan; Genomics Institute of the Compound mining Novartis Research Foundation, USA; GlaxoSmithKline, Tres Proactive acquisition and investigation of compounds from Cantos, Spain; Institute of Medical Microbiology, Immunology, selected series associated with a signifi cant level of available and Parasitology, Hospital University of Bonn, Germany; information (biological activities, pre-clinical dossier, published Medicines for Malaria Venture, Switzerland; Merck (MSD), USA; data, safety profi le, among others) enables identifi cation of Northwick Park Institute for Medical Research, UK; Novartis Institute for Tropical Diseases, Singapore; Pfi zer, USA; Pfi zer candidates with potential for further development – ideally Animal Health, USA; Sanofi , France; Sigma-Tau, Italy; ready to enter into pre-clinical or later stage without further WHO-TDR; TB Alliance, USA; Institut Pasteur Korea (IPK), South optimization – for the target diseases. A successful example Korea; Drug Discovery Unit (DDU) at the University of Dundee, of this strategy is fexinidazole. DNDi has extended and applied UK; Swiss Tropical and Public Health Institute (Swiss TPH), this strategy in collaboration with its pharmaceutical partners. Switzerland; Laboratory of Microbiology, Parasitology, and Hygiene (LMPH), University of Antwerp, Belgium; and London School of Hygiene & Tropical Medicine (LSHTM), UK; TI Pharma, Reference screening centres The Netherlands The Swiss Tropical and Public Health Institute (Swiss TPH), Leadership: the University of Antwerp (LMPH), and the London School Discovery and Pre-Clinical Director: Robert Don; of Hygiene & Tropical Medicine (LSHTM) serve as reference Discovery Manager: Jean-Robert Ioset 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 standards. The High-throughput screening centres also provide expert parasitology advice that ensures High-throughput screening (HTS) of large libraries for Leish- the quality of DNDi’s data and work. mania (IPK and DDU) and T. cruzi (IPK) have been developed and used to identify novel hit compounds. Adequate screening capacity is a key element of DNDi’s discovery strategy, as it ena- bles the screening of large libraries/series of compounds and LEAD OPTIMIZATION therefore a quicker identifi cation of hits/leads for optimization. Main partners: Centre for Drug Candidate Optimisation (CDCO)/Monash Chemical diversity University, Australia; Epichem, Australia; Murdoch University, This approach aims to mine new chemical territories to identify Australia; Federal University of Ouro Preto (UFOP), Brazil; additional classes of molecules of potential interest in terms Institut Pasteur Korea (IPK), Korea; iThemba, South Africa; of drug development for DNDi’s target diseases. Illustrating LMPH, University of Antwerp, Belgium; LSHTM, UK; Murdoch this approach is the 2011 research collaboration with Pfi zer University, Australia; SCYNEXIS Inc., USA; TB Alliance, USA; University of Auckland, New Zealand; Pace University, USA; to screen the Pfi zer GDRS II set (representative of the entire Pfi zer, USA; WuXi AppTech, China Pfi zer library in terms of chemical diversity, i.e. 150,000 com- Leadership: pounds) against all three kinetoplastid diseases. In addition, Discovery and Pre-Clinical Director: Robert Don; Head of Drug DNDi is evaluating access to various libraries based on chemical Discovery: Eric Chatelain; Head of Drug Discovery: Charles diversity with its pharmaceutical partners, including, among Mowbray; Project Coordinator: Stéphanie Braillard others, Sanofi and GSK.

Mining for chemical classes DNDi’s strategy for its lead optimization consortia is es advance Discovery activities are typically associated with high attri- new chemical classes identified through screening pro- tion rates, especially in the case of candidates not associated grammes, as well as to develop backup compounds that with any pre-clinical data other than in vitro effi cacy. In order can rapidly replace frontrunner compounds in case of fail- to lower this attrition rate, mining for chemical classes relies ure. These consortia bring together expertise in chemistry, on the identifi cation of promising chemical classes of which a biology, drug metabolism, and pharmacokinetics (DMPK), member has been successfully advanced in drug development in vivo screening, drug safety assessment, and pre-formula- for other disease indications. From libraries originating from tion. Optimization efforts are focused on improving the lead collaborating pharmaceutical and biotech companies, prom- compound’s properties for absorption into the bloodstream ising compound classes are identifi ed by sampling a subset following oral dosing, distribution of the compound to the site of representative compounds and testing for antiprotozoal of infection(s), modifi cation of residues in the compound that activity. Examples of interesting classes include oxaboroles are prone to breakdown or clearance and which increase tol- (Anacor Pharmaceuticals), pyridones (GSK), and nitroimidazoles erability and safety for the patient.

DNDi Annual Report 2012 17 R&D MODEL, STRATEGY & PORTFOLIO

HUMAN AFRICAN TRYPANOSOMIASIS (HAT) Working together to develop the right Sleeping Sickness tools for elimination

he WHO, in its recently published NTD Roadmap,(1) has The reality of HAT management remains challenging, even Tslated human African trypanosomiasis for elimination by more so in the most remote settings such as the small vil- 2020, measuring elimination by an annual prevalence rate of lages where the current treatments are not feasible for use, less than 1 case per 10,000 population in historical foci.(2) This and where the current diagnostics still require specialized objective comes at a time when a steady decline in the numbers mobile teams. The rapid diagnostics, in addition to the two of reported cases has been recorded over 15 years, resulting oral treatments in development by DNDi and partners, could from intensifi ed efforts to detect and promptly treat patients dramatically change diagnosis and treatment by making tools and to control the disease. In 1995, there were 30,000 reported available in the rural health centres in sub-Saharan Africa, and 300,000 estimated cases of HAT. Today there are approxi- thus facilitating the decentralization of HAT services and sur- mately 7,000 reported cases and approximately 30,000 esti- veillance, and so directly contributing to elimination targets. mated cases annually, thanks to the efforts and successes of In the current context of a declining number of patients that National Control Programmes (NCPs) of endemic countries, can participate in clinical research projects and with several together with WHO, MSF, Sanofi , Bayer, and many other key promising tools still requiring clinical trial testing, the need actors. A new combination therapy, NECT, that is effective and for stronger collaboration and coordination of the key players safe, but also simplifi es treatment, was introduced by DNDi is vital. It will later ensure that the right tools reach patients and partners in 2009 for patients with stage 2 HAT, and two oral through national programmes. drugs are currently in clinical trials. Eliminating the disease, however, will not happen Ideal Target Product Profi le without concerted efforts for HAT to bring simple and safe oral drugs and rapid diagnostics (1) Accelerating work to overcome the global impact of neglected tropical A new treatment for adults and to the field, supported by diseases: A roadmap for implementation, WHO, January 2012. children www.who.int/neglected_diseases/NTD_RoadMap_2012_Fullversion.pdf fine-tuned control strate- (2) Report of a WHO meeting on elimination of African trypanosomiasis > Effective against both stages of gies according to disease (Trypanosoma brucei gambiense), World Health Organization, April 2013. the disease (3) (3) Simarro PP. et al. (2013) Diversity of human African trypanosomiasis prevalence and sustained epidemiological settings requires fi ne-tuning control strategies to facilitate > Active against both causative surveillance programmes. disease elimination. Research and Reports in Tropical Medicine 4:1–6. parasite sub-species: Trypanosoma brucei gambiense and T.b. rhodesiense > With less than 0.1% drug-related mortality > With at least 95% effi cacy at 18 months follow-up > Safe for pregnant and lactating women > Easy to use: short-course (7, maximum 10 days), oral, once a day, requiring no monitoring. > Affordable > Adapted to tropical climates (three-year shelf-life)

18 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO

FACT SHEET

Human African T. b. gambiense Trypanosomiasis T. b. rhodesiense Epidemic Endemic Sleeping Sickness

WHAT IS THE IMPACT OF HAT? WHAT ARE THE CURRENT TREATMENTS treatment requires trained health staff and The number of reported cases is AND THEIR LIMITATIONS? an extended hospital stay (56 intravenous approximately 7,000, but the number of Available treatments are limited, diffi cult to infusions taking two hours each to actual cases is estimated to be 30,000.(1) administer, often toxic, and stage-specifi c. administer, over 14 days and four times each day); NECT (nifurtimox-efl ornithine Fatal if untreated, the disease affects > Stage 1: pentamidine and suramin, mainly those living in remote areas with combination therapy), a simplifi ed therapy require injections and are ineffective for option for stage 2 T. b. gambiense sleeping limited access to adequate health services. stage 2. Almost eliminated in the 1960s, sickness, with only 14 infusions of transmission increased again as a result of > Stage 2: melarsoprol, a toxic arsenic efl ornithine over 7 days and 10 days of oral war, population displacement, poverty, and derivative that causes pain and fatal treatment with nifurtimox. While not the encephalopathies in up to 5% of those who most appropriate treatment to support the collapse of adequate support to the (3) control activities conducted within health receive it, and is increasingly ineffective, elimination efforts as it requires a hospital systems. with reports of drug resistance and setting, NECT does provide a major treatment failure in some foci; improvement in case management. Recent successes and an impressive drop efl ornithine, diffi cult to administer as in the number of reported cases call for renewed hope, but there is still work to be done, as some areas are not covered by WHAT IS DNDi DOING TO ADDRESS UNMET TREATMENT NEEDS? surveillance and control efforts. At its inception, DNDi’s short-term strategy was to make better use of HOW IS HAT TRANSMITTED? existing treatments by combining drugs already in use. In September 2009, HAT is transmitted to humans DNDi and partners launched the fi rst new treatment for sleeping sickness by two sub-species of the in 25 years: nifurtimox-efl ornithine combination therapy (NECT). NECT was parasite Trypanosoma brucei included on the WHO Essential Medicines List (EML) in 2009 and is now (T. b.) through the bite of the recommended as fi rst-line treatment in 12 endemic countries. In December tsetse fl y: T. b. gambiense 2012, it was submitted for inclusion on the WHO EML for children. (West and Central Africa, As a medium-term strategy, DNDi initiated a compound mining effort to responsible for the vast majority of cases) identify existing chemical compounds with potential against kinetoplastid and T. b. rhodesiense (East Africa). The disease affects 36 countries in sub- diseases. This resulted in the rediscovery of fexinidazole, which completed Saharan Africa, but 8 countries report 97% Phase I clinical development in 2011. Fexinidazole entered a pivotal of all cases (see map), and over two-thirds Phase II/III study in 2012 and is currently recruiting patients in the DRC. of those are reported in the Democratic An agreement was signed in 2009 with Sanofi as the industrial partner for Republic of the Congo.(2) Man is the this project. essential reservoir for T. b. gambiense. In order to build a strong pipeline for long-term drug discovery, DNDi WHAT ARE THE SYMPTOMS? established a HAT Lead Optimization Consortium. The identifi cation of the HAT occurs in two stages: oxaborole SCYX-7158 represents the fi rst success of this consortium. SCYX-7158 successfully progressed through pre-clinical development and > Stage 1: the hemolymphatic stage – after some additional studies, entered Phase I clinical development in early includes non-specifi c symptoms like 2012 and should be completed in 2013. Other backup compounds continue headaches and bouts of fever (and generally goes undiagnosed without active to be evaluated by the consortium. HAT surveillance). In addition, DNDi supports the HAT Platform (see page 49) that was > Stage 2: the later, neurologic stage launched in Kinshasa (Democratic Republic of the Congo – DRC) in 2005. – occurs when the parasite crosses the The HAT Platform is a clinical research and access-supporting network that blood-brain barrier and leads to serious brings together key players in the fi ght against sleeping sickness from sleep cycle disruptions, paralysis, Angola, the Central African Republic, Chad, DRC, Republic of the Congo, progressive mental deterioration, and Sudan, South Sudan, and Uganda. ultimately, without effective treatment, death. By 2018, DNDi aims to deliver from its HAT-specifi c portfolio: A lumbar puncture is needed to > An oral, safe, effective treatment for stage 2 HAT, ideally to be used differentiate between the two stages for with the same regimen for stage 1 HAT the administration of proper treatment.

(1) www.who.int/mediacentre/factsheets/fs259/en/ (2) Simarro PP. et al. (2008) Eliminating human African trypanosomiasis: where do we stand and what comes next? PLoS Med 5: 55. (3) Blum J. et al. (2001) Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis. Trop Med Int Health 6: 390-400.

DNDi Annual Report 2012 19 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Partners: Lead Optimization Consortium – TB Alliance, USA; University of Nitroimidazoles backup – Oxaborole backup Auckland, New Zealand; SCYNEXIS Inc., USA; Pace University, USA; 2012 OBJECTIVES: The nitroimidazole backup programme for HAT Research Wuxi AppTech, China > Continue the lead optimization has been searching for a compound with a programme with the goal of a backup lower projected human dose than fexinidazole Leadership: oxaborole. Assess the front-running to simplify dosing and mitigate any potential Discovery and Pre-clinical Director: compounds SCYX-6086 and SCYX- issues with tolerance. Work at WuXi AppTech Robert Don; Head of Drug 8210 in rat toxicity studies and the University of Auckland allowed the Discovery: Charles Mowbray; > Evaluate the lead nitroimidazole preparations of enantiomers of the nitroimida- Project Manager: Ivan Scandale; backup RJ164 to determine if suitable zole SN29971/SCYX-1227; after parasitology Project Coordinators: Delphine to progress further and in vitro DMPK profi ling, the enantiomer Launay, Stéphanie Braillard > Initiate a new Lead Optimization SCYX-2035811 was identifi ed as the active iso- Project start: (LO) programme with the LO USA mer and retained the good metabolic stability Consortium to select a new chemical April 2007 of the racemate. A synthetic route to SCYX- series for LO 2035811 has been developed and scaled-up to provide active pharmaceutical ingredient (API) for further characterization. In the mouse The prototype oxaborole SCYX-7158 is pro- acute model of HAT, SCYX-2035811 has shown gressing through Phase I clinical trials. A excellent activity at doses down to 12.5 mg/kg range of structurally diverse oxaboroles with for 7 days. The dose response for this com- good activity against T. brucei were profi led pound will be further explored and a paral- in an animal pharmacokinetic (PK) study and lel PK assessment, including brain levels, will several promising candidates with shorter be carried out before the progression of this half-lives than SCYX-7158 were identifi ed. In compound into the mouse stage 2 CNS model depth DMPK and in vitro parasitology profi l- to enable a full comparison with fexinidazole. ing narrowed the selection to SCYX-8210 and The nitroimidazole fexinidazole is progressing SCYX-0682, which may offer good backups well in Phase II/III clinical trials. The need for a to SCYX-7158 if needed. SCYX-7158 continues backup compound is therefore not urgent at to make good progress in Phase I clinical tri- this stage and only limited work will be carried als, so at present there is no urgent need for a out in 2013 on the backup programme. backup compound. Thus, only limited further development of SCYX-8210 and SCYX-0682 will be performed in 2013.

Oxaborole SCYX-7158 Partners: Anacor Pharmaceuticals Inc., USA; 2012 OBJECTIVES: development progressed SCYNEXIS Inc., USA; Advinus > Completion of a GLP (Good successfully through Therapeutics, India; Penn Pharma, Translation Laboratory Practice) safety pack- 2010, and all pre-clinical UK; Swiss TPH, Switzerland; Pace 14 PATIENTS age (reprotox), process development, data were published in University, USA out of manufacture of the API, formulation, 120 recruited PLoS NTDs in June 2011.(1) Leadership: and be ready for regulatory submis- at 1 site Batches of drug sub- Discovery and Pre-clinical Director: sions for Phase I clinical trials stance and drug product Robert Don; Head of HAT Clinical > Initiate oxaborole SCYX-7158 Phase 1 (capsules) were produced Programme: Antoine Tarral; study according to current good manufacturing prac- Clinical Manager: Séverine Blesson; tices (cGMP) and supplied for the Phase I clini- Head of Pharmaceutical cal trial. In 2012, a robust tablet formulation Development: Steve Robinson; SCYX-7158 belongs to a unique boron-based was also developed in order to supply Phase Project Coordinator: Delphine chemical class, the oxaboroles, which was II/III clinical trials, and manufacturing is planned Launay originally provided by Anacor Pharmaceuticals for mid-2013. and screened for activity against T. brucei at Following clearance by the French ethics com- Project start: January 2010 the University of California San Francisco. A mittee and regulatory authority, SCYX-7158 unique collaboration between DNDi, Anacor entered fi rst-in-human studies in March 2012 and Pharmaceuticals (a biopharmaceutical com- became DNDi’s fi rst entity resulting from its own pany in Palo Alto, California, USA) and lead optimization efforts to enter Phase I clinical SCYNEXIS (a drug discovery and develop- studies. These studies are performed in order to ment company based in Research Triangle assess its safety, tolerability, pharmacokinetics, Park, North Carolina, USA), within a consor- and pharmacodynamics in healthy volunteers of tium that also included Pace University (USA) sub-Saharan origin. Following the fi rst dose of and Swiss TPH, enabled the identification SCYX-7158, pharmacokinetic results showed a of SCYX-7158, selected as a promising pre- longer than expected half-life in human plasma. clinical candidate in late 2009. In pre-clinical Additional cohorts in humans assessed the safety studies, SCYX-7158 was shown to be safe and profi le, and following results from the intermediate effi cacious to treat stage 2 HAT, as it is able dog study, the ascending dose study re-started to cross the blood-brain barrier. Pre-clinical in early 2013. (1) Jacobs RT. et al. (2011) SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis. PLoS Negl Trop Dis 5: e1151. 20 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Fexinidazole Partners: Sanofi , France; Swiss TPH, 2012 OBJECTIVES: Sanofi : DNDi is responsi- Switzerland; Programme > Start pivotal Phase II/III trial in three ble for pre-clinical, clinical, National de la Lutte Contre la Development African countries 17 PATIENTS and pharmaceutical devel- Trypanosomiase Humaine Africaine > Launch the trial in Q2 in three sites out of 510 opment, while Sanofi is (PNLTHA) DRC; Médecins Sans (DRC) and Q3 in the remaining sites recruited responsible for the indus- Frontières; and other HAT Platform (CAR, DRC, South Sudan) at 4 sites trial development, registra- members > Prepare EMA discussion for stage 1 tion, and production of the of the disease drug at its manufacturing Leadership: > Collaborate with FIND to develop new sites. A safe API manufacturing process, able Head of HAT Clinical Programme: tools for diagnosis and follow up to be commercialized, has been developed in Antoine Tarral; Medical Manager: collaboration with Sanofi . The study will recruit Olaf Valverde; Clinical Manager: patients at six clinical sites in DRC and one Séverine Blesson; Head of Fexinidazole is the fi rst success of the exten- in CAR. By the end of 2012, 17 patients had Pharmaceutical Development: sive compound mining efforts pursued by been recruited at four active sites in DRC. Two Steve Robinson DNDi within the nitroimidazole project initi- additional sites will open in 2013: one in CAR, ated in 2005. This drug entered Phase I fi rst- another in DRC ready to start Q2 2013. No site Project start: in-human studies in September 2009 and was chosen in South Sudan. April 2007 Phase II/III in October 2012. This single piv- otal Phase II/III study aims to prove the safety and effi cacy of fexinidazole, with NECT as the active comparator. The study was initiated and is conducted by DNDi in collaboration with the Swiss TPH and the human African trypanosomiasis national control programmes of the Democratic Republic of the Congo (DRC) and Central African Republic (CAR), in addition to MSF. DNDi is co-developing the drug with

NECT – Nifurtimox-Efl ornithine Combination Therapy Partners: Médecins Sans Frontières (MSF); 2012 OBJECTIVES: In September 2012, DNDi Swiss TPH; PNLTHA DRC; > Support replacement of melarsoprol and its partners concluded HAT Platform members Implementation by NECT as fi rst-line treatment for 3,000 the follow-up of patients 2nd stage HAT in remaining sites TREATMENTS included in the ‘NECT- Leadership: > Increase advocacy for continued in 2012, Field’ study, launched Head of HAT Clinical Programme: international support to R&D activities 2,618 of which in 2009. The final report Antoine Tarral; Medical Manager: in DRC. (including diagnostics) for HAT On the EML is being prepared, and Olaf Valverde results will be shared of 12 countries Project start: through scientific publi- May 2004 NECT was developed by Epicentre, MSF, cations. This Phase IIIb DNDi, Swiss TPH, and the national HAT con- study documents the safety, effectiveness, trol programmes of the Republic of the Congo and ease-of-use of NECT in real-life conditions, and DRC as a combination of eflornithine in specifi c populations such as children and and nifurtimox. It quickly became first- pregnant and breastfeeding women. A total line treatment for the neurological stage of of 630 patients were enrolled in the study, T. b. gambiense sleeping sickness, as it is including 100 children, 13 pregnant women, simpler to administer than efl ornithine alone, and 34 breastfeeding women. making it more adapted to fi eld conditions. NECT was included on the WHO Essential Medicines List in 2009. As of December 2012, Distribution of stage 2 HAT treatments all countries endemic to T. b. gambiense had in DRC, 2012 added NECT to their national essential medi- DFMO (Efl ornithine) 1% cines list. Apart from Angola, all receive free supplies from WHO: 3,000 treatment kits were Arsobal distributed in 2012. (Melarsopol) 3% The HAT Platform continues to advocate for the use of NECT, including supporting its inclu- sion in the WHO Essential Medicines List for NECT 96% children, for which a decision will be taken in 2013.

DNDi Annual Report 2012 21 R&D MODEL, STRATEGY & PORTFOLIO

Overcoming geographical variations LEISHMANIASIS to implement the most effective treatments

eishmaniasis, caused by more than 20 species of The natural history of VL is itself complex, its transmission L Leishmania, is comprised of complex diseases which fuelled by poverty and environmental degradation, the latter range from localized skin ulcers to lethal systemic disease. allowing the interplay of the different elements in the disease Visceral leishmaniasis (VL) is characterized by prolonged cycle (vectors and reservoirs) with humans. The different fever, enlarged spleen and liver, substantial weight loss, and Leishmania species and their adaptation to specifi c reservoirs progressive anaemia, and is usually fatal within two years if determine the cycle, zoonotic (transmission from animals to left untreated. Cutaneous leishmaniasis (CL) is characterized humans via the vector) or anthroponotic (transmission from by lesions of the skin that can become chronic and/or disfi g- humans to humans via the vector), which has implications uring, while post-kala azar dermal leishmaniasis (PKDL) is for disease control. a disseminated skin infection. A common sequel of VL, PKDL The last decade has seen improvements in the treatment, serves as a parasite reservoir, thus contributing to the trans- diagnosis, and prevention of leishmaniasis in South Asia, mission of the disease. notably through the development of liposomal amphotericin B, paromomycin, and miltefosine. Through a combination Ideal Target Product Profi le of active case detection, early treatment, vector control, for VL and social mobilization, the WHO expects to reach its aim A new treatment for adults and children > Effi cacious against all species of parasite in all regions > At least 95% effi cacy > Easy to use: short-course, oral or intra-muscular, requiring no monitoring > Safe in pregnant and lactating women > Affordable > Adapted to tropical climates

22 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO

of eliminating anthroponotic visceral leishmaniasis from the Indian sub-continent by 2020.(1) More work, however, is needed to achieve similar results in other parts of the world, particularly East Africa and Latin America. Response to treatment varies between regions, requiring higher doses of the VL drugs, notably in East Africa, than in South Asia. Furthermore, there is evidence of geographical variations within East Africa. While the progress achieved has led to a clearer notion of how to treat patients across different con- tinents, existing treatments are not ideal: potential of resist- ance development, low tolerability, long treatment duration and diffi culty in administration, as well as high cost are still major drawbacks. New treatments that address these issues and address geographical variations and local realities are essential, notably in East Africa. Although cutaneous leishmaniasis (CL) is not life-threatening, it can have devastating effects on local communities. Indeed, the disfi guring lesions it causes can lead to social stigmatiza- tion, with consequences such as ostracism, impaired educa- tion, and economic loss – all of this in populations with already limited resources. There is currently no satisfactory treatment for any form of CL, as none bring signifi cant advantages while some have unacceptable safety profi les. The ideal treatment for VL is a safe, effective, oral, short- course (10 days maximum) drug that would be effi cacious in all geographic regions as well as against PKDL. The ideal treatment for CL is a safe, short-course, affordable, fi eld- friendly topical or oral agent that cures lesions fast, with minimal scarring. Ideal Target Product Profi le for CL

A new or oral treatment > Effi cacious against all species of Leishmania > At least 95% effi cacy > Easy to use: short-course, requiring no monitoring > Leaving minimal scarring > Safe in pregnant and lactating women > Affordable > Adapted to tropical climates (minimum three-year shelf-life)

(1) Sustaining the drive to overcome the global impact of neglected tropical diseases: second WHO report on neglected tropical diseases World Health Organization, 2013.

DNDi Annual Report 2012 23 FACT SHEET

Leishmaniasis

Visceral leishmaniasis

WHAT IS THE IMPACT OF LEISHMANIASIS? erythema develops into a papule, then a A total of 98 countries and 3 territories on nodule that progressively ulcerates to 5 continents reported endemic become the lesion characteristic of the high transmission. Serious cardiotoxicity leishmaniasis transmission. Among disease. Depending on the species, leading to death is well documented. parasitic diseases, morbidity and CL usually heals spontaneously within one mortality caused by leishmaniasis are to two years, but results in lifelong scars, Require a 30-day parenteral treatment for surpassed only by malaria and lymphatic which, depending on the size and location, VL. Registered in South-East Asia, Latin fi lariasis. 350 million people are at risk of may cause substantial trauma in affected America, and some Mediterranean and the disease, most of them children. The individuals, particularly children. African countries. annual incidence is estimated at MCL is characterized by partial or total > Amphotericin B deoxycholate: approximately 0.7 to 1.2 million CL cases destruction of mucous membranes of the fi rst-line treatment for VL in areas with and 0.2 to 0.4 million VL cases, with a nose, mouth, and throat. high rates of unresponsiveness to case-fatality rate of 10% for VL per year antimonials and second-line treatment PKDL is characterized by a macular, (i.e. 20,000 to 40,000 deaths per year).(1) elsewhere. Need for hospitalization, maculopapular, and nodular rash; starting However, mortality data are extremely constant renal monitoring of patients, from the face, it spreads to other parts of sparse and generally represent hospital- 15-20 day treatment, and infusion-related the body. PKDL is subject to geographical based deaths only, so actual fi gures are adverse events are notable drawbacks. variations and can spontaneously heal, but expected to be higher. Co-infection with Amphotericin B displays dose-limiting can also develop into severe or persistent other infectious diseases is an increasing toxicity. Registered in South Asia and some forms, requiring long courses of treatment. concern: HIV-VL co-infection has been countries in Africa and Latin America. reported in 35 countries worldwide. CURRENT TREATMENTS AND THEIR > AmBisome®: a liposomal formulation of HOW IS LEISHMANIASIS TRANSMITTED? LIMITATIONS amphotericin B, much safer and highly Existing therapies for VL have serious effi cacious. A single infusion of 10 mg/kg More than 20 species of the (3) kinetoplastid protozoan drawbacks in terms of safety, resistance, has shown a 96.4% cure rate in Asia. stability, and cost.(2) They have low However, high cost and the need for a cold parasite Leishmania (L.) (4) can be transmitted to tolerability, long treatment duration, and chain limit its widespread use. Registered humans via some 30 species are diffi cult to administer. in India, USA, and Europe and used as a of phlebotomine sandfl ies. > Pentavalent antimonials (sodium second-line drug for PKDL in East Africa and for VL in Brazil. VL is usually caused by L. donovani and stibogluconate – SSG – and meglumine ® L. infantum. antimoniate, such as Glucantime ): used > Miltefosine: oral drug registered and for VL and CL for over 60 years. Acquired recommended in India, but expensive(5) CL is most frequently caused by L. major, resistance in areas of high prevalence and and requires 28-day treatment. Major L. tropica, and L. aethiopica in the Old World, and L. braziliensis, L. mexicana, and related species in the New World. Mucocutaneous leishmaniasis (MCL) can develop as a complication of CL. PKDL occurs during, or more often after, recovery from VL. It is caused by L. donovani and is believed to be a parasite reservoir for human VL. WHAT ARE THE SYMPTOMS? VL is characterized by progressive fever, weight loss, enlarged spleen and liver, and anaemia. Untreated symptomatic Cutaneous and mucocutaneous VL is fatal in almost all cases. leishmaniasis Cutaneous CL is a small erythema that develops after leishmaniasis a variable period at the site where an infected sandfl y has bitten the host. The

(1) Alvar J. et al. (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7: e35671. (2) Seifert K. (2011) Structures, targets and recent approaches in anti-leishmanial drug discovery and development. Open Med Chem J 5: 31–9. (3) Sundar S. et al. (2011) Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet 377: 477-86. (4) Through the WHO, signifi cant cost reduction of both AmBisome® and miltefosine is available for the public sector of key endemic countries as of 2007. (5) Ibid.

24 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO

FACT SHEET

common and there are increasing reports thermotherapy and cryotherapy are used of drug resistance emergence. in certain clinics, but are expensive. > Pentavalent antimonials: given as > A promising approach is to combine fi rst-line drugs through a series chemotherapy with immune-modulation: of intramuscular, intravenous, or initial elimination of parasites with intralesional injections. Serious side chemotherapy, followed by modifi cation effects, require long treatment, not of the patient’s immune response by an affordable for most patients and diffi cult to administer in poor rural areas. immune-enhancing agent (either a therapeutic vaccine or an appropriate > Alternative treatments: Liposomal adjuvant) could lead to quick recovery and amphotericin-B, not fully tested on CL. Even if effi cacious, cannot be deployed control of persisting parasites. Therapeutic widely because of cost and delivery vaccines have yielded positive results requirements. Miltefosine, potentially for CL in Brazil and Venezuela. Several teratogenic and has side effects that make chemical immunomodulators have been limitations include low compliance, with it unsuitable to treat CL. Registered in tested for cancer and other diseases, risk of resistance, and contraindication in Colombia. Other treatments, such as and could be useful for CL therapy. pregnancy and mandatory contraception for women of child-bearing age for the duration of therapy and three months WHAT IS DNDi DOING TO ADDRESS UNMET TREATMENT NEEDS? beyond. A recent study in Asia indicated an emerging lack of effi cacy in monotherapy DNDi’s short-term approach was to develop new treatments by combining in the region.(1) existing drugs and/or shortening treatment duration in order to increase tolerability, reduce burden on health systems, and offer greater > Paromomycin (PM): a low-cost parenteral formulation that requires affordability, whilst also preventing or delaying emergence of resistance. three weeks of painful intramuscular Another objective was to assess effi cacy and safety of existing drugs in administration and is associated with other countries and regions to extend registration and availability to some degree of renal and ototoxicity. patients. In 2010, DNDi and LEAP partners Leishmania-HIV co-infection is a newly emerging problem. It is very diffi cult delivered the SSG&PM combination to manage, due to poor response to treatment with frequent relapses of therapy for East Africa that is now disease, and is eventually fatal. DNDi is working towards a new treatment recommended as fi rst-line treatment for HIV/VL co-infected patients in Africa. for VL in the region by the WHO Expert DNDi’s long-term strategy is to bring new drug candidates into clinical Committee on the Control of Leishmaniases. In India, DNDi also conducted a Phase III development through its lead optimization programme. trial to evaluate the combination of already For CL, DNDi’s objective is to develop short, safe, effi cacious, affordable, registered drugs: AmBisome®, miltefosine, and fi eld-adapted treatments against L. tropica and L. braziliensis – and paromomycin. They are now because of the severity of the disease and its public health importance. recommended by the WHO Expert As a short-term strategy, DNDi is developing a topical treatment of an existing Committee on the Control of drug. In the longer term, DNDi aims to develop a novel fi eld-adapted Leishmaniases (see page 29). modality of treatment that would combine anti-parasite and immune- Together with OWH/PATH and TDR, DNDi modifying agents, with a strong emphasis on safety, effi cacy, cost, quality of is collaborating with the National Control scar and reduced need for follow-up and interaction with health systems. Programmes of India and Bangladesh, MSF, the Bihar State Health Society, and In addition, DNDi supports the Leishmaniasis East Africa Platform (LEAP) the Indian Council for Medical Research (see page 48) that aims to geographically extend all currently available VL to assess the feasibility of these new drugs in East Africa and to develop new therapies suitable for the region, treatments at the primary health care level as well as to build and sustain capacity in the region for conducting clinical and facilitate their introduction for trials. the treatment of VL in South Asia. In Latin America, DNDi is participating in a By 2018, DNDi aims to deliver from its VL-specifi c portfolio: study sponsored by the Brazilian Innovation Agency (FINEP) to evaluate the safety and > An oral, safe, effective, low-cost and short-course treatment effi cacy of Glucantime®, AmBisome®, > A new treatment for PKDL that is shorter course and better tolerated and amphotericin B as monotherapies, than current options and of AmBisome®-Glucantime® > Treatment options for HIV/VL co-infected patients combination to treat VL patients. By 2018, DNDi aims to deliver from its CL-specifi c portfolio: Existing treatments for CL are not > A safe, effective, and shorter-course treatment for CL satisfactory. Many treatment regimens are associated with signifi cant failure rates and considerable toxicity. Relapses are

(1) Rijal S. et al. (2013) Increasing failure of miltefosine in the treatment of kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance. Clin Infect Dis 56: 1530-8.

DNDi Annual Report 2012 25 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Partners: Nitroimidazole backup TB Alliance, USA; Advinus Therapeutics, India; Central Drug 2012 OBJECTIVE: does not successfully complete pre-clinical Research Institute, India; LSHTM, > Profi le potential backup candidates testing. Over 200 analogues have been pre- Research UK; Auckland University, New to VL-2098 for the treatment of VL pared so far. Zealand; Laboratory of A number of backup compounds have now Microbiology, Parasitology and been identified as meeting the targets set In 2010, the Global Alliance for Tuberculosis Hygiene (LMPH), University of at the start of the project, including in vivo Drug Development (TB Alliance) and DNDi Antwerp, Belgium; WuXi AppTech, effi cacy. Additional studies are in progress entered into a fi rst-ever royalty-free license China to further characterize these and select the agreement between two not-for-profi t drug compound with the best chance of becoming developers. The TB Alliance granted rights to Leadership: a successful clinical candidate meeting the DNDi to develop a class of potential anti-TB Head of Drug Discovery: criteria for good in vivo effi cacy and an accept- compounds that also show signifi cant prom- Eric Chatelain; able safety profi le. Project Coordinator: ise for treating other neglected diseases, such Delphine Launay as VL. Within TB Alliance’s nitroimidazole library, VL-2098 was identifi ed as a candidate Project start: with potent effi cacy against VL (see below). A July 2010 focused programme is ongoing to identify a backup pre-clinical candidate in case VL-2098

Partners: VL-2098 TB Alliance, USA; Advinus Therapeutics, India; Central Drug 2012 OBJECTIVE: testing with administrations at several multi- Research Institute, India; LSHTM, > Complete the pre-clinical package ples of the effi cacious dose is ongoing and we Translation UK; Auckland University, New (regulatory safety studies and API expect to complete these studies and propose and drug product manufacturing) VL-2098 as a clinical candidate late in 2013. Zealand; Bertin Pharma, France; in order to start a clinical Phase I ChemDepo Inc., USA study in 2015 Leadership: Discovery & Pre-clinical Director: From 70 nitroimidazoles belonging to four Robert Don; Project Coordinators: chemical sub-classes, VL-2098 was identifi ed Stéphanie Braillard, Delphine as the most potent molecule with a favourable Launay safety profi le for in-depth evaluation as a clini- Project start: cal candidate. VL-2098 profi les as selective for July 2010 L. donovani with effi cacy in acute and chronic VL animal models following oral dosing. Safety

Partners: Anfoleish PECET (Program for the Study and (Cutaneous Leishmaniasis) Control of Tropical Diseases), Universidad de Antioquia Medellin, 2012 OBJECTIVE: The rationale for development of a topical for- Translation Colombia; Humax Pharma, > Develop a topical anti-parasitic mulation of amphotericin B was to provide a Columbia; Imperial College of treatment containing amphotericin B treatment to be applied locally at the CL lesion, Science, Technology and Medicine, for the treatment of CL with high anti-parasitic effect, but without the UK; Centro de Pesquisas René systemic toxicity associated with ampho- Rachou, Brazil tericin B. Anfoleish was selected by DNDi for clinical development after completion of pre- Leadership: clinical assessments. The fi rst study will be a Head of CL Clinical Programme: Phase Ib/II trial aiming to assess the safety, Farrokh Modabber / Byron Arana; PK, and effi cacy of an amphotericin B cream Clinical Managers: Fabiana Alves, in patients with CL caused by L. braziliensis. Gwenaëlle Carn If this trial shows that Anfoleish is effi cacious Project start: against L. braziliensis, a multi-country Phase III September 2011 study will be planned in several endemic coun- tries in Latin America.

26 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Fexinidazole Partners: Kenya Medical Research Institute 2012 OBJECTIVE: Fexinidazole has shown potent activity against (KEMRI), Kenya; Institute of > Initiate a Phase II proof-of-concept L. donovani in vitro and in vivo in a VL mouse Endemic Diseases (IEND), study to determine the effi cacy and model. It was assessed in three Phase I studies University of Khartoum, Sudan; Translation safety of using fexinidazole for the in healthy volunteers and was shown to be safe MSF; LEAP; BaseCon, Denmark; treatment of visceral leishmaniasis when given as a single dose or as repeated Utrecht University, The Netherlands dosing after 14 days. This Phase II proof-of- Leadership: concept study will evaluate fexinidazole for the Head of VL Clinical Programme: treatment of primary VL patients in Sudan. If Manica Balasegaram; Clinical successful, it will be followed by a Phase II/III Manager: Sally Ellis; Project programme in South Asia, East Africa, and Coordinator: Clélia Bardonneau Brazil. Project start: September 2012

New VL treatments – Bangladesh Partners: Ministry of Health and Family 2012 OBJECTIVE: end of 2012, 431 out of 674 patients had been Welfare, Bangladesh; International > Conduct Phase III/IV study to recruited. The trial is expected to end in 2013 Centre for Diarrhoeal Disease demonstrate feasibility of and results will be available in 2014. Research (ICDDR,B), Bangladesh; Development implementing new treatment Shaheed Suhrawardy Medical modalities recommended by College and Hospital (ShSMC), WHO (miltefosine-paromomycin, Bangladesh AmBisome®-miltefosine, AmBisome®-paromomycin, single- Leadership: dose AmBisome®) in primary Head of Leishmaniasis Clinical healthcare settings in Bangladesh Programme: Manica Balasegaram; DNDi India Director of R&D Operations: Bhawna Sharma; The Phase III trial conducted by DNDi and its Clinical Managers: Sally Ellis and partners in 2010 demonstrated the effi cacy of Vishal Goyal; Project Coordinator: combination therapies based on AmBisome®, Abhijit Sharma; Assistant Project miltefosine, and paromomycin. This two-step Coordinator: Pankaj Kumar Phase III study (fi rst in hospital settings, then in primary healthcare centers) is using these Project start: July 2010 combination therapies in Bangladesh. By the

New VL treatments – Africa Partners: KEMRI, Kenya; IEND, University of 2012 OBJECTIVES: ended in March 2012. The trial collected safety, Khartoum, Sudan; Addis Ababa > Develop new shorter-course treatments effi cacy, and pharmacokinetic data on milte- University, Ethiopia; Gondar for VL in East Africa and geographically fosine to geographically extend the use of the University, Ethiopia; University of Development extend available anti-leishmanial drugs drug into East Africa. In addition, combination Makerere, Uganda; LSHTM, UK; to all countries of the region ® treatments of AmBisome with either miltefos- Slotervaart Hospital, > Support ongoing registration activities ine or SSG were evaluated. Preliminary safety The Netherlands Cancer Institute, for use of SSG&PM and effi cacy results available at the beginning The Netherlands; Royal Tropical > Assess the effi cacy and safety of of 2013 will inform the decision to evaluate one Institute (KIT), The Netherlands; miltefosine combinations for East of these combinations in a Phase III trial. Ministries of Health of Ethiopia, Africa The LEAP AMBI 0106 trial which aimed to Sudan, Kenya, and Uganda; MSF; determine the minimum dose of AmBisome® i+solutions, The Netherlands; Since 2004, DNDi and the Leishmaniasis East that is effi cacious, safe, and cost-effective to OneWorld Health (OWH/PATH), USA; Africa Platform (LEAP) have embarked on a treat VL in Africa was completed in 2011 and LEAP; Institute of Tropical clinical research programme with two specifi c results have been submitted for publication. Medicine-Antwerp, Belgium objectives: to geographically extend all cur- Leadership: rently available VL drugs and to develop one Head of DNDi Africa: Monique to two new treatments. Wasunna; Head of VL Clinical The LEAP 0208 Study, coordinated by DNDi Programme: Manica Balasegaram; and LEAP, to assess combinations of existing Clinical Manager: Sally Ellis; Project drugs to treat VL in Africa, aimed to evaluate Coordinator: Clélia Bardonneau the safety and effi cacy of miltefosine mono- Project start: therapy, AmBisome®-SSG, and AmBisome®- November 2004 miltefosine combination treatments. Recruit- ment started in Kenya and Sudan in 2010 and

DNDi Annual Report 2012 27 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Partners (AfriCoLeish): HIV/VL LSHTM, UK; Institute of Tropical Medicine-Antwerp, Belgium; 2012 OBJECTIVE: In anthroponotic transmission areas, the WHO MSF, The Netherlands; > Identify and deliver a safe and highly recommends secondary prophylaxis with Development Addis Ababa University, Ethiopia; effective treatment for VL in HIV drugs not given in treating primary VL cases co-infected patients that will to avoid resistance development. A second, Gondar University, Ethiopia; improve long-term survival of follow-up study, sponsored by the Institute IEND, University of Khartoum, these patients of Tropical Medicine-Antwerp, Belgium, will Sudan; LEAP; Slotervaart Hospital, assess the use of pentamidine as secondary The Netherlands Cancer Institute, prophylaxis for HIV/VL co-infected patients. The Netherlands; Utrecht A fi rst study will evaluate the effi cacy of a com- University, The Netherlands bination regimen of AmBisome® with miltefo- sine, and of AmBisome® (at a higher dose) Leadership: monotherapy in Ethiopian patients co-infected Head of Leishmaniasis Clinical with VL and HIV. A secondary objective is Programme: Manica Balasegaram; to assess relapse-free survival at day 390 Clinical Manager: Sally Ellis; Project (after initial cure at day 28 or at day 56 after Coordinator: Clélia Bardonneau extended treatment). Viral load and CD4 count Project start: will be measured in all patients, and the phar- ® September 2011 macokinetics of antiretrovirals, AmBisome , and miltefosine, as well as immune func- tion markers will be examined in a subset of patients.

Partners: New VL treatments – Latin America René Rachou Research Institution – Fiocruz-MG, Brazil; Paediatric 2012 OBJECTIVE: is expected to be com- Hospital Joao Paulo II – FHEMIG, > Support the Brazilian Ministry of pleted by 2014. Evidence Development Brazil; Brasilia University, Brazil; Health and its partners to conduct 205 PATIENTS provided by this project a Phase III trial assessing the recruited will guide policies on the Montes Claros State University, effi cacy and safety of amphotericin B at 5 sites treatment of VL caused by Brazil; Piaui Federal University, deoxycholate, AmBisome®, and L. infantum in Brazil. Brazil; Sergipe Federal University, AmBisome®-Glucantime® combination Brazil; Leishmaniasis Control for the treatment of VL in Latin Programme/Ministry of Health, America Brazil; Universidade Estadual do Rio de Janeiro, Brazil About 90% of VL cases in Latin America occur DNDi support: in Brazil, and most of them affect children. In Clinical Manager: Fabiana Alves 2011, Brazil reported 3,894 new cases with Project start: a fatality rate of 6.7%. DNDi is supporting February 2011 the implementation of a Phase III clinical trial sponsored by the Brazilian Ministry of Health to assess treatments for VL. The primary objective of the study is to assess the effi cacy 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. The study progressed well during 2012, with fi ve active sites and a total of 205 patients recruited (out of 426 total), and

28 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

SSG&PM – Sodium stibogluconate & paromomycin Partners: KEMRI, Kenya; IEND, University of 2012 OBJECTIVE: was obtained in Uganda Khartoum, Sudan; University of > Facilitate implementation of at the end of 2011, and Makerere, Uganda; Addis Ababa and access to SSG&PM in key 2,332 PATIENTS registration was obtained University, Ethiopia; Gondar Implementation endemic areas of East Africa in the pharmaco- in Kenya in January 2013. University, Ethiopia; LSHTM, UK; vigilance study by supporting registration of The registration process Slotervaart Hospital, paromomycin (PM) and document treated since 2011 in 4 countries is underway in Sudan and The Netherlands Cancer Institute, safety through a pharmacovigilance Ethiopia. Nonetheless, The Netherlands; KIT, The study implementation has Netherlands; Ministries of Health already begun in the region, as the treatment of Ethiopia, Sudan, Kenya, and was recommended. In addition, it has been Uganda; MSF; i+ solutions, In 2010, DNDi and LEAP successfully showed included in the national drugs lists of Sudan, The Netherlands; OWH/PATH, USA; that the combination of SSG and PM (17 days) South Sudan, and Ethiopia and in Kenya’s LEAP was as efficacious as SSG monotherapy national VL guidelines. SSG&PM treatment (30 days), with the advantage of being shorter has been rolled out in Sudan and Uganda in Leadership: course, therefore lessening the burden on public health structures, as well as in MSF Head of Leishmaniasis Clinical patients and health systems, and more cost- centres. A pharmacovigilance study with Programme: Manica Balasegaram; effective. Since then, DNDi and LEAP have MSF to monitor safety and effectiveness of Clinical Manager: Sally Ellis; Head worked with local ministries of health to ensure SSG&PM was initiated in 2011 and, by the of DNDi Africa: Monique Wasunna recommendation and uptake of the new treat- end of 2012, approximately 2,300 patients Project start: ment following its recommendation as fi rst- had been treated in Ethiopia, Sudan, Kenya, November 2004 line therapy for VL patients in East Africa by and Uganda. SSG&PM is also being used to the WHO Expert Committee on the Control treat VL patients in South Sudan as part of its of Leishmaniases. First registration (of PM) national programme.

New VL treatments – Asia Partners: Indian Medical Research Council 2012 OBJECTIVE: treatments can be safely (ICMR); Rajendra Memorial > Conduct effectiveness studies implemented through pri- Research Institute of Medical Implementation in South Asia to demonstrate 213 PATIENTS mary healthcare systems Sciences (RMRI), India; Kala Azar feasibility in implementing the new out of 450 in both the public and Medical Research Centre, India; treatment modalities recommended recruited at the private sectors. This State Health Society, Bihar (BSHS), by WHO (miltefosine-paromomycin, 10 sites in India includes a pilot project in India; National Vector Borne AmBisome®-miltefosine, AmBisome®- 431 PATIENTS the Bihar State of India Disease Control Programme paromomycin, single-dose out of 674 implementing combina- (NVBDCP), India; Community Based AmBisome® 10 mg/kg) in primary recruited tion therapies at the pri- at 3 sites Medical College (CBMC), healthcare settings in India with in Bangladesh mary healthcare level and a view to extending their use in single-dose AmBisome® at Mymensingh, Bangladesh; Ministry the region to support control and the hospital level. The pro- of Health and Family Welfare, elimination strategies in the countries ject is monitoring pharmacovigilance as well as Bangladesh; ICDDR,B, Bangladesh: of highest prevalence in South Asia treatment effectiveness of the different treat- ShSMC, Bangladesh; University of ment options when used outside of a clinical Tokyo, Japan; OWH/PATH, USA; Institute of Tropical Medicine- The Phase III trial conducted by DNDi and its trial by the public sector. The study began in Antwerp, Belgium; LSHTM, UK; partners in 2010 demonstrated the effi cacy of 2012 in two districts in India. By the end of the combination therapies based on AmBisome®, year, 213 patients had been recruited, out of WHO-TDR; WHO (SEARO, Geneva); miltefosine, and paromomycin. An additional 7,000 planned. The trial is expected to end in MSF 2015 and results will be available in 2016. study by Sundar et al. showed the effi cacy Leadership: of single-dose AmBisome® given as an intra- Head of Leishmaniasis Clinical venous infusion. To facilitate the introduc- Programme: Manica Balasegaram; tion of these new treatments for VL in South DNDi India Director of R&D Asia, DNDi developed a partnership consor- Operations: Bhawna Sharma; tium with TDR and OWH/PATH, in collabo- Clinical Managers: Sally Ellis and ration with health authorities at state and Vishal Goyal; Project Coordinator: national levels. DNDi will work to implement Abhijit Sharma; Assistant Project single-dose AmBisome® in the public sec- Coordinator: Pankaj Kumar tor in India (with TDR) and new combination therapies in the private sector (with OWH/ Project start: PATH). Effectiveness studies are being imple- December 2006 mented in the region to demonstrate that such

DNDi Annual Report 2012 29 R&D MODEL, STRATEGY & PORTFOLIO

CHAGAS DISEASE American trypanosomiasis Treat now and boost innovation for tomorrow – millions are waiting

ver a century after its discovery, Chagas disease is still The only two drugs approved for treating acute Chagas dis- Oendemic to 21 countries in Latin America, where PAHO ease were developed over 40 years ago and are far from ideal. estimates that approximately 8 million people are infected Symptom management has generally been the only treatment and 100 million are at risk of the disease.(1) Imported Chagas option for patients with cardiac or digestive involvement at disease affecting patients from endemic regions is increas- the chronic stage of the disease. There is no vaccine and no ingly recognized as an emerging problem in the USA and appropriate test of cure. Until recently, the main focus of the Europe, due to migration from Latin America. The Centers fi ght against Chagas disease was to interrupt transmission for Disease Control and Prevention (CDC) estimates that over through the deployment of vector-control strategies and 300,000 persons with Trypanosoma cruzi infection live in the the screening of blood donors. Sustaining and consolidating USA. Most of the true burden of Chagas disease can remain advances made in controlling the disease is a key challenge, hidden for years – many infected people remain asympto- as well as expanding availability of diagnosis and treatment matic for more than a decade.(2) Despite an economic burden of patients. equivalent to that of other prominent global diseases, such For the existing drugs, benznidazole and nifurtimox, which (3) as rotavirus, Chagas dis- have been used for decades, strong clinical trial evidence for Ideal Target Product Profi le ease is among the neglected the effi cacy of either drug for the treatment of adults with for Chagas Disease diseases that receive the chronic disease is lacking,(5) though this is likely to change with least investment for R&D upcoming results of TRAENA and BENEFIT studies. Safety A new treatment for both acute and – less than USD 25 million chronic phases: and tolerability remain important concerns. Side effects in 2011, only half of which range from skin rashes to seizures and other nervous system > Useful against most parasite was invested in drug dis- disorders.(6) In addition, long treatment periods (60-90 days) species in all regions (4) covery for the disease – of make patient compliance challenging, with increased risk of > Better safety profi le than existing the more than USD 3 billion drug resistance development. Despite these issues, there drugs spent for R&D for neglected is consensus that in the lack of better options, drug treat- > Non-inferior effi cacy to diseases. ment should be offered to adults (19-50 years of age) without benznidazole advanced Chagas heart disease and be considered optional > Easy-to-use treatment: oral, for those older than 50. once-a-day for less than 30 days, requiring no hospitalization and In order to effectively fi ght the disease, new treatments that little or no monitoring are safe and effective against the chronic phase of the disease > Affordable – which is when most patients are diagnosed – are sorely needed. Today, approximately 99% of people who require > Adapted to tropical climates treatment for Chagas disease are not receiving it. In addition, (minimum three-year shelf-life) to gain understanding of the disease progression and ease the development of test-of-cure diagnostic tools that support drug development, identifi cation of biomarkers is essential.

(1) http://new.paho.org/hq/index.php?option=com_content&view=article&id= 5856&Itemid=4196. (2) Bruce YL. et al. (2013) Global economic burden of Chagas disease: a computational simulation model, Lancet Infect Dis 13: 342-8. (3) Ibid. (4) G-FINDER Neglected Disease Research and Development: a fi ve year review, Policy Cures, December 2012: http://policycures.org/downloads/ GF2012_Report.pdf. (5) Clayton, J. (2010) Chagas disease: pushing through the pipeline. Nature 465: S12–5. (6) Ibid.

30 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO

FACT SHEET

Chagas Disease American Trypanosomiasis

WHAT IS THE IMPACT OF CHAGAS DISEASE? tract pathologies, and nervous system chronic disease with target organ (4) Chagas disease is endemic to 21 countries irregularities. Chagas disease is the involvement. In 2011, DNDi and partners in Latin America, where 100 million leading cause of infectious heart disease produced a paediatric dosage form of people are at risk. It is estimated that (cardiomyopathy) in Latin America. benznidazole to fi ll the treatment gap for 8 million people are infected, leading to WHAT ARE THE CURRENT TREATMENTS this population. approximately 12,000 deaths every year AND THEIR LIMITATIONS? in the region(1) Approximately 55,000 new Current treatments, cases arise each year.(2) Increased benznidazole and nifurtimox, migration and population movements are effective against the acute have changed the epidemiology and phase of infection, and while geographic distribution of Chagas disease, there is increasing evidence of their which is now found outside Latin America, effi cacy against the chronic phase of including in the United States, Europe, the disease, broad use of these drugs is Australia, and Japan. limited due to safety and tolerability HOW IS CHAGAS DISEASE TRANSMITTED? issues. Drawbacks include long treatment Chagas disease is caused by periods (60-90 days), dose-dependent the kinetoplastid protozoan toxicity, and a high drop-out rate of parasite Trypanosoma cruzi, patients due to side-effects. There is Endemic transmitted through the bite currently no approved treatment for Non-endemic but present of a triatomine vector known as the ‘kissing bug’. Other routes of transmission include blood WHAT IS DNDi DOING TO ADDRESS UNMET TREATMENT NEEDS? transfusion, organ transplantation, as well as congenital and, less often, oral routes DNDi’s short-term goal was to make better use of existing treatments, through ingestion of contaminated food notably through the development of a paediatric dosage form of or beverage especially in Amazonia. benznidazole – a goal which was achieved: this treatment was granted WHAT ARE THE SYMPTOMS? registration by the Brazilian regulatory authorities in December 2011 and DNDi is working with LAFEPE, the manufacturer, to ensure it is widely The disease has two clinical phases: accessible to all those in need. > The acute phase (fatal for 2-8% of As a medium-term strategy, DNDi is assessing known compounds already (3) children), often asymptomatic or in development against fungal infections, such as the new azole antifungal unrecognized due to non-specifi c drug, E1224, for activity against T. cruzi in adult chronic patients. Also, we symptoms, such as fever, malaise, and are searching for potential biomarkers of treatment response to enhance enlarged lymph nodes, spleen, and liver. clinical trial capabilities of new substances. In less than half the cases, fi rst visible signs can be a skin lesion or a purplish As part of its long-term strategy, DNDi continues to identify and engage swelling of one eyelid (known as partners from private and public sectors in order to identify, characterize, Romaña’s sign). These symptoms and advance the development of promising compounds as well as to pursue spontaneously resolve in 4-6 weeks. discovery efforts for innovative therapies. > The chronic phase, which can be In addition, DNDi supports clinical research capabilities through the Chagas divided into two stages: Clinical Research Platform (see page 50), which was launched in 2009. • The chronic, silent, and asymptomatic ‘indeterminate’ stage, during which By 2018, DNDi aims to deliver from its Chagas-specifi c portfolio: patients can transmit the parasite to > An effective and safe oral treatment for the treatment of chronic others, especially through vertical Chagas disease, ideally effective also against the acute form of the transmission or transfusion, while disease showing no signs of the disease, and which may last decades after infection. > Biomarkers to gain understanding of disease progression and ease the development of test-of-cure diagnosis tools that support drug • The chronic, symptomatic stage, development developing later in up to 30% of infected patients, causes cardiopathies, digestive

(1) http://new.paho.org/hq/index.php?option=com_content&task=view&id=5856&Itemid=4196. (2) Organizacion Panamericana de la Salud. Estimacion cuantitativa de la enfermedad de Chagas en las Americas. Montevideo, Uruguay: Organizacion Panamericana de la Salud, 2006. (3) Parada H. et al. (1997) Cardiac involvement is a constant fi nding in acute Chagas’ disease: a clinical, parasitological and histopathological study. Int J Cardiol 60: 49–54. (4) www.msfaccess.org/sites/default/fi les/MSF_assets/NegDis/ Docs/NEGDIS_report_Chagas_UpdateOnProgress_ENG_2006.pdf.

DNDi Annual Report 2012 31 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Nitroimidazole Partners: University of Auckland, New Zealand; TB Alliance, USA; Centre 2012 OBJECTIVE: > Assess the nitroimidazole series for Drug Candidate Optimisation Research (developed by TB Alliance) for its (CDCO)/Monash University, potential to identify a candidate Australia; Epichem, Australia; for Chagas disease treatment, with Murdoch University, Australia; the goal of proposing a pre-clinical Federal University of Ouro Preto candidate (UFOP), Brazil; Institut Pasteur Korea (IPK), South Korea Lead optimization activities have provided a Leadership: better understanding of the essential features Head of Drug Discovery: Eric for a drug to be effi cacious for the treatment Chatelain; Project Coordinator: of Chagas disease. This insight will be used Delphine Launay to propose a new pre-clinical candidate from Project start: the nitroimidazole class that is more potent April 2012 and with a better safety profi le than the drugs currently used (nifurtimox and benznidazole). Work on the nitroimidazooxazines series has concentrated on compounds from the VL-2098 backup programme (see page 26). Fexinidazole is a nitroimidazole currently in Phase IIb/III development for HAT. It is very effi - cacious in a wide variety of rodent Chagas dis- ease models and current work aims to assess fexinidazole suitability for development as a Chagas disease therapy. As safety, pre-clini- cal and clinical data are available, we aim to rapidly progress fexinidazole to clinical proof- of-concept studies.

K777 Partners: University of California San Francisco (UCSF), USA 2012 OBJECTIVE: of the project is to perform the required pre- > Review the potential of K777 clinical studies (safety pharmacology and toxi- Translation Leadership: as a clinical candidate: progress cology) in order to complete the Investigational Head of Drug Discovery: Eric IND-enabling studies New Drug (IND) application for clinical evalu- Chatelain; Project Coordinator: ation of K777 for the treatment of Chagas Stéphanie Braillard K777 is a vinyl sulfone cysteine protease inhib- disease. Safety pharmacology studies were itor, which inhibits cruzain, a key protease completed, and no effects on electrocar- Project start: required for the survival of T. cruzi. K777 was diogram (ECG) or respiratory function were September 2010 originally characterized by the Sandler Center observed, even at the high dose. Dose Range for Research in Tropical Parasitic Disease at Finding/Maximum Tolerated Dose (DRF/MTD) in UCSF and has since been shown to be safe non-human primates and 28-day toxicity study and effi cacious in animal models of acute and will be performed in 2013 in order to fi nalize chronic Chagas disease. The main objective writing of IND for submission by early 2014.

32 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Biomarkers Partners: Médecins Sans Frontières (MSF); 2012 OBJECTIVE: biomarkers, and deter- Universidad Mayor de San Simon, > Identify and evaluate biomarkers mine whether blood PCR Bolivia; Universidad Autónoma Juan to be used in Chagas disease PCR STUDY: assays can differentiate Misael Saracho, Bolivia; Barcelona Translation 220 patients Phase III clinical trials and future between parasitological Centre for International Health registration cure and treatment fail- Research (CRESIB), Spain; Dr Mario ure. The study, conducted Fatala Chaben National Institute of in collaboration with the Texas Biomedical Parasitology (INP), Argentina; An important hurdle for the development of Research Institute and the University of University of Georgia, USA; Texas new drugs for chronic Chagas disease is the Georgia, will be completed at the end of 2014. lack of clear and early markers that can indi- Biomedical Research Institute, USA; • Finally, DNDi is working with FIND and PAHO/ cate treatment parasitological outcome and University of Texas at El Paso, USA; TDR to optimize PCR (in particular the extrac- later indicate defi nite cure. To date, the only National Council of Scientifi c and tion step). defi nite outcome is seroconversion, which may Technological Research (INGEBI- take up to ten or more years. There is therefore In the longer-term, DNDi is working towards CONICET), Argentina; McGill a need to measure treatment effect via an indi- identifying new biomarkers of treatment University, Canada; Geneva rect, surrogate marker. response and to understand the progression University Hospitals, Switzerland; Short-term objectives aim to assess the best of Chagas disease: NHEPACHA network sampling strategy to measure parasite clear- • The study on macaques will evaluate lytic Leadership: ance via Trypanosoma cruzi DNA quantifi ca- antibodies, T-cell assays, multiplex serodiag- Head of Drug Discovery: Eric tion through polymerase chain reaction (PCR) nostic assay and gene expression profi ling. Chatelain; Head of Chagas Clinical and validate PCR as a measure of treatment • In the context of the E1224 study, markers of Programme: Isabela Ribeiro; response in Chagas disease, i.e. as a surrogate treatment response, such as conventional and Clinical Trial Manager: Jayme marker for Phase III clinical trials and regulatory non-conventional serology, multiplex serodiag- Fernandes; Project Coordinator: submission: nostic assays, selected pro-thrombotic factors Bethania Blum • A clinical trial conducted in collaboration and apolipoprotein A1, will be assessed. with MSF-Spain, with PCR assay support pro- Project start: • A project with Geneva University Hospitals February 2010 vided by the UMSS in Bolivia and quality assur- and McGill University will assess the use of ance from INGEBI-CONICET in Buenos Aires, proteomic signatures and other biomark- Argentina aims to evaluate sampling proce- ers as potential test of efficacy in sera sam- dures for PCR. Patient recruitment was fi nalized ples of nifurtimox-treated Chagas patients. A in December 2011 and patients were followed- first study was concluded in 2012, for which up for 12 months. Results are expected by results will be available in 2013. Results from mid-2013. available proteomic studies will be compiled • In 2012, evaluation of samples from the and additional evaluation may be conducted TRAENA study (a collaboration to support using adult sera from larger cohorts (e.g. the use of PCR as a method to evaluate treat- TRAENA and NHEPACHA), and an exploratory ment response) was concluded. Results are study using children sera will be carried out. expected in 2013. • DNDi is part of the NHEPACHA network of • Funding from the Wellcome Trust was investigators created for the long-term cohort obtained in 2011 for a study on naturally evaluation of potential biomarkers. infected macaques to evaluate candidate

Fenarimol Partners: Centre for Drug Candidate 2012 OBJECTIVE: Two interesting candidates from the fenarimol Optimisation (CDCO)/Monash > Complete studies needed for the series of compounds were identifi ed through University, Australia; Epichem, nomination of the pre-clinical lead optimization efforts. The project is now in Australia; Murdoch University, Translation candidate out of the optimized leads its non-regulatory pre-clinical phase, with fur- Australia; Federal University of from the fenarimol series ther profi ling of candidates before nominating Ouro Preto (UFOP), Brazil; Institut one candidate for further regulatory pre-clinical Pasteur Korea (IPK), Korea development. The objective is to perform Good Laboratory Practice (GLP) safety studies, as Leadership: well as Chemistry, Manufacturing, and Control Head of Drug Discovery: Eric (CMC) studies on the selected candidate com- Chatelain; Project Coordinator: pound in order to fi le a formal investigational Delphine Launay new drug (IND) application and move the can- didate to fi rst-in-man studies. Project start: December 2011

DNDi Annual Report 2012 33 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Azole E1224 Partners: Eisai Co. Ltd, Japan; Platform of Integral Care for Patients with 2012 OBJECTIVE: placebo-controlled, safety > To evaluate the safety and effi cacy and efficacy study will Chagas Disease, Spain/Bolivia; Translation of E1224 for the treatment of adult evaluate three oral E1224 Universidad Mayor de San Simon, 231 PATIENTS patients with chronic indeterminate recruited dosing regimens (high Bolivia; Universidad Autónoma Juan Chagas disease; conclude at 2 sites dose for four weeks and Misael Saracho, Bolivia; Collective recruitment of Phase II study and eight weeks; low dose for of Applied Studies and Social start planning for Phase III eight weeks) and includes Development (CEADES), Bolivia; benznidazole (5 mg/kg/day) as a positive control. NUDFAC – Nucleus of Pharmaceutical and Cosmetics In 2009, DNDi joined forces with Eisai Co. The study concluded recruitment of 231 adult Development, Brazil; Centre de Ltd – the Japanese pharmaceutical company patients with chronic indeterminate stage of Recerca en Salut Internacional de that discovered E1224 – to develop this new Chagas disease in June 2012. Twelve month follow-up will be completed mid-2013 and Barcelona (CRESIB), Spain; National chemical entity for Chagas disease. E1224 is a pro-drug which converts to the active drug results will be available Q4 2013. Council of Scientifi c and ravuconazole in the human body, leading to Technological Research (INGEBI- improved absorption and bioavailability. The CONICET), Argentina Phase II proof-of-concept study started in Leadership: July 2011 in Cochabamba and Tarija, Bolivia, Head of Chagas Clinical the country which carries the world’s largest Programme: Isabela Ribeiro; Chagas disease burden. Clinical Trial Manager: Glaucia The study evaluates the potential of E1224 Santina; Project Coordinator: Erika as an oral, easy-to-use, safe, and affordable Correia, Bethania Blum treatment for Chagas disease and will explore Project start: promising biomarkers of therapeutic response February 2010 in Chagas disease (see also ‘Biomarkers’ project). This randomized, multicentre,

Partners: Paediatric dosage form of benznidazole Laboratório Farmacêutico do Estado de Pernambuco (LAFEPE), 2012 OBJECTIVE: DNDi is collaborating with Brazil; Hospital de Niños Ricardo > Implement an access plan for broad LAFEPE to make the drug Implementation Gutierrez, Argentina; Instituto availability and implementation of REGISTERED widely available, notably Nacional de Parasitología Dr M paediatric benznidazole in Latin in Brazil, in the priority countries Fatala Chabén , Argentina; Hospital America 17,550 TABLETS where Chagas disease distributed de Niños de Jujuy, Argentina; prevalence is high and Ministério de Salud, Província de treatment is urgently Jujuy, Argentina; Hospital Público Until recently, adequate treatment options for needed. The institutions Materno Infantil – Salta, Argentina; children were lacking: benznidazole was only also worked together for the submission for the Centro de Chagas y Patologia available as an adult formulation. In July 2008, WHO Essential Medicines List for Children. As DNDi and LAFEPE entered a joint development an additional component of the paediatric pro- Regional, Hospital Independencia, programme that led to the determination and gramme, a population pharmacokinetic study Santiago del Estero, Argentina; production of the most appropriate paediat- involving 80 Chagas disease patients was CONICET/INGEBI, Argentina; ric dosage formulation, strength, and dosing conducted in Argentina to gain more informa- Centro Nacional de Diagnóstico e regimen of benznidazole. The paediatric for- tion on pharmacokinetics, treatment safety, Investigación de Endemo-epidemias mulation, adapted for babies and children up and effi cacy in children aged 0-12 years. The (CeNDIE), Ministry of Health, to two years of age, was granted registration results of the study will be available in 2013. Argentina; University of Liverpool, by Brazil’s National Health Surveillance Agency UK; NUDFAC, Brazil; (ANVISA) in December 2011. Administración Nacional de Laboratorios e Institutos de Salud (ANLIS), Argentina Leadership: Head of Chagas Clinical Programme: Isabela Ribeiro; Clinical Trial Manager: Jayme Fernandes; Project Coordinator: Bethania Blum Project start: May 2011

34 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

DNDi Annual Report 2012 35 R&D MODEL, STRATEGY & PORTFOLIO

FILARIAL DISEASES Aiming for a faster cure

for fi larial patients

ilarial diseases are caused by a sub-group of helminths, The success of programmes such as the Global Programme Fthe nematodes, which are transmitted by insect vectors to to Eliminate Lymphatic Filariasis (GPELF) and the African humans. Onchocerciasis (or river blindness), lymphatic fi la- Programme for Onchocerciasis Control (APOC) has made it riasis (LF, or elephantiasis) and loiasis (Loa loa, or African eye- possible to consider eliminating LF (defi ned as 70% of coun- worm) affect millions across the world, particularly in Africa. tries verifi ed free of LF and 30% engaged in post-interven- While they do not kill, fi larial tion surveillance activities) and controlling onchocerciasis diseases cause life-long by 2020.(1) These programmes have been in place for over Ideal Target Product Profi le disabilities, such as blind- twenty years and rely on mass drug administration (MDA) of for Filarial Diseases ness (onchocerciasis) and safe and donated anti-helminthic drugs: community-directed A new treatment for adults and swelling of the limbs and treatment with ivermectin, albendazole, and diethylcarba- children genitals (LF), causing great mazine citrate (DEC) . > Macrofi laricide: Effi cacious against suffering and social stigma- These drugs kill the juvenile form of the worms: the micro- the adult form of worms tization of those infected. fi lariae cause most of the symptoms and are transmitted > Oral , short-course treatment to insect vectors. > No side-effects following death of However, the drugs used in MDA programmes need to be worms administered repeatedly at regular intervals until adult forms > Safe in pregnant and breastfeeding of the worms (macrofi lariae) die naturally and there are no women more microfi lariae in the body. For LF, patients are treated > Affordable annually or bi-annually for 4-6 years and for onchocerciasis, > Adapted to tropical climates the treatment duration is 10 years. Importantly, MDA can- (minimum three-year shelf-life) not be undertaken in areas of loiasis co-endemicity: indeed, even though loiasis is not life-threatening and is usually not treated, infected patients often have a high burden of micro- fi lariae, and the sudden death of juvenile forms causes a serious adverse reaction, known as Loa loa encephalopathy, which can be fatal or leave long-term sequelae.(2) The risk of severe adverse reactions is considered to be unacceptable in areas where the microfi larial prevalence exceeds 20%.(3) A macrofi laricide drug, which would kill the adult form of the worm, would enable not only the treatment of patients in regions of loiasis co-endemicity, but could also be used in individual case management at the end of MDA programmes, known as ‘mopping up’, when the incidence rate is too low to justify initiating a new round of MDA. In addition, if suffi ciently safe, the drug could potentially be used for MDA, in which case one or two rounds of treatment would be suffi cient to eliminate the diseases from a given community.

(1) Sustaining the drive to overcome the global impact of neglected tropical diseases: second WHO report on neglected tropical diseases World Health Organization, 2013. (2) Boussinesq M. (2006) Loiasis. Ann Trop Med Parasitol 100: 715-31. (3) Boussinesq M. et al. (2001) Relationships between the prevalence and intensity of Loa loa infection in the Central province of Cameroon. Ann Trop Med Parasitol 95: 495-507.

36 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO

FACT SHEET

Filarial diseases

WHAT IS THE IMPACT OF FILARIAL mosquitoes. When a mosquito with and poverty are immense. DISEASES? infective stage larvae bites a person, the Loiasis leads to recurrent episodes of Onchocerciasis (or river blindness): parasites are deposited on the person’s itchy swellings and to ‘eye-worm’, the A total of 18 million people are affected skin and from there they enter the body. visible migration of the adult worm across The larvae then migrate to the lymphatic worldwide, in 36 countries in Africa, as the surface of the eye, which resolves vessels where they develop into adult well as in Guatemala, southern Mexico, after a few days. some areas of Venezuela, small areas worms in the human lymphatic system. in Brazil, Colombia, and Ecuador, and in > Loiasis is caused by the parasitic worm WHAT ARE THE CURRENT TREATMENTS the Arabian Peninsula.(1) Loa loa. The adult worms migrate AND THEIR LIMITATIONS? Lymphatic fi lariasis (LF, or elephantiasis): throughout the body just under the skin Current treatments for onchocerciasis More than 1.4 billion people in 73 countries and sometimes cross into the sub- and LF are based on mass drug worldwide are threatened by LF, conjunctival tissue of the eye where they administration (MDA) of anti-parasitic commonly known as elephantiasis. can easily be seen. It is transmitted drugs through programmes directed by Over 120 million people are currently through the repeated bites of deerfl ies the WHO. Drugs used by MDA infected, with about 40 million disfi gured (also known as mango fl ies or mangrove programmes include ivermectin for and incapacitated by the disease.(2) fl ies) of the genus Chrysops. onchocerciasis, albendazole plus either The infection is usually acquired in WHAT ARE THE SYMPTOMS? ivermectin in areas where onchocerciasis childhood, but its visible manifestations Onchocerciasis is the world’s second is also endemic or diethylcarbamazine usually occur later in life, causing (4) citrate (DEC) in areas where temporary or permanent disability. leading infectious cause of blindness. The WHO estimates that there are about onchocerciasis is not endemic for LF. Loiasis (African eye-worm): On the basis half a million blind people due to These drugs remove existing microfi lariae of the rapid assessment procedure of onchocerciasis. It also causes intense from skin, thus preventing vector-borne Loa loa (RAPLOA) results, it is tentatively itching, skin discoloration, rashes, and eye transmission, and provide long-term estimated that some 14.4 million people disease. sterilization of adult worms, preventing live in high risk areas where the estimated LF can become chronic, and when it does, re-population of the patient with prevalence of eye worm history is greater microfi lariae for six months or longer. than 40%, and 15.2 million in intermediate it leads to lymphoedema (tissue swelling) or elephantiasis (skin/tissue thickening) of However, in patients co-infected with Loa areas with estimated eye worm loa, the sudden death of large numbers of prevalence between 20 and 40%.(3) The limbs and fl uid accumulation (hydrocele) in the testes. Such body deformities lead microfi lariae can lead to serious adverse number of people at high risk varies events, such as encephalopathy, which considerably between countries. While the to social stigma, as well as fi nancial can be fatal or leave patients with severe overlap with the geographic distribution of hardship from loss of income and sequelae. Patients infected only with onchocerciasis or lymphatic fi lariasis is increased medical expenses. not well documented, where it does exist, The socio-economic burden of isolation Loa loa are not usually treated. there is signifi cant risk of severe adverse events with ivermectin treatment. HOW ARE FILARIAL DISEASES WHAT IS DNDi DOING TO ADDRESS UNMET TREATMENT NEEDS? TRANSMITTED? DNDi’s short-term strategy is to assess fl ubendazole, an anti-helminthic The parasitic worms that drug with proven effi cacy against gastrointestinal infections of soil- cause fi larial diseases are transmitted helminths in animals and man. The aim is to produce a transmitted by insect vectors reformulated version of fl ubendazole with properties for systemic exposure to humans. in the patient for use as a safe and fi eld-adapted macrofi laricidal drug > Onchocerciasis is a parasitic disease candidate in MDA programmes and/or for patient case management. caused by Onchocerca volvulus, a thin parasitic worm that can live for up to As a medium-term strategy, DNDi is assessing additional opportunities 14 years in the human body. The disease through an active screening programme of drugs emanating from animal is transmitted from one person to another health and pharmaceutical companies, with the goal of selecting one or two through the bite of a blackfl y. The candidates for proof-of-concept trials in patients. transmitted worm larvae develop into adult worms and settle into fi brous By 2015, DNDi aims to deliver from its fi larial diseases portfolio a new nodules in the human body close to the oral drug candidate, available for proof of concept in patients that surface of the skin or near the joints. could be used for case management of onchocerciasis and lymphatic > LF is caused by nematodes of the fi lariasis, especially in Loa loa co-endemic regions. Filarioidea family, mainly Wuchereria bancrofti, transmitted to humans through

(1) www.who.int/water_sanitation_health/diseases/oncho/en/ (2) www.who.int/mediacentre/factsheets/fs102/en/ (3) Zouré HGM, et al. (2011) The geographic distribution of Loa loa in Africa: results of large-scale implementation of the rapid assessment procedure for loiasis (RAPLOA). PLoS Negl Trop Dis 5: e1210. (4) www.who.int/blindness/partnerships/onchocerciasis_home/en/index.html

DNDi Annual Report 2012 37 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Partners: Flubendazole Johnson & Johnson, USA; Michigan State University, USA; 2012 OBJECTIVE: enterally,(2) fl ubendazole showed very specifi c AbbVie (formerly Abbott > Reformulate fl ubendazole for the potency against the adult stage of the worm. Translation Laboratories), USA; University of treatment of onchocerciasis and Despite this selective potency, it has not been Buea, Cameroon; McGill lymphatic fi lariasis considered as a treatment for fi larial infections, University, Canada as all of the current formulations have very low bioavailability and these oral forms would not Leadership: This project aims to develop fl ubendazole as provide suffi cient systemic exposure. The fi rst Discovery and Pre-clinical a safe, highly efficacious, and field-usable step of this project was to develop, with the Director: Robert Don; Project macrofi laricidal drug candidate for the treat- help of AbbVie, a new pre-clinical formulation Manager: Ivan Scandale ment of onchocerciasis and LF. Flubendazole of fl ubendazole that allows oral absorption. Project start: belongs to the benzimidazole class of mole- Non-clinical development of flubendazole April 2011 cules. Developed by Janssen Pharmaceuticals is ongoing in collaboration with Janssen (a pharmaceutical company of Johnson & Pharmaceuticals: in particular, the necessary Johnson) in the mid-1970s, it is a potent and studies required to fi le an Investigational New effi cacious anti-helminthic drug for gastroin- Drug (IND) application followed by submis- testinal nematode infections in swine, poultry, sion of a dossier to the FDA are supported by companion animals, and humans. In Europe, Janssen Pharmaceuticals, which will also pro- fl ubendazole is marketed for human use as vide DNDi with drug supplies to support clini- Fluvermal. In several animal models(1) and cal development. DNDi will conduct extensive in a small human clinical trial for onchocercia- PK/PD studies to guide/refi ne the selection of sis, in which the drug was administered par- human therapeutic doses.

(1) Zahner H., Schares G. (1993) Experimental chemotherapy of fi lariasis: comparative evaluation of the effi cacy of fi laricidal compounds in Mastomys coucha infected with Litomosoides carinii, Acanthocheilonema viteae, Brugia malayi and B. pahangi. Acta Trop 52: 221-66. (2) Dominguez-Vazquez A. et al. (1983) Comparison of fl ubendazole and diethylcarbamazine in treatment of onchocerciasis. Lancet 1: 139-43.

38 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO

Optimizing antiretroviral therapy PAEDIATRIC HIV for infants and young children in resource-poor settings

espite the successes of programmes rolled out to reduce With growing evidence of its superiority in infants and young Dthe number of new HIV infections in children, 330,000 children with very high viral loads, protease inhibitor (PI)- children acquired HIV infection in 2011, more than 90% of based cART is increasingly preferred as fi rst-line therapy in whom were in sub-Saharan Africa. An estimated 3.3 mil- low- and middle-income countries, as recommended by the lion children under the age of fi fteen were living with HIV in 2013 WHO guidelines.(5) However, currently available PI-based 2011 and 230,000 died of AIDS-related causes.(1) While the paediatric formulations have serious limitations. They are in absolute number of infants newly infected with HIV is now an alcohol-based liquid form with poorly tolerated taste, are declining due to progress in prevention of mother-to-child diffi cult to administer, and carry a high risk of dosing errors. transmission (PMTCT), the need for paediatric treatment will In addition, they have a short shelf-life, require a cold chain, continue to increase until 2020 at least. and are voluminous and expensive. The majority of children with HIV are infected through peri- Finally, many children need to be treated for both HIV and natal transmission during foetal development, birth, or whilst tuberculosis (TB) and there are signifi cant negative drug- being breastfed. Whereas in high-income countries, HIV trans- drug interactions between anti-TB drugs and anti-HIV drugs. mission in young children has largely been eliminated due to HIV-infected children co-infected with TB have a particu- effective PMTCT interventions, in low- and middle-income larly poor prognosis.(6) These drug interactions need to be countries many pregnant women do not have access to ante- addressed either by new natal care and HIV testing. Therefore they do not benefi t from drugs or adapted dosages. Ideal Target Product Profi le interventions to prevent transmission to their child: in those Improved fi rst-line ther- for Paediatric HIV countries, coverage of effective antiretroviral regimens for apies for children are PMTCT reached only 57% in 2011.(2) A fi rst-line, protease inhibitor-based urgently needed. all-in-one antiretroviral regimen Provision of adequate treatment to those children who do for HIV-infected children: become infected is vital. HIV-infected infants frequently > Safe and effi cacious develop illness within their fi rst months of life. In the absence of antiretroviral therapy (ART), almost one-third of them die > Adapted formulation suitable for infants and children before their fi rst birthday, and about half die before they are two years old.(3) Even though the 2010 WHO guidelines recommend > Easy-to-use fi xed dose that all children younger than two years start immediately combination on ART, less than one-third of eligible children under the age > Palatable of fi fteen were receiving the life-saving medicines in 2011.(4) > No drug-drug interaction with ART coverage is even lower in children under the age of fi ve, medicines for tuberculosis notably because of the lack of appropriate tools to diagnose > Adapted to tropical climates HIV early in the child’s life and of therapeutic options adapted (no refrigeration needed) to their needs. Although more than 25 drugs are approved for adults, many have not yet been tested and approved for use in children, limiting the number of therapeutic options for caregivers and children. The drugs that are approved for children need to be associated to act synergistically in order to suppress HIV replication. These combination antiretroviral therapies (cARTs) of three or four drugs are few, complex to administer, and will have to be taken for life.

(1) Global report: UNAIDS report on the global AIDS epidemic 2012, Geneva, 2012. (2) Ibid. (3) Newell, M. et al. (2004) Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet 364: 9441. (4) Global report: UNAIDS report on the global AIDS epidemic 2012, Geneva, 2012. (5) Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, WHO, June 2013. (6) Children and AIDS: Fifth Stocktaking Report. New York, UNICEF/ UNAIDS/WHO/UNFPA/UNESCO, 2010.

DNDi Annual Report 2012 39 FACT SHEET Paediatric HIV

WHAT IS THE IMPACT OF PAEDIATRIC HIV? However, this combination therapy is not In many areas, HIV-positive infants and At the end of 2011, an estimated 3.3 million being widely used. According to a WHO children are co-infected with tuberculosis children below the age of 15 were living survey performed in 45 countries, only (TB). Drug-drug interactions between PIs with HIV, more than 90% of whom in 12.2% of children with HIV were receiving a in particular and rifampicin, one of the sub-Saharan Africa. An estimated 230,000 fi rst-line treatment containing a PI (mostly drugs used to treat TB, greatly diminish the children under 15 years of age died of lopinavir/ritonavir, LPV/r), 97% of whom blood levels of PIs and hinder the effi cacy AIDS-related illness in 2010. In low- and were in South Africa. The only available PI of the ARV treatment. In order to middle-income countries, access to for young children, LPV/r does not come counteract this interaction, extra ritonavir treatment has expanded to reach an in a child-friendly formulation: the oral needs to be added to the standard estimated 562,000 HIV-infected children solution formulation is unpalatable, proportion of LPV/r. This is called under the age of 15. Still, only 28% of contains 42% alcohol, and is not adapted ‘superboosting’, and requires the HIV-positive children are estimated to be to resource-poor settings due to major development of an infant-friendly on antiretroviral therapy (ART), compared logistical constraints: it requires formulation of ritonavir. The currently to 68% of adult women and 47% of adult refrigeration, has a short shelf-life when available ritonavir formulation suffers the men.(1) exposed to heat, is expensive, and is same limitations as the current diffi cult to store and transport. formulation of LPV/r with regard to taste, HOW IS PAEDIATRIC HIV TRANSMITTED? high alcohol content, and logistical In children, HIV transmission can occur constraints. during pregnancy through the placenta, during delivery through exposure to body fl uids and cervical secretions, and through breastfeeding. In the absence of WHAT IS DNDi DOING TO ADDRESS UNMET TREATMENT NEEDS? antiretroviral preventive treatment, 30 to In 2010, DNDi was called on by various organizations, including Médecins 40% of children born to an HIV-infected Sans Frontières, WHO, and UNITAID, to apply its expertise to the mother acquire infection themselves. development of paediatric HIV treatments. DNDi’s position, notably that However, with antiretroviral prophylaxis paediatric HIV is a neglected disease, was published as a ‘Perspective’ in throughout pregnancy, delivery, and the New England Journal of Medicine in August 2011.(3) breastfeeding, transmission can be decreased to a few percent. DNDi is pursuing two objectives to address the needs of HIV-infected WHAT ARE THE SYMPTOMS? children: • Develop and register two solid fi rst-line 4-in-1 LPV/r-based fi xed-dose HIV is diffi cult to diagnose in children and combinations (FDCs) with 2 NRTIs. All components of the combination will infants: indeed, signs and symptoms are be developed in the form of taste-masked granules, stable with no need for non-specifi c and are very common in refrigeration, presented in a single unit with appropriate strengths to resource-poor settings, such as chronic accommodate weight band dosing. diarrhea, recurrent infection, and failure • Develop and register a stand-alone ritonavir booster formulation that can to thrive. However, the disease progresses be added to any PI-based paediatric ARV regimen and can be used to rapidly and can lead to death before HIV counteract the negative drug-drug interactions between PIs and rifampicin- has been diagnosed or even suspected. containing TB treatments. All children born to HIV-infected mothers carry maternal anti-HIV antibodies, and As a short-term strategy, DNDi will start implementing the use of are thus seropositive. A positive PI-based treatment with existing LPV/r-based products before the serological test therefore does not availability of the 4-in-1 FDC, in order to provide better treatment for necessarily indicate HIV infection. Only infants today and promote in-country adoption. DNDi participated in the very expensive diagnostic tests that detect CHAPAS-2 trial that compared LPV/r sprinkles (hereafter referred to as the virus itself can give an accurate minitablets) to the LPV/r liquid formulation. These minitablets will be used diagnosis in the fi rst months of life. New in association with NRTI dispersible tablets in implementation studies as tests are currently under development. part of this short-term strategy. WHAT ARE THE CURRENT TREATMENTS In the mid-term, DNDi is working with its industrial partner, Cipla Ltd., on AND THEIR LIMITATIONS? combining LPV/r granules with two NRTIs into a single unit dose. This The 2010 WHO guidelines recommend modular concept is fl exible, so that any of the components can eventually early diagnosis and immediate treatment be substituted to provide new fi xed-dose combinations. of HIV-positive infants and children under In addition, in order to address the needs of HIV/TB co-infected children, the age of two; for those with prior DNDi is developing a formulation of ritonavir for superboosting LPV/r at a exposure to PMTCT, PI-based fi rst-line 1:1 ratio. A pharmacokinetic study to establish the effi cacy and safety of therapy is recommended, but results of a superboosted LPV/r is ongoing in South Africa with the existing ritonavir superior response to such therapy in solution. children without prior exposure to PMTCT have also been reported.(2) The combination of a boosted protease By 2015-2016, DNDi aims to deliver from its paediatric HIV portfolio: inhibitor with two nucleoside reverse > Two new all-in-one paediatric formulations containing a PI and two NRTIs transcriptase inhibitors (NRTIs) is considered by many experts as the most > One stand-alone paediatric booster for HIV-TB co-infected children effective fi rst-line therapy for infants and children, regardless of prior exposure to ARVs.

(1) Global report: UNAIDS report on the global AIDS epidemic 2012, Geneva, 2012. (2) Violari A. et al. (2012) Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med 366: 2380-9. (3) Lallemant M. et al. (2011) Pediatric HIV - A Neglected Disease? N Eng J Med 365: 581-3.

40 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

Improved PI for fi rst-line treatment Partners: Cipla Ltd., India 2012 OBJECTIVE: rifampicin-containing TB treatment, a stand- > Develop an improved PI that can alone booster ritonavir (RTV) formulation will Leadership: be incorporated into a fi xed-dose be developed. Head of Paediatric HIV Programme: Translation combination Marc Lallemant; A paediatric pharmacokinetic expert group has Project Coordinator: Janice Lee; been created to determine the optimal weight Senior Pharma Advisor & Product The project aims to improve the formulation of band dosing of LPV/r and NRTIs in order to Manager: Jean-René Kiechel PI-based fi rst-line treatment for young infants deliver all components in an FDC. These and children living with HIV. The development doses are modelled using WHO weight band Project start: plan includes putting together all four drugs recommendations. December 2011 needed for the treatment of HIV in children into a single unit, also known as a fi xed-dose com- The two 4-in-1 FDCs and the stand-alone RTV bination (FDC), which is heat-stable, well taste- booster will be tested in healthy human volun- masked, solid, does not contain alcohol or teers in 2013. inappropriate solvents and, most importantly, 2012 2013 2014 is easy to dose (using WHO-recommended weight band dosing) for the caregiver. The two FDCs in development are AZT/3TC/LPV/r and ABC/3TC/LPV/r. In order to counteract negative drug interactions between PIs and

PI Sprinkles (minitablets) (Chapas-2) Partners: DNDi joined this trial sponsored by 2012 OBJECTIVE: observed in infants, older children, and adults. the Medical Research Council > Clinically assess the Variability in LPV/r pharmacokinetic parameters (MRC), UK, as an additional partner. Development pharmacokinetics and acceptability was similar in both formulations and neither Other partners include Cipla Ltd., of LPV/r in the existing sprinkle formulation resulted in sub-therapeutic con- India; Joint Clinical Research (minitablet) formulation in children centrations. Caretakers preferred the minitablet Centre, Uganda; Makerere between 1-4 years of age (additional formulation, particularly for storage/transport University/Mulago Hospital, CHAPAS-2 cohort) reasons. For this group of children, acceptabil- Uganda; Radboud University ity of both formulations was similar, in particular Nijmegen Medical Centre, as regards to taste (these minitablets are not The results of the PK study of LPV/r minitab- The Netherlands lets versus syrup (CHAPAS 2) in children aged taste-masked). 1 to 4 years were presented at CROI 2013.(1) Leadership: Exposure to LPV/r minitablets was slightly Head of Paediatric HIV Programme: higher than that to the liquid formulation. LPV Marc Lallemant; Project exposure in this age group was similar to that Coordinator: Janice Lee Project start: May 2012

‘Superboosting’ – TB/HIV Partners: SOUTH AFRICA: Stellenbosch 2012 OBJECTIVE: October 2012, and the fi rst ethics approval was University and Tygerberg Children’s > Evaluate the safety and received from Cape Town Tygerberg Hospital Hospital; Perinatal HIV Research Development pharmacokinetics of increasing LPV/r at the end of the year. Unit; Shandukani Research Centre; boosting ratio from 4:1 to 1:1 in HIV/ The study is expected to end in 2014 and results Empilweni Services and Research TB co-infected infants and children will be available at the beginning of 2015. Unit, Rahima Moosa Mother and in order to counteract the negative Child Hospital; Enhancing Care drug-drug interactions between Foundation; Department of Health; PIs and rifampicin-containing TB Department of Science and treatments Technology Leadership: This study is essential to support and pre- Head of Paediatric HIV Programme: pare the development of a stand-alone ritona- Marc Lallemant; Project vir booster formulation that can be added to Coordinator: Janice Lee any PI-based paediatric ARV regimen. It will be performed in infants and young children co- Project start: infected with TB and HIV at 5 sites in South May 2012 Africa. Site initiation visits were conducted in

(1) Kitaka S. et al. Pharmacokinetics and acceptability of a new generic lopinavir/ritonavir sprinkle formulation in African, HIV+ children 1-4 Years: CHAPAS-2. CROI 2013. Poster 975b.

DNDi Annual Report 2012 41 R&D MODEL, STRATEGY & PORTFOLIO

MALARIA Ensuring access to ACTs to fi ght malaria

alaria is a major public health problem that continues have recently been developed and pre-qualifi ed by the WHO. Mto affect millions across the world, mainly children Together with diagnosis and vector control tools, they repre- under the age of fi ve. The development of multi-drug resist- sent a key improvement of the antimalarial arsenal. ant Plasmodium falciparum parasites and resulting failure of treatment with chloroquine and sulfadoxine-pyrimethamine led the World Health Organization (WHO) to recommend the use of artemisinin-based combination therapies (ACTs) FACT SHEET for the treatment of uncomplicated P. falciparum malaria Malaria in 2001. Recently, delayed parasite clearance indicative of WHAT IS THE IMPACT OF MALARIA? resistance to artemisinin has been reported in some areas The WHO estimates that there were 216 million of of South-East Asia, sparking a global response to contain cases of malaria in 2010, and that 660,000 deaths resistant parasites before they spread around the world. were attributable to the disease, 86% of which occured in children under fi ve and 91% in sub- Despite these concerns, ACTs remain the best available anti- Saharan Africa. A study by C. Murray et al., however, malarial medicines and are still highly effective in the majority estimates that in 2010 malaria was the underlying of malaria endemic areas. Fixed-dose combinations (FDCs) cause of death for 1.24 million individuals, including (1) of ACTs are preferred and recommended, as they promote 714,000 children younger than fi ve years. adherence to treatment and reduce the potential of selec- Recent successes and a reduction in the number of cases are reason for optimism, but many people tive use of the medicines as monotherapy. Since 2005, the at risk of malaria still lack access to critical number of ACT treatment courses procured by the public treatment and prevention options, including to ACTs, sector has increased from 11.2 million to 76 million in 2006, and malaria control continues to face serious (2) and reached 181 million in 2010. challenges. HOW IS MALARIA TRANSMITTED? In 2002, the Fixed-Dose Artesunate-Based Combination Malaria is caused by Plasmodium parasites, spread Therapies (FACT) Consortium, created by the DND Working to people through the bite of an infected female Group and TDR, started to develop two fi xed-dose artesunate anopheles mosquito. Four species of the parasite (AS)-based combination therapies (out of the four initially cause malaria in humans: P. falciparum, recommended by WHO): P. vivax, P. malariae, and P. ovale. P. vivax and P. falciparum are the most common, with > ASAQ, the FDC of artesunate and amodiaquine developed P. falciparum the most deadly. in partnership with Sanofi , was fi rst registered in 2007 and Approximately half of the world’s population is at pre-qualifi ed by WHO in 2008; risk of malaria. Most malaria cases and deaths occur in sub-Saharan Africa, but Asia, Latin > ASMQ, the FDC of artesunate and mefl oquine developed America, and to a lesser extent the Middle East in partnership with Farmanguinhos (fi rst registered in and parts of Europe are also affected. In 2010, 99 countries and territories had active malaria Brazil in 2008) and then, after a technology transfer, also transmission. produced by Cipla Ltd. (fi rst registered in India in 2011), WHAT ARE THE SYMPTOMS? and pre-qualifi ed by WHO in 2012. Malaria is an acute febrile illness with initial FSCs enable simple treatment regimens, therefore increas- symptoms that can be diffi cult to recognize. ing patient compliance. ASAQ and ASMQ, together with Symptoms of uncomplicated malaria include fever, ® headache, chills, and vomiting. If treatment is not CoArtem (the FDC of artemether and lumefantrine devel- given within 24 hours, P. falciparum malaria can oped by Novartis and the fi rst ACT pre-qualifi ed by the WHO progress to severe illness, which can lead to death in 2001), Pyramax® (the FDC of artesunate-pyronaridine) and or serious brain damage, especially in children, who Eurartesim® (the FDC of dihydroartemisinin-piperaquine are particularly vulnerable due to their lack of immunity to the parasite. (DHA/PQP)), both developed by the Medicines for Malaria Venture (MMV) and approved in 2011, strengthen the global (1) Murray, CJL et al. (2012) Global malaria mortality between ACT portfolio of FDCs now available for the treatment of 1980 and 2010: a systematic analysis. Lancet 379: 413–31. uncomplicated P. falciparum malaria. Fixed doses of some (2) A Decade of Partnerships and Results, Progress and Impact Series, number 7, World Health Organization, Geneva, 2011. of these combinations, developed by other manufacturers,

42 DNDi Annual Report 2012 R&D MODEL, STRATEGY & PORTFOLIO HUMAN AFRICAN TRYPANOSOMIASIS (HAT)LEISHMANIASIS CHAGAS DISEASE FILARIAL DISEASES PAEDIATRIC HIV MALARIA

ASMQ FDC Partners: Farmanguinhos, Brazil; Cipla Ltd., 2012 OBJECTIVES: pre-agreed prices. The India; Shoklo Malaria Research Unit, > Technology transfer and registration: product was registered in Thailand; Universiti Sains Malaysia; Implementation • Support activities for PHASE IIIB India in 2011, in Malaysia Oxford University, UK; WHO-TDR; prequalifi cation by WHO and PAHO study in children: in March 2012, and in Indian Council of Medical Research • Obtain registration authorization 751/940 patients Myanmar in October 2012. (ICMR), India; Epicentre, France; recruited in India and South-East Asia In September 2012, Cipla Centre Hospitalier Universitaire • Reduce cost of mefl oquine to by end 2012 Ltd.’s ASMQ FDC received at 4 sites Vaudois, Switzerland; National decrease the price of ASMQ FDC in 3 countries WHO prequalification, an Institute of Medical Research, > Clinical studies important step in acceler- Tanzania; Kenya Medical Research • Progress the multicentre ating access in Asia. Institute (KEMRI), Kenya; Centre comparative study conducted in Additional clinical studies are ongoing that will National de Recherche et de three African countries provide information on use in children, adults, Formation sur le Paludisme, and pregnant women in Africa. According to Burkina Faso; Medicines for Malaria The ASMQ fixed-dose combination (FDC) WHO recommendation, AS+MQ could be con- Venture (MMV), Switzerland; Ifakara was developed by the FACT consortium cre- sidered for use in some countries in Africa. To Health Institute, Tanzania ated by DNDi and TDR in 2002. Within FACT, provide information on the effi cacy and tol- Leadership: the Brazilian government-owned pharmaceuti- erability of ASMQ FDC, DNDi is sponsoring Senior Pharma Advisor & Product cal company, Farmanguinhos/Fiocruz, was the a multicentre Phase IIIB study in Tanzania, Manager: Jean-René Kiechel; fi rst manufacturer of ASMQ FDC, which was Burkina Faso, and Kenya to assess its effi - Clinical Manager: Gwénaëlle Carn; registered in Brazil in March 2008. Through cacy, safety, and pharmacokinetics compared Medical Coordinator FACT Project: a South-South technology transfer, ASMQ to artemether-lumefantrine in children below Graciela Diap FDC production was transferred to the Indian the age of 5. The study is expected to end in pharmaceutical company Cipla Ltd. in 2010 to October 2013 and the fi rst results will be avail- Project start: January 2002 ensure availability in India and Asia at affordable, able at the beginning of 2014.

ASMQ FDC WHO Prequalifi ed At a special DNDi event in Kuala Lumpur, Malaysia, on 3 October 2012, WHO prequalifi cation of the Cipla-manufactured ASMQ FDC is announced at a press conference with Malaysia’s Minister of Health, Dato’ Sri Liow Tiong Lai. A prequalifi ed status makes ASMQ FDC eligible to tenders that receive funding from international procurement agencies, such as UNICEF and the Global Fund to Fight AIDS, Tuberculosis and Malaria.

ASAQ Winthrop Partners: Sanofi , France; MMV, Switzerland; 2012 OBJECTIVE: By the end of 2012, over AEDES, Belgium; Zenufa, Tanzania; > Diversify ASAQ suppliers by 180 million treatments National Centre for Research and transferring technology to a partner had been distributed in Implementation 180 MILLION Training on Malaria, Burkina Faso; in Africa treatments 30 African countries. First Universiti Sains Malaysia; Oxford > Facilitate implementation of ACTs distributed registered in Morocco, in 30 African University, UK; Institute of Research FDC in general and specifi cally where it is manufac- countries for Development (IRD), Senegal; ASAQ, in all countries where it could by the end tured, ASAQ is now reg- Université Bordeaux Segalen, benefi t patients and abides by local of 2012 istered in 30 African practices countries, as well as in Faculté de Pharmacie, France; India, Bangladesh, and Mahidol University, Thailand; Bertin Pharma, France; Médecins Sans ASAQ Winthrop, the fi xed-dose combination Colombia. In 2010, ASAQ Winthrop obtained Frontières; Epicentre, France; (FDC) of artesunate (AS) and amodiaquine WHO authorization for a three-year shelf life, WHO-TDR; KEMRI, Kenya; ICMR, (AQ), was the fi rst treatment made available by giving the product the longest shelf-life of any India; National Malaria Control DNDi in 2007 through an innovative partnership pre-qualified FDC artemisinin-based treat- Programme, Ministry of Health, with Sanofi . ASAQ Winthrop was pre-qualifi ed ment available for malaria. In partnership with Burundi; Ministry of Health, Sierra by WHO in October 2008 and included on the Sanofi, MMV, and National Malaria Control WHO Essential Medicines List (EML) in 2011. Programmes, high-quality data on ASAQ Leone; Ministry of Health, Ghana; effectiveness and safety in the fi eld is being Komfo Anokye Teaching Hospital collected, as part of a Risk Management Plan (KATH), Ghana (RMP). This was the fi rst RMP submitted to Leadership: the WHO, and the fi rst to be set up entirely in Senior Pharma Advisor & Product Africa. It is expected to contribute to building capacity on drug safety and effi cacy monitor- Manager: Jean-René Kiechel; ing in sub-Saharan African countries and could Clinical Manager: Gwénaëlle Carn; set the precedent for further real-life assess- Medical Coordinator FACT Project: ment studies of new ACTs. Together with part- Graciela Diap ners, DNDi is also working on the transfer of Project start: technology to a second manufacturer in Africa, January 2002 Zenufa, in Tanzania.

DNDi Annual Report 2012 43 R&D MODEL, STRATEGY & PORTFOLIO 44

IN-KIND CONTRIBUTIONS 2006-2012 IN-KIND CONTRIBUTIONS2006-2012 inleveraging resources increase Stark of partner M). 0.2 +EUR costs, screening and LO the of 43% M(approx. 2.5 EUR was activities screening and consortium (LO) optimization lead the for investment M);total 0.3 EUR (+ co-infection 0.1 HIV/VL M)and EUR (+ fexinidazole for Africa in trials clinical new two of M);preparation 0.5 EUR (+ 2012 end at phase clinical to enter ready treatment topical leishmaniasis M);cutaneous 0.8 EUR (+ study in implementation patient the Asia recruitment substantial activity: illustrates increase 1.9 Expenditure EUR M. with Plan, Business the in projected as (34%) expenditure R&D of part substantial most the Leishmaniasis: M). 0.2 EUR (- completed was follow-up two-year NECT M);and 0.5 EUR (- analysis PK and studies topharmacological dedicated mainly was expenditure project SCYX-7158 oxaborole M);the 0.5 EUR (+ fexinidazole for starting activities 1.1 clinical EUR (- and M), partner external toan optimization lead and screening toredirecting due HAT: highlights: by expenditure disease 2012 R&D of breakdown percentage The 2012. in M) 2.7 %(EUR 13.5 by Mincreased 22.8 EUR of expenditure R&D Overall R&D EXPENDITUREBYDISEASE2011-2012 to match afl expenditures R&D in 22.8 million EUR 2012 0 1 2 3 4 5 DND in millionEUR

0.7 0620 082009 2008 2007 2006 With a total of EUR 5 M, investments decreased (- EUR 1.3 M) M) 1.3 EUR (- decreased investments 5M, EUR of atotal With i i 2012 2011 Annual Report 2012 5 4 3 %4 9% 4% 5% 11% 23% 24% 34% 27% 25% 35% 0.4 For the fi the For ourishing portfolio ourishing 0.5 rst time, leishmaniasis projects became became projects leishmaniasis time, rst 1.1

INDICATORS KEY FINANCIALPERFORMANCE 2.3 2010 5.0 2011 2012 5.8 Portfolio expansion: expenditure). R&D of (23% Chagas disease: 20% of total expenses. total of 20% approximately reached contribution in-kind 2012 2011, in total the As partners. industrial with (HAT) fexinidazole and disease) (Chagas E1224 azole of development topharmaceutical relates present, to 2009 from totals annual all of 50% reported, contribution major The R&D. disease neglected in partners these of engagement increasing the refl This eight-fold. increased have contributions in-kind years, seven In individuals). and groups, academic companies, (private partners generous its of contribution in-kind the DND activities, its of picture acomprehensive topresent order In M). 0.25 EUR (+ activities ing toscreen- addition in M), 0.35 EUR (+ use clinical human for suitable sier for fl Dos- Product Medicinal Investigational the topreparing due 270% by The Ghana. M)in 0.25 (EUR project CHAPAS DND M)and 0.25 (EUR Africa South in LPV/r) superboosting for (ritonavir project boosting super- the for study aclinical of preparation activities: two with bled, expenditure. R&D of 9% represents ects the investment by DND by investment the ects ubendazole and to the development of an oral formulation formulation oral an of development tothe and ubendazole Projects remained stable in stable 2012 remained EUR 4.7 with M Projects Chagas projects Leishmaniasis projects HAT projects Expansion to include two new diseases areas areas diseases new two toinclude Expansion i ’s participation to the PI sprinkles (minitablets) (minitablets) sprinkles PI tothe ’s participation i in consolidating such partnerships and and partnerships such consolidating in Paediatric HIV %2% 2% fi laria Malaria projects projects HIV Paediatric Filaria projects project increased increased project expenditure dou- i values

KEY FINANCIAL PERFORMANCE 2012 INDICATORS

Development and implementation expenditure increases as treatments approach the end of the pipeline R&D EXPENDITURE BY R&D STAGE

Research Translation Development Implementation Screen Hit to Lead Lead Opt. Pre-clinical Phase I Phase IIa/PoC Phase IIb/III Registration Access

Nitroimidazole Oxaborole Fexinidazole NECT backup SCYX-7158 HAT Nifurtimox-Eflornithine Combination Therapy Oxaborole backup

Nitroimidazole VL-2098 Fexinidazole New VL treatments SSG&PM backup (VL) for Bangladesh (VL) Sodium Stibogluconateg S I S & Paromomycin S New VL treatments Combination Therapy IA C

N for Africa for VL in Africa A R Anfoleish M (CL) H New treatments for New treatments Portfolio S I E HIV/VL co-infection for VL in India

LE for Africa

E N New VL treatments 2012 I for Latin America

N Fenarimol Azoles Benznidazole & PORTFOLIO STRATEGY R&D MODEL, E

S series E1224 Paediatric S

A G A

G dosage form E S I HA Nitroimidazole K777 D C

Biomarkers S L E S A

E Flubendazole S ILARIA

F DI Macrofilaricide

C Improved PI PI Sprinklesp for first-line (CHAPAS-2) IATRI

D treatment E

A Superboosting HIV P - TB-HIV

ASAQ FDC Artesunate Amodiaquineq Fixed-Dose Combination MALARIA

ASMQ FDC Artesunate-Mefloquineq Fixed-Dose Combination

New Chemical Entity (NCE) Fexinidazole (for HAT and VL) = 1 NCE

7.6 7.7 6.6 5.6 5 4.5

2.9 3

in million EUR

2011 2012

Research Translation Development Implementation

In 2012, the most important fl uctuations relate to growth of clinical development and progress of implementation activities (+ EUR 3.7 M). Research: Screening and lead optimization activities remain stable Development: The progression of two projects to clinical development (+ EUR 0.1 M). However, some changes occurred in the set-up of activi- led to an increase of expenditure (+ EUR 2.1 M): fexinidazole for HAT ties, namely in screening for fi larial diseases and in the partnerships started Phase II/III study, and the VL and HIV/VL co-infection study that have been redesigned in a more suitable way, allowing for greater started Phase IIb/III. cost effi ciency. Implementation: With six projects in implementation phase, expendi- Translation: Expenditure decreases between 2011 and 2012 (- EUR 1 M), ture increased by 50% (+ EUR 1.5 M) mainly due to the paediatric dosage mainly due to: progression of fexinidazole for HAT to clinical develop- form of benznidazole implementation after registration in December ment; four projects in transition phase (VL-2098, oxaborole SCYX-7158, 2011, and the start of recruitment in India for the VL Asia study, with azole E1224 and biomarkers, and K777 ); increasing activities of the two 300 patients recruited. new disease areas of the portfolio, fi larial diseases and paediatric HIV.

DNDi Annual Report 2012 45