R&D Model & Portfolio

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R&D Model & Portfolio R&D MODEL & PORTFOLIO ADAPTED TREATMENTS FOR THE BENEFIT OF NEGLECTED PATIENTS The R&D strategies developed by DNDi since its inception aim to Phase II trials as a potential single- address the immediate needs of patients by improving existing dose oral treatment and is the first therapeutic options in the short term, whilst undertaking longer molecule to arise from DNDi’s lead term research to identify and develop entirely new compounds optimization programme. which will be valuable adapted tools, particularly for elimination targets set by the World Health Organization. Although not Leishmaniasis is a complex family necessarily breakthrough medicines, six new treatments have of diseases, and the identification been delivered to date as a result of the short-term strategy, of new compounds has proved which have brought significant benefits to patients. challenging. Compound libraries from a variety of sources have been screened and, despite the inevitable The year 2015 has been a turning are orally available compounds for loss of compounds to attrition, NCEs point for DNDi, as long-term systemic use. The most clinically from the nitroimidazole, oxaborole, investments have now filled the advanced of these are for sleeping and aminopyrazole chemical drug development pipeline with sickness: fexinidazole, which was families are undergoing lead thirteen new chemical entities identified from compound mining optimization to combat Leishmania (NCEs) included by the end of the and is a ten day oral treatment, infections, with the nitroimidazole year, the vast majority of which and SCYX-7158, which is entering VL-0690 selected to go forward to 14 › DNDi Annual Report 2015 R&D MODEL & PORTFOLIO pre-clinical development in 2015. A two-pronged approach aims to This increased number of com- Additional drug candidates have develop direct-acting or indirect- pounds in development has resulted come from the drug discovery acting compounds for treating in a concomitant increase in the programmes of GSK/Dundee Drug filarial diseases. Emodepside, used number of clinical trials. At the end Unit (two classes), and Celgene in veterinary healthcare, began of 2015 more than 30 clinical trials (one class). These six classes are its clinical evaluation in healthy were in preparation, on-going, or also undergoing testing in animal volunteers in 2015 as a potential reporting results worldwide. models of CL. The three classes treatment for onchocerciasis. The extension of DNDi’s portfolio from the DNDi series have already Additional NCEs are being sought with the new Business Plan 2015- shown efficacy against L. major in a by screening focused libraries 2023 (see p. 6) led to the inclusion of mouse model of infection, with the with known anthelmintic activity two new diseases. Fosravuconazole, aminopyrazole class showing sterile from animal health companies and already available to DNDi because cure in animals. This is the first time repurposing libraries from human of its previous evaluation for Chagas this has been observed with a drug health companies. Although drug disease, is the most promising drug candidate. The NTD Drug Discovery repurposing is high risk, the wealth candidate for fungal mycetoma Booster, a multilateral experiment of information available for drugs and DNDi will begin recruiting launched in 2015, aims to speed up which have already undergone 130 patients in Sudan in the first the discovery of new compounds for clinical development can speed up ever randomized clinical trial to leishmaniasis and Chagas disease. the development process drastically, be undertaken for eumycetoma. The lack of clinical markers of and new treatments reach patients A combination of sofosbuvir with disease, and of animal models faster. A macrofilaricide which ravidasvir will be evaluated in capable of accurately predicting the indirectly leads to the death of the DNDi 750 patients in Malaysia and South translation of drugs from laboratory parasite by killing its Wolbachia East Thailand as a potential public health Asia to patient, has proven to be a major symbiont entered the development tool to treat Hepatitis C. obstacle in developing new drugs for pipeline in 2015. Chagas disease. 29 ongoing clinical studies in 2015, on 4 continents, for 7 diseases Phase I Phase II Phase III Phase IV 3 STUDIES 11 STUDIES 10 STUDIES 5 STUDIES Efficacy studies with fexinidazole in human African DNDi Chagas disease aims to determine if the safety and Latin DNDi trypanosomiasis (HAT) patients in the Democratic America tolerability issues of benznidazole can be managed by DRC Republic of Congo and Central African Republic will reduced doses and treatment duration, or by combination ultimately collect information from 750 adults and with fosravuconazole. children above the age of 6 years with both stages of DNDi is seeking to address the urgent need for better gambiense disease, including an evaluation of its ease of medicines for children living with HIV. In June 2015 use under real-life conditions. A later study will examine lopinavir/ritonavir (LPV/r) pellets were awarded its efficacy in patients with rhodesiense HAT. tentative approval for use by the U.S. Food and Drug Fexinidazole is also being investigated for treating Administration (FDA). This was followed by the initiation of patients with the related kinetoplastid diseases DNDi an implementation study (the LIVING study) in – leishmaniasis and Chagas disease. A combination Africa 3,000 Kenyan children, which will provide information of fexinidazole and miltefosine for the treatment of on their use as part of a combination treatment with DNDi Africa visceral leishmaniasis (VL) patients in eastern Africa AZT/3TC or ABC/3TC administered under normal living could be the first oral-only combination therapy for VL: conditions. A “superboosting” study was undertaken an allometric dosing study of miltefosine to address in 96 African children infected with both HIV and drug underexposure in children was undertaken in tuberculosis (TB), aiming to compensate for the negative 2015. Twelve month follow-up of efficacy and safety drug interactions between LPV/r and the TB-treatment data of fexinidazole in adult Chagas disease patients rifampicin. The study was finalized in 2015 and results was concluded in 2015, with the results expected in early led the South African government to change its treatment 2016. A planned study in 270 adult patients with chronic guidelines for HIV/TB coinfected children. DNDi Annual Report 2015 › 15 R&D MODEL & PORTFOLIO PROJECTS ARE DIVIDED INTO FIVE CATEGORIES: New treatments (involving NCEs) developed from BUILDING novel compounds identified through screening, lead optimization, or licensing. These drugs must A ROBUST meet target product profiles (TPPs) and may be used in monotherapy or as part of combination therapies PORTFOLIO when appropriate. DISEASES Research Translation Development Screen Hit to Lead Lead Opt. Pre-clinicalPhase IPhase IIa/PoC Phase IIb/III Registration Human SCYX-1330682 SCYX-7158 Fexinidazole African Trypanosomiasis SCYX-1608210 Leish Fexi/MF New Treatments Screening H2L Oxaborole DNDI-0690 combo for HIV/VL Amino New Treatments pyrazoles for PKDL Leishmaniasis VL Treatment Latin America CpG-D35 Anfoleish New CL (CL) (CL) combos Chagas New Benz Screening H2L Regimens Chagas Fexinidazole Biomarkers Filaria Screening Macro Filaricide 2 Emodepside Two ‘4-in-1’ LPV/r pellets with LPV/r dual NRTI FDC FDC Paediatric HIV granules Superbooster Therapy Paediatric HIV/TB Sofosbuvir/ Hepatitis C Ravidasvir Treatments Mycetoma Fosravuconazole New Chemical Entity (NCE); Fexinidazole (for HAT, VL, and Chagas disease) = 1 NCE 16 › DNDi Annual Report 2015 R&D MODEL & PORTFOLIO New treatments developed from Combinations or new formulations of existing drugs that compounds with known antimicrobial/ are better adapted to field conditions and patient needs antiparasitic activities aiming to maintain (paediatric dosage forms, long-acting forms, new route or improve efficacy and tolerability. of administration, fixed-dose combinations, co-packaging, or co-administration). Compound repurposing for new indications of existing treatments in other diseases Geographical extension of existing treatments, including (therapeutic switching). completion of regulatory dossiers in new countries. Implementation KEY R&D MILESTONES IN 2015 Access DISCOVERY NECT • Successful implementation of NTD Drug Discovery Booster Nifurtimox-Efl ornithine • New series in H2L and lead optimization for leishmaniasis Combination Therapy and Chagas disease • Screening of 300,000 compounds from pharmaceutical and other libraries completed • Two optimized lead candidates under review for VL with backup compounds in three different chemical classes – including one very potent for CL SSG&PM Africa HUMAN AFRICAN TRYPANOSOMIASIS (HAT) • Recruitment to three fexinidazole studies (pivotal late stage, early stage, children) completed New VL Treatments • Phase I study for SCYX-7158 completed Asia LEISHMANIASIS • DNDI-0690 nominated as new pre-clinical candidate for VL • Miltefosine allometric dosing study recruitment completed in Africa • Dose selection and decision to initiate drug-drug interaction study on fexinidazole/miltefosine as a potential oral combination in Africa • Development of PKDL study for India and PKDL infectivity study Benznidazole in Bangladesh Paediatric • Study on new VL treatments in Latin America completed Dosage form • 12-month follow-up of VL-Asia study ongoing – collaboration with Kalacore for further implementation
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