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Human African Trypanosomiasis (HAT) Major Progress Seen, Punctuated by fi Rst Improved Treatment for Stage 2 Sleeping Sickness in 25 Years

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Human African Trypanosomiasis (HAT) Major Progress Seen, Punctuated by fi Rst Improved Treatment for Stage 2 Sleeping Sickness in 25 Years SLEEPING SICKNESS Human African Trypanosomiasis (HAT) Major progress seen, punctuated by fi rst improved treatment for stage 2 sleeping sickness in 25 years PRIORITY TARGET PRODUCT PROFILE FOR HAT • A new treatment for stage 2 HAT in adults and children – Preferably useful for stages 1 and 2 – Active against Trypanosoma brucei (T. b.) gambiense and T. b. rhodesiense • Better safety profi le than existing drugs – Ideally requiring little or no monitoring • Equal or better e cacy profi le than existing drugs – Ideally ≥ 95% clinical e cacy at 18 months after treatment • Easy-to-use treatment t the forefront of DNDi’s efforts to underreporting. Due to the resource-poor – Short course (ideally ≤ 7 days, up A develop new treatments is the need areas where the disease occurs, control to 14 days is acceptable) to understand the realities and treatment efforts are often mobilised into vertical – Preferably oral; if injectable, needs of patients and health care staff in programmes. Consisting of a series of intramuscular preferred the fi eld. specifi cally equipped and trained diagnosis – Preferably once-a-day treatment The ultimate goal for human African and treatment centres and mobile teams in • A ordable trypanosomiasis (HAT) is a truly simplifi ed endemic areas, but these programmes are • Stable in tropical climate treatment which can be orally adminis- not integrated into regional health centres. (minimum 2-year shelf life) tered, implemented at the primary health There is an immediate need to improve – Preferably 3-year shelf life care level, and effective against both stag- current treatment options, particularly for es of the disease. Currently, both diagnosis patients with advanced stage of the disease and treatment require a complicated series where the few drugs that are available are programmes, DNDi has conducted proac- of tests and trained medical supervision. either toxic, and increasingly ineffective in tive compound mining activities to identify A key issue with HAT is that it affects hard- killing the parasite, or diffi cult to use. Ide- existing compounds with potential against to-access communities in regions with ally, a treatment will be safe enough to be kinetoplastid diseases. The compound poor health infrastructure. Poor access used in the fi rst stage of the disease and mining activities of DNDi have led to the to medical facilities, a lack of resources effective enough in the second stage of the revival of the nitromidazole class as po- and skills, and misdiagnosis contribute to disease. In addition to lead optimisation tential drug candidates: the most notable... Best science for the most neglected For more info, please contact: DNDi 15 Chemin Louis Dunant 1202 Geneva – Switzerland Tel. +4122906 9230 – Fax: +41229069231 [email protected] – www.dndi.org 1093_DNDi_4pag_HAT_v4.indd 1 12/11/09 12:04 Human African Trypanosomiasis (HAT) ̈ HAT R&D Projects - 2010 Outlook Discovery Preclinical Clinical Available to Patients S LS LO Compound Nitroimidazole backup Fexinidazole NECT mining Nifurtimox - Eflornithine Chemical HAT LO Co-Administration classes Consortium Stage 2 HAT • Scynexis Oxaborole Target-based • Pace Univ Phenotypic screening DNDi DNDi Others DD@D IV CPD-0801 3-day pentamidine CPDD Stage 2 HAT Stage 1 HAT (TDR) ... example is fexinidazole, upon which DNDi DISCOVERY This phase requires a close, highly inter- has begun clinical development for HAT. active collaboration between the biologists Several groups worldwide have specifi c es- LEAD OPTIMISATION and chemists, who form a feedback loop: initiative tablished expertise and knowledge in drug CONSORTIUM the biologists test the biological proper- discovery that are readily applicable to the • Partners: Scynexis, USA; Pace Univer- ties of compounds on biological systems discovery of new antitrypanosomal drugs. sity, USA while the chemists perfect the chemical In this context, DNDi has established: • DNDi project manager and coordinator: structure of these compounds based on ■ Partnerships with pharmaceutical / bio- Robert Don, Ivan Scandale information obtained by the biologists. Two technology / academic groups for interac- • Project start: April 2007 compound series have been chosen as tion and access to natural product as well lead series: as synthetic chemical libraries, chemistry, With an objective to develop optimised ■ Oxaboroles, provided by Anacor and pos- HTS, biological models, and drug design. leads by progressing ‘hit’ molecules with sessing a unique boron-based chemistry, ■ A network of key international laborato- a good safety profi le and activity against Drugs for Neglected Diseases i were identifi ed as hits against T. brucei ries to support discovery efforts with phar- T. brucei parasites, these consortia bring together expertise in chemistry, biology, at the Sandler Centre of the University of DND macokinetic, pharmacodynamic, and toxi- California San Francisco, and have shown cological expertise, and defi ned synergy screening, and pre-formulation. Optimi- in vivo activity. between these laboratories. sation focuses on the molecule’s capac- During the course of the last 15 months, At the clinical stage of development, DNDi is ity to be absorbed into the bloodstream, chemists at Scynexis have synthesized ap- working to both investigate new medicines be distributed effectively to the infection, proximately 400 compounds and screened and to also strengthen capacity for clinical survive in the body, kill the parasite and research on HAT. With the recent inclusion not harm the patient. With two full lead an additional 330 compounds from the of NECT onto the WHO Essential Medi- optimisation teams in place (a total of 18 Anacor libraries. Some compounds and in cines List, DNDi is well on its way to meet- scientists), a number of hits identifi ed from particular, SCYX 6759 cured murine cen- ing its short-term objective to bring a new, DNDi screening partners are undergoing tral nervous system infection but appeared shortcourse, co-administration treatment hit expansion. Scientists within the consor- to be actively transported from the brain. for stage 2 HAT to the patients. Through tia use advanced techniques to study how Compounds which are not effl uxed from the this project, DNDi has also built important the selected molecules interact with the brain have been synthesised. One of these relationships with other groups involved in therapeutic target (ie. a protein or an en- compounds such as SCYX-7158 is expected HAT clinical research as well as with the zyme) and optimise the drug-like charac- to become a preclinical candidate in 2010. WHO, national HAT control programmes teristics of these molecules to ensure that ■ Kinase inhibitors, of which approximately and NGOs working to control HAT. they comply with the target product profi le. 300 analogs have been synthesized to date. Signifi cant in vitro and in vivo potency has ̈ Sample compound structure of oxaboroles and kinase inhibitors been developed across the series. However no activity is expected in the second stage Oxaboroles of the disease and the series has been abandoned. To replace kinase inhibitors hit to lead pro- gram has been restarted at Scynexis and another optimized lead is expected to be Kinase inhibitors Ongoing delivered in 2011. collaboration This strategy and the promising early results with Dundee were presented during the 2008 meeting of American Society of Medicine & Tropical Thiazoles University Pyrimidines Hygiene, and are available at www.dndi.org. 1093_DNDi_4pag_HAT_v4.indd 2 12/11/09 12:04 Human African Trypanosomiasis (HAT) CLINICAL NIFURTIMOXEFLORNITTHINE FEXINIZADOLE COMBINATION THERAPY NECT • Stage: Phase I clinical development • Major Partners: sanofi -aventis, France; Swiss Tropical Institute, Switzerland; HAT Platform partners Now available and added to the • DNDi Project Manager: Olaf Valverde Mordt WHO Essential Medicines List • DNDi Project Coordinator: Séverine Blesson as treatment against stage 2 • Project start: February 2007 sleeping sickness Fexinidazole as a drug candidate for stage 2 HAT is the fi rst success of the proactive compound mining efforts DNDi has pur- • Stage: available (fi eld studies e cacious as efl ornithine. At the end sued in particular in the nitroimidazoles ongoing) of 2008, the fi nal e cacy and safety project. • Major Partners: Epicentre, France; results of the Phase III study were A 5-nitroimidazole that was in preclinical Médecins Sans Frontières (MSF); the available and led to DNDi ’s submission development as a broad-spectrum anti- HAT National Control Programmes of of NECT for inclusion on the WHO protozoal by Hoechst in the early 1980s, the Democratic Republic of the Congo Essential Medicines List (EML). The fi nal fexinidazole was rediscovered by DNDi and the Republic of Congo; the Swiss results were published in The Lancet1 after being an abandoned compound. Ex- Tropical Institute (STI); HAT platform and were presented by Epicentre tensive profi ling by DNDi has shown that • DNDi project manager: during the 2008 meetings of American fexinidazole is orally active, crosses to the Olaf Valverde Mordt Society of Medicine & Tropical Hygiene and the HAT Platform, and are brain and has cured in vivo models for both • Project start: April 2004 acute and chronic infection with African available at www.dndi.org. The EML initiative The DNDi project has shown that trypanosomes. Importantly, fexinidazole is application and support statements the use of the nifurtimox-efl ornithine of the HAT community are available not mutagenic in a panel of in vitro and in combination therapy (NECT) is on the website of the WHO Essential vivo mammalian genetic toxicology tests, as e ective and safe as standard Medicines List. confi rming its favorable activity/toxicity efl ornithine monotherapy, but easier In May 2009, MSF, Epicentre, and profi le as a drug candidate. to use, and safer than melarsoprol DNDi announced that NECT had In 2007, a full preclinical programme (toxic though still widely used in 50% been included on the EML. According was established to enable fi rst-in-human of patients with stage 2 HAT). NECT is to the WHO, NECT can now be studies.
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