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Overview of current chemotherapy for Kinetoplastid diseases

The Class Kinetoplastida encompasses unicellular flagellated organisms among which some  species are responsible for life-threatening human diseases. Trypanosoma cruzi, T. brucei  and Leishmania sp. are the causative agents of Chagas Disease, Human African  Trypanosomiasis and leishmaniasis, respectively. Most of the affected population has very  limited purchasing power (some living under $1 per day), attracting little economic interest  from the major pharmaceutical companies. The drugs currently used for the treatment of  these diseases were developed decades ago and have serious limitations due to toxicity or  lack of efficacy. Chagas Disease, also known as American Trypanosomiasis is the leading cause of heart  failure in Latin America. Migration of infected individuals in the indeterminate chronic phase  (without symptoms) has spread the disease to other continents, leading to many cases in  Spain, Japan, the U.S., and Australia. The available drugs to treat Chagas Disease are  Benznidazole and Nifurtimox; neither one is FDA approved despite hundreds of thousand of  cases in the USA. Benznidazole is the most commonly used drug in Latin America. The  treatment course is 60 to 120 days. The course is interrupted due to the severe side effects,  including skin rash, peripheral neuropathy, granulocytopenia, lymphadenopathy, articular and  muscular pain, septicemia, hemorrhagic blister, and mucosal bleeding. Efficacy of  Benznidazole in the chronic phase to prevent the heart pathology is controversial. Recently,  clinical trials with Noxafil (Posaconazole) and E1224 (a Ravuconazole pro-drug) did not show  improvement over Benznidazole.  K777, an inhibitor of cruzain (cruzipain), the major protease  of T. cruzi, is a clinical candidate developed by Kindred. Currently in IND-enabling studies,  K777 has promising animal data and safety profiles that suggest it will be tolerated better than  currently available therapies.   Human African Trypanosomiasis, also called sleeping sickness, is the most needy of the three diseases in terms of available drugs. The disease progression has two distinct stages. Stage I  can last for weeks, and is characterized by fever, rash and fatigue. Stage II occurs when the  parasites cross the blood-brain-barrier and invade the central nervous system. The symptoms  evolve to personality changes, mental deterioration, increased sleep, and other neurological  manifestations, leading to coma and death after few weeks or months. Melarsoprol is the  treatment in Stage II, and the drug itself was responsible for 5-10% mortality. A clinical trial,  now in Phase III, with a combination therapy of Nifurtimox and Eflornithine is ongoing. For  Stage I, the alternative drug options are Pentamidine and Suramin. SCYX-7158 and  Fexinidazole are two additional drug candidates in Phase I.  Leishmaniasis, caused by a several Leishmania species, is characterized by clinical  manifestations ranging from cutaneous lesions (Cutaneous Leishmaniasis - CL or Muco-  Cutaneous Leishmaniasis - MCL) to visceral organ damage (Visceral Leishmaniasis - VL).  Leishmaniasis is endemic in 88 countries in the American, African and Asian continents.  Pentavalent antimonials have been the recommended treatment for decades, but due to high  incidence of resistant parasites and serious toxic effects their use is becoming less frequent.  Side effects may include cardiotoxicity, pancreatitis and nephrotoxicity. Hospitalization is  required during the chemotherapy. Alternative treatment options are amphotericin B and  miltefosine. Amphotericin B shows good efficacy against VL, but is associated with  nephrotoxicity. New formulations including the AmBisome (liposomal formulation) and  Amphomul (emulsion formulation) are being evaluated. Miltefosine is the only available oral  drug, but has variable efficacy depending on the region.   There is clearly an urgent need to develop safer and more effective chemotherapies to reduce  the burden caused by Chagas Disease, HAT and leishmaniasis. Given the challenges and low  success rate in moving drug discovery programs to the patients, it is critical to have a broader  portfolio of potential therapeutics moving forward in the pipeline, especially in the field of  neglected diseases. The Kindred Consortium fills this gap, combining academic excellence  from topnotch research organizations and biotech expertise, to form a public-private-  partnership aimed at delivering pre-clinical candidates for these diseases in the ambitious  timeframe of five years.  Further information  CDC_Centers for Disease Control and Prevention  http://www.cdc.gov/dpdx/trypanosomiasisAfrican/index.html  Infection landscapes  http://www.infectionlandscapes.org/2011/04/trypanosomiasis-part-1-sleeping.html  World Health Organisation  http://www.who.int/trypanosomiasis_african/en/ 

Current therapies


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© IP Research Consulting 2014
Current Chemotherapy