R&D status September 2014: DNDi Leishmaniasis programme

[September 2014]

Leishmaniasis is transmitted by the bite of a sandfly. It is a complex disease with over a million new cases occurring every year and 350 million people living at risk worldwide in 98 countries. The disease presents several different forms, the most common of which are visceral leishmaniasis (VL), which is fatal without treatment, and cutaneous leishmaniasis (CL).

India, Bangladesh, Brazil, Ethiopia, South Sudan and Sudan account for 90% of all reported cases of VL. Existing treatments are either difficult to administer, toxic, or costly. Drug resistance is also an increasing problem. The WHO Roadmap (2012) has set the objective to eliminate VL from the Indian subcontinent by 2020. To contribute to the control and the elimination of the disease, DNDi’s leishmaniasis programme is working to develop new treatments by combining existing drugs and/or shortening their treatment duration, while also developing new chemical entities (NCEs).

The current leishmaniasis portfolio includes:


Research
Research


Two projects in the research phase
:

  • A programme is ongoing to identify nitroimidazole backups in case VL-2098 (see projects in pre-clinical development) does not successfully complete pre-clinical testing. Over 200 analogues have been prepared so far. Two backup compounds originating from two different core structures have now been selected and are being further profiled for in vivo efficacy and safety.
  • A programme to identify oxaborole backups called Oxaleish identified oxaborole 2035804 as potential optimized lead. Further profiling is ongoing before moving into a pre-clinical programme. A number of backup compounds with similar oral efficacy have also been developed so that if the primary candidate (Oxa 2035804) fails in the safety assessment, the backup can be pursued.

 

Translation
Translation


Four projects in the translation phase
:

  • In 2013, VL-2098 was identified among the nitroimidazoles as a very potent and safe molecule. Reproductive toxicology studies were completed with positive results. Following the completion of toxicology/safety packages as well as chemistry and manufacturing controls (CMC), VL-2098 is expected to enter into Phase I in 2015.
  • The CpG-D35 project for CL, recently  entering DNDi’s portfolio, aims at producing an immunomodulator to stimulate the innate immune system to fight the parasitic infection as an adjunct to drug therapy.
  • A Phase II proof-of-concept (PoC) study (22 patients) for VL with the NCE fexinidazole started late 2014 in Sudan

Development
Development

 

Four projects in the development phase:

  • A Phase III study of treatments for HIV/VL co-infection (132 patients), testing the combination treatment, AmBisome® and miltefosine, and monotherapy with AmBisome® at a higher dose than current practice, is being initiated in 2014 at two sites in Ethiopia
  • A Phase III study (sponsored by the Brazilian Ministry of Health) with new VL treatments based on combination therapies[1] for the treatment of VL patients in Brazil) started in 2011 at five sites and recruited 380 patients. The national guidelines for VL were revised in 2013 based on the interim safety data for AmBisome® in the trial. Glucantime® remains the first-line treatment, while Ambisome® replaced Amphotericin B deoxycholate as second-line treatment.
  • A Phase III/IV study was completed in 2013 with new VL treatments based on combination therapies (miltefosine-paromomycin, AmBisome®-miltefosine, AmBisome®-paromomycin, single dose AmBisome®) in Bangladesh. 602 patients were recruited in four sites. Results will be available later in this year.
  • A project on generic AmBisome® that aims to make a quality-assured generic Ambisome® available will start in 2014.

Implementation
Implementation

 

Implementation and access to treatments:

  • DNDi also continues to support the implementation of SSG&PM, a new VL treatment for Africa delivered in 2010 by DNDi and the Leishmaniasis East Africa Platform (LEAP). Whereas this new combination was recommended as first-line therapy for VL patients in East Africa by the WHO Expert Committee on the Control of Leishmaniases in 2010 and by the most affected countries, efforts are still required to ensure registration, notably of paromomycin, and treatment availability to VL patients in the region. In Asia, DNDi and partners, working closely with the Indian government, have provided data to support policy change expressed in the revised national kala-azar elimination roadmap, which recommends the use of AmBisome® single infusion and paromomycin/miltefosine combination as appropriate in low endemic districts.

 

By 2018, DNDi aims to deliver from its leishmaniasis-specific portfolio:

  • An oral, safe, effective, low-cost and short-course treatment
  • A new treatment for post-Kala azar dermal leishmaniasis (PKDL) that is shorter course and better tolerated than current options
  • Treatment options for HIV/VL co-infected patients
  • A safe, effective, and shorter-course treatment for CL


For more information on the partners and donors involved in DNDi Leishmaniasis programme, please click on each hyperlink that will refer you to each project.

 


 [1] Amphotericin B deoxycholate, AmBisome®, and AmBisome® combined with Glucantime®, as compared to the first-line treatment, Glucantime®