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DNDi: Championing the cause of infectious diseases
While cancer and diabetes might be on the rise in the past few years, the
proportion of infectious diseases that plague the developing world cannot be
ruled out.
The world's pharma biggies might be focusing all their
attention on lifestyle and non-communicable diseases in the light of the
increasing effects of globalization, but it seems that does not undermine the
danger that infectious diseases present. A new study by the World Health
Organization (WHO) outlining the global burden of disease reveals that four out
of the top 10 causes of death globally are infectious diseases. The report
outlines the leading causes of death globally as heart disease, stroke,
pneumonia, chronic respiratory disease, diarrhea, HIV/AIDS and tuberculosis as
according to Colin Mathers, Coordinator for Epidemiology and Burden of Disease
at WHO and lead author of the study.
India is also not untouched by the burden of infectious
diseases. Malaria and Visceral leishmaniasis are largely prevalent in India and
affect more than 3 million Indians each year, according to government estimates.
India has been increasing the focus of medical research as it bears a large
burden of two types of diseases: on the one hand, that of neglected tropical
diseases, which represent major health problems, and on the other, an increase
in non-communicable lifestyle diseases. These along with India emerging as a
pharmaceutical hub with low research costs and large pools of skilled medical
research and drug development manpower were some of the reasons why DNDi (Drugs
for Neglected Diseases initiative) has been active in the country since 2004. It
recently opened its office in India to further its commitment to the cause.
DNDi is a collaborative, patients' needs-driven,
not-for-profit drug R&D organization that is currently developing new
treatments against the world's most neglected infectious diseases such as
sleeping sickness (human African trypanosomiasis, HAT), visceral leishmaniasis (VL),
Chagas disease, and malaria. It was established in 2003 by Institut Pasteur and
Médecines Sans Frontières along with four publicly-funded research
organizations in neglected disease-endemic countries such as Kenya (Kenya
Medical Research Institute (KEMRI), Malaysian MOH in Malaysia, Oswaldo Cruz
Foundation Brazil and the Indian Council for Medical Research (ICMR) in India.
WHO/TDR function as the permanent observer. Today, DNDi is a small team of
permanent staff in Geneva along with four regional support offices in Kenya,
India, Brazil, and Malaysia; an affiliate in North America, and two regional
project support offices in the Democratic Republic of the Congo and Japan.
Working in partnership with industry and academia, DNDi has built the largest
ever R&D portfolio for the kinetoplastid diseases and currently has six
clinical and four preclinical projects.
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Achievements
Malaria
ASAQ for treatment of malaria in sub-Saharan Africa; launched in March
2007; registered in 23 disease-endemic countries and ASMQ for treatment in
Latin America and registered in Brazil in March 2008 and in use by
Brazilian national authorities as part of ongoing intervention study
(25,000 patients)
Visceral Leismaniasis (VL)
Lead optimization partnership with Advinus and CDDRI Lucknow
VL combination trial to evaluate safe and short-course
combination therapy using existing drugs registered in region
Paromomycin trial. Over 1,000 patients included in
multi-centre trial in East Africa
Leishmaniasis East Africa Platform-research capacity
strengthening in Africa for VL
Human African Trypanosomiasis
(HAT, sleeping sickness)
Lead optimization partnership to progress molecules from early-stage
screening research with Scynexis and Pace University
Fexinidazole, first compound mining success from DNDi's
nitroimidazoles project; finalizing preclinical studies; will enter
first-in-human Phase I trials in early 2009
Clinical trial of Nifurtimox-Eflornithine
co-administration-promising study data being finalized; shows for NECT
as easier to use, more practical, and safe therapy; full dossier will be
submitted to WHO Essential Medicines List in 2008
HAT Platform-research capacity strengthening in
Africa for HAT
Chagas Disease
Lead optimization partnership with Centre for Drug Candidate Optimization
(CDCO),
Epichem, and Murdoch University (Australia); Federal
University of Ouro Preto (Brazil)
Pediatric Benznidazole-agreement established with
LAFEPE to develop first benznidazole formulation for children that is
affordable.
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DNDi's activities in India
According to Dr Bernard Pécoul, executive director, DNDi,
"The primary objective of DNDi is to deliver six to eight new treatments by
2014 for these diseases and to establish a strong R&D portfolio. In doing
so, DNDi is also working to use and strengthen existing capacities in
disease-endemic countries, and raise awareness and advocate for the need to
develop new treatments for the most neglected diseases." DNDi opened the
regional support office in India in 2005 with support from the India Council of
Medical Research (ICMR) to support and catalyze its operational activities in
the field of malaria and visceral leishmaniasis (VL). In fact, DNDi is currently
carrying out more than 30 percent of its R&D activities in India.
"India has an important role to play in the fight against infectious
diseases. What is needed is a political leadership to start and sustain the
efforts in "essential health R&D' and redefine the R&D priorities
to initiate and stimulate research for neglected diseases."
Work on Visceral leishmaniasis
In December 2007, DNDi signed a five-year collaborative
agreement with Advinus Therapeutics as primary partner in lead optimization
consortium for VL. The project is to obtain optimized leads by processing
"hit" molecules with good safety profiles and proven activity against
Leishmania parasites. This consortium brings together expertise in chemistry,
screening, pharmacology, and pre-formulation in order to optimize a molecule's
drug properties to be orally absorbed and reach the bloodstream, be distributed
effectively to infection sites, remain intact in the body to kill the parasites,
and yet not harm the patient. With a full team in place, Advinus Therapeutics in
Bangalore has identified two promising series of compounds and conducted an
assessment of the first series of synthetic compounds and initiated
chemistry-biology activities. Screening at the Central Drug Research Institute (CDRI),
in Lucknow, began in 2008 for in vitro and in vivo biological activities.
| Ongoing clinical trials on drugs for Malaria and
Visceral leishmanisis
MALARIA
While clinical trials for ASAQ have been conducted, the clinical
research for ASMQ has just started.
Malaria is present in over 100 countries and threatens
half of the world's population. In sub-Saharan Africa, it is the single
leading cause of death for children under five. It is unevenly distributed
in India-80 percent of the population lives in low transmission areas
and 20 percent in a high transmission belt. India holds 77 percent of the
South-east Asia's malaria burden. The region also witnesses a large
number of P. falciparum cases (up to 50 percent) and chloroquine
resistance.
ASAQ: A clinical trial studying tolerability and
effectiveness in real-life conditions has recently been conducted for ASAQ,
the fixed-dose combination of artesunate (AS) and amodiaquine (AQ) for its
eventual registration in India. The drug was launched in 2007 by DNDi in
an innovative partnership with Sanofi-aventis. The study was carried out
in partnership with the Indian Council of Medical Research (ICMR) and
National Institute of Malaria Research (NIMR), namely in Orissa and
Jharkhand regions and the study results were recently presented at the
XVII International Congress on Tropical Medicine and Malaria.
Status
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Clinical trials in India (N=300)
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2 sites (Ranchi and Rourkela) enrolled 300 patients
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Study completed in Q12008; Results presented at
ICID and ICTM17 in 2008
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Consistent with previous studies with ASAQ in
Africa
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Supports consideration of ASAQ as 1st-line therapy
in India where appropriate
ASMQ: This new fixed-dose combination of artesunate
(AS) and mefloquine (MQ), developed by DNDi and Farmanguinhos/Fiocruz, was
successfully registered in Brazil in March 2008. To facilitate its future
availability in Southeast Asia, upon approval from the ethics committee
and the relevant national and local authorities, further clinical research
is being conducted in the Goa and Mangalore regions in association with
ICMR and NIMR. Further enabling the Southeast Asia expansion,
Farmanguinhos/Fiocruz has agreed to the principle of technology transfer
to the Indian pharmaceutical company, Cipla.
Status
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Clinical trials in India (N=84)
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Dec 2007: Enrolment started at2 sites (Goa;
Mangalore). 77 patients enrolled (Sept 08)
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End of enrolment expected in Q42008
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Results expected by Q32009
VISCERAL LEISHMANIASIS (VL)
Clinical trials are on for VL combination therapies of Ambisome (lipid
formulations of Amphotericin B), paromomycin, and miltefosine.
Leishmaniasis affects approximately 12 million people
in 88 countries. The seven most affected countries represent over 90
percent of all reported new cases. India has about 1 lakh new cases of VL
annually, of which approximately 90 percent are from Bihar. Until
recently, pentavalent antimony complex was one of the very few standard VL
treatments, despite all of its limitations: toxicity, lengthy treatment,
and growing resistance. Presently, amphotericin B, paromomycin, and
miltefosine have been evaluated and officially approved by all relevant
authorities for the treatment of VL in India. All of these drugs have
advantages and disadvantages with regards to cost, toxicity, length, and
ease of administration. Therefore, to reduce the treatment period, to
increase compliance, and to reduce the possibility of resistance
developing, DNDi and its partners are investigating the use of
combinations of these drugs to treat VL.
A clinical study to evaluate various drug combinations
has been initiated in collaboration with ICMR and the Rajendra Memorial
Research Institute (RMRI), at Patna, the Kala-azar Medical Research Centre
(KMRC), and GVK Bio at Muzaffarpur. This project will be extended to Nepal
and Bangladesh. The data collected will be used to make a recommendation
to the national control programs in highly endemic areas of VL in the
region. A total of 147 patients have been recruited so far out of the
proposed 640 for clinical trials. Enrolment will continue through 2009 and
the results are expected by early 2010.
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Shalini Gupta
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