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DNDi Offices in Africa
DNDi has two offices in Africa:
DNDi Africa: Established in 2003, and based at the Kenya Medical Research Institute (KEMRI)
in Nairobi, this regional office supports and conducts R&D activities in the region, including
clinical research for leishmaniasis and capacity building within the LEAP and HAT platforms.
DNDi DRC: this DNDi project support office was established in 2005 and is based in Kinshasa,
Democratic Republic of the Congo (DRC). It provides essential logistical and administrative
support to the fexinidazole trial, to the implementation of the nifurtimox-eflornithine
combination therapy (NECT) and to the HAT platform.
DNDi Partners in Africa
DNDi collaborates with some 50 African partner organizations, with a total of 300 people
involved in its ongoing R&D projects in Africa, for Africa, and from Africa. The different
projects are related to various stages of drug development, be they in the Research
(Screening), Translational (Pre-clinical, Phase I, Phase IIa / Proof-of-concept), Development
(Phase IIb/III, Registration), or the Implementation phase. DNDi’s partners consist of a
balanced mix of public and private organizations (academia, research institutes,
pharmaceutical industries, etc.)
Clinical Research Platforms
Leishmaniasis East Africa Platform (LEAP)
The Leishmaniasis East Africa Platform (LEAP), founded in 2003 in Khartoum, Sudan is a
research capacity strengthening network of health agencies and scientists from the four
African countries most affected by visceral leishmaniasis (Ethiopia, Kenya, Sudan, Uganda) as
well as international experts. The LEAP mandate is to study, validate, and
facilitate registration of improved treatment options for neglected VL
patients in the East African region. It provides capacity strengthening for
treatment, evaluation, and clinical studies in the region. LEAP was
instrumental in the development of the combination drug SSG&PM (sodium
stibogluconate and paromomycin) for the treatment of visceral leishmaniasis
(kala azar) in East Africa.
Human African Trypanosomiasis (HAT) Platform
The HAT Platform was founded in 2005 in Kinshasa, Democratic Republic of the Congo. It is a
research capacity strengthening network of clinicians, national control programme
representatives, and scientists from the African countries most affected by sleeping sickness
(Angola, Central African Republic, Chad, Democratic Republic of the Congo, Republic of
Congo, Uganda, South Sudan, Sudan) as well as international institutions.
The overall aim of this platform is to build and strengthen clinical trial
capacities (human resources, infrastructure, equipment) and
methodologies in HAT-endemic countries so that new and promising
treatments for this fatal disease can be rapidly and effectively evaluated,
registered, and made available to patients. The HAT Platform played a
major role in the development of nifurtimox-eflornithine combination
therapy
(NECT)
for
the
treatment
of
late-stage
HAT.
The Data Management Centre in Nairobi, Kenya
The DNDi/LEAP Data Centre in Nairobi, Kenya, was established in 2004 when the first clinical
trial was set up in the region. It is responsible for the creation and maintenance of data
management and statistical analyses, which meet ICH Good Clinical Practice (GCP)
standards. Initially, the data handling processes were performed manually, due to limited
expertise and inexperience. However, with time, increased human resources and improved
technology has led to mostly automated processes, resulting in increased efficiency and an
audit trail. An efficient query management system (QMS) has been developed in-house to
complement the data handling process prior to analyses. Future improvements will include
electronic data capture as a way of having real-time data to further reduce the time taken to
produce trial results.
Diseases and existing treatments
HAT
Human African Trypanosomiasis (HAT), also known as sleeping sickness, is transmitted to
humans by the parasites T. b. gambiense (West and Central Africa, responsible for the vast
majority of cases) and T. b. rhodesiense (East Africa) through the bite of the tsetse fly. The
disease affects 36 countries in sub-Saharan Africa, with approximately 7,000 reported cases,
1
but the number of actual cases is estimated to be 30,000. The disease affects mainly those
living in remote areas with limited access to adequate health services. HAT occurs in two
stages: stage 1 (early, hemolymphatic) is characterized by non-specific clinical symptoms,
whereas stage 2 (late, meningoencephalic) is characterized by neurological symptoms,
which, if left untreated, lead to coma and death.
Available treatments are limited, difficult to administer, often toxic, and stage-specific.
• Stage 1: pentamidine and suramin require injections and are ineffective for stage 2.
• Stage 2: melarsoprol, a toxic arsenic derivative that causes pain and sometimes fatal
encephalopathies is increasingly ineffective, with reports of drug resistance and treatment
failure in some foci; eflornithine, difficult to administer as treatment requires trained health
staff and an extended hospital stay (56 intravenous infusions taking two hours each to
administer, over 14 days and four times each day).
In 2009, DNDi and partners developed NECT (nifurtimox-eflornithine combination therapy),
a simplified therapy option for stage 2 T.b. gambiense sleeping sickness, with only 14
injections of eflornithine over 7 days and 10 days of oral treatment with nifurtimox (WHO
recommended).Clinical trials for an oral-only treatment are underway.
VISCERAL LEISHMANIASIS
Visceral Leishmaniasis (VL) is caused by the kinetoplastid protozoan parasites L.
donovani and L. infantum, transmitted to humans via phlebotomine sandflies. Its annual
incidence is estimated at 0.2 to 0.4 million VL cases with a case-fatality rate of 10% (i.e.
2
20,000 to 40,000 deaths per year). However, mortality data are extremely sparse and
generally represent hospital-based deaths only, so actual figures are expected to be higher.
Co-infection with other infectious diseases is an increasing concern: HIV-VL co-infection has
been reported in 35 countries worldwide. VL is characterized by progressive fever, weight
loss, enlarged spleen and liver, and anaemia. Untreated symptomatic VL is fatal in almost all
cases. Existing therapies for VL have serious drawbacks in terms of safety, resistance,
3
stability, and cost. They have low tolerability, long treatment duration, and are difficult to
administer.
1
http://www.who.int/mediacentre/factsheets/fs259/en/
Leishmaniasis Worldwide and Global Estimates of Its Incidence. Alvar J. et al. (2012) PLoS ONE 7(5): e35671.
doi:10.1371/journal.pone.0035671
3
Structures, Targets and Recent Approaches in Anti-Leishmanial Drug Discovery and Development. Seifert K., Open Med Chem
J. 2011; 5:31–39. doi: 10.2174/1874104501105010031
2
Pentavalent antimonials (sodium stibogluconate – SSG – and meglumine antimoniate): used
for over 60 years, acquired resistance has appeared in areas of high prevalence and high
transmission. Cardiotoxicity has been reported as a drug-induced effect and serious
cardiotoxicity leading to death is well documented.
Amphotericin B deoxycholate: requires hospitalization, constant renal monitoring of
patients, prolonged duration of treatment, and infusion-related adverse events are notable
drawbacks.
AmBisome®: a liposomal formulation of amphotericin B, it is much safer and highly
4
efficacious. However, high cost and the need for a cold chain limit its widespread use.
Miltefosine: an oral drug registered and recommended for use in India for VL, it is
5
expensive and requires 28-day treatment. Major limitations include low compliance, with
risk of resistance development, and contraindication in pregnancy and mandatory
contraception for women of child-bearing age for the duration of therapy and 3 months
beyond.
Paromomycin (PM): a low-cost parenteral formulation that requires 3 weeks of painful
intramuscular administration and is associated with some degree of renal and ototoxicity.
In 2010, DNDi and LEAP partners delivered the SSG&PM combination therapy for East
Africa that is now recommended as first-line treatment for VL in the region by the WHO
Expert Committee on the Control of Leishmaniases. Clinical trials are ongoing for other
combination treatments and for an oral-only treatment.
FILARIAL DISEASES
The parasitic worms that cause filarial diseases are transmitted by insect vectors to humans.
Onchocerciasis (or river blindness) is caused by Onchocerca volvulus, a thin parasitic worm
transmitted from one person to another through the bite of a blackfly. It affects 18 million
6
people worldwide and occurs in 36 countries in Africa and is the world's second leading
7
infectious cause of blindness. Lymphatic filariasis (LF, or elephantiasis) is caused by
nematodes of the Filariodidea family, mainly Wuchereria bancrofti, transmitted to humans
through mosquitoes. More than 1.4 billion people in 73 countries worldwide are threatened
by LF. Over 120 million people are currently infected, with about 40 million disfigured and
8
incapacitated by the disease. Body deformities lead to social stigma, as well as financial
hardship from loss of income and increased medical expenses. The socio-economic burden
of isolation and poverty are immense. Loiasis (African eye-worm) is caused by the parasitic
worm Loa loa. It is tentatively estimated that some 14.4 million people live in high risk areas
where the prevalence of eye worm history is greater than 40%, and 15.2 million in
intermediate areas with estimated eye worm prevalence between 20 and 40%.
Current treatments for onchocerciasis and LF are based on mass drug administration (MDA)
of anti-parasitic drugs through programmes directed by the WHO. Drugs used by MDA
programmes include ivermectin for onchocerciasis, albendazole plus either ivermectin in
areas where onchocerciasis is also endemic or diethylcarbamazine citrate (DEC) in areas
where onchocerciasis is not endemic for LF. These drugs remove existing microfilariae from
skin, thus preventing vector borne transmission, and provide long-term sterilization of adult
worms, preventing re-population of the patient with microfilariae for six months or longer.
However, in patients co-infected with Loa loa, the sudden death of large numbers of
microfilariae can lead to serious adverse events (SAEs), such as encephalopathy, which can
be fatal or leave patients with severe sequelae. Patients infected only with Loa loa are not
usually treated.
4 Through the WHO, significant cost reduction of both AmBisome® and miltefosine is available for the public sector of key endemic
countries as of 2007.
5 Ibid.
6 http://www.who.int/water_sanitation_health/diseases/oncho/en/
7 http://www.who.int/blindness/partnerships/onchocerciasis_home/en/index.html
8 http://www.who.int/mediacentre/factsheets/fs102/en/
PAEDIATRIC HIV
In children, HIV transmission can occur during pregnancy through the placenta, during
delivery through exposure to body fluids and cervical secretions, and through
breastfeeding. In the absence of antiretroviral preventive treatment, 30 to 40% of children
born to an HIV-infected mother acquire infection themselves. At the end of 2011, an
estimated 3.3 million children below the age of 15 were living with HIV, more than 90% of
which in sub-Saharan Africa. An estimated 230,000 children under 15 years of age died of
AIDS-related illness in 2010. Only 28% of HIV-positive children are estimated to be on anti9
retroviral therapy, compared to 68% of adult women and 47% of adult men. The 2010 WHO
guidelines recommend early diagnosis and immediate treatment of HIV-positive infants and
children under the age of two; for those with prior exposure to prevention-of-mother-tochild-transmission (PMTCT), protease inhibitor (PI)-based first-line therapy is recommended,
but results of a superior response to such therapy in children without prior exposure to
10
PMTCT have also been reported. The combination of a boosted protease inhibitor with
two nucleoside reverse transcriptase inhibitors (NRTIs) is considered by many experts as
the most effective first-line therapy for infants and children, regardless of prior exposure to
anti-retrovirals. However, the only available PI for young children, LPV/r does not come in a
child-friendly formulation: the oral solution formulation is not palatable, contains 42%
alcohol, and is not adapted to resource-poor settings due to major logistical constraints. In
many areas, HIV-positive infants and children are co-infected with tuberculosis (TB). Because
of drug-drug interactions between PIs in particular and rifampicin, one of the drugs used to
treat TB, extra ritonavir needs to be added to the standard proportion of LPV/r. This is called
‘superboosting’, and requires the development of an infant-friendly formulation of ritonavir.
MALARIA
Malaria is caused by Plasmodium parasites, spread to people through the bite of an
infected female anopheles mosquito. Four species of the parasite cause malaria in humans:
P. falciparum, P. vivax, P. malariae, and P. ovale. P. vivax and P. falciparum are the most
common, with P. falciparum the most deadly. Malaria is an acute febrile illness with initial
symptoms that can be difficult to recognize. Symptoms of uncomplicated malaria include
fever, headache, chills, and vomiting. If treatment is not given within 24 hours, P.
falciparum malaria can progress to severe illness, which can lead to death or serious brain
damage, especially in children, who are particularly vulnerable due to their lack of immunity
to the parasite. Approximately half of the world's population is at risk of malaria. Most
malaria cases and deaths occur in sub-Saharan Africa, but Asia, Latin America, and to a lesser
extent the Middle East and parts of Europe are also affected. In 2010, 99 countries and
territories had active malaria transmission.
The use of artemisinin-based combination therapies (ACTs) for the treatment of
uncomplicated P. falciparum malaria is recommended by the World Health Organization
(WHO) since 2001. Recently, delayed parasite clearance indicative of resistance to
artemisinin has been reported in some areas of South East Asia, sparking a global response
to contain resistant parasites before they spread around the world. Despite these concerns,
ACTs remain the best available anti-malarial medicines and are still highly effective in the
majority of malaria endemic areas. Fixed-dose combinations of ACTs are preferred and
recommended, as they promote adherence to treatment and reduce the potential of
selective use of the medicines as monotherapy.
9
Global report: UNAIDS report on the global AIDS epidemic 2012, Geneva, 2012.
10
Violari A, Paed. F. C., Lindsey J.C., Hughes M.D., Mujuru H.A., Barlow-Mosha L, et al. Nevirapine versus ritonavir-boosted lopinavir for
HIV-infected children. N Engl J Med 2012; 366(25):2380-9.
R&D Projects for Africa
FOR HAT
Oxaborole SCYX-7158
Objective: Progress the clinical development of SCYX-7158 for the treatment of stage 2 HAT
caused by T.b. gambiense, as well as for stage 1 HAT and HAT caused by T.b. rhodesiense.
Fexinidazole
Objective: Progress fexinidazole through a clinical Phase II/III pivotal study in order to
register the drug as a new treatment for stage 2 HAT caused by T.b.gambiense, as well as for
stage 1HAT and HAT caused by T.b. rhodesiense.
NECT- Nifurtimox/Eflornithine Combination Therapy
Objectives: Continue to facilitate implementation of NECT, currently the most field-adapted,
simple and safe treatment for stage 2HAT and support its implementation in endemic
countries.
FOR VISCERAL LEISHMANIASIS
VL-2098
Objective: Undertake pre-clinical assessment of VL-2098, a promising compound of the
nitroimidazole class for treatment of VL.
Fexinidazole
Objective: Initiate a Phase II proof-of-concept study to determine the efficacy and safety of
using fexinidazole for the treatment of VL.
New VL treatments for Africa
Objective: Develop new shorter-course treatments for VL in East Africa and geographically
extend available anti-leishmanial drugs to all countries of the region. Support ongoing
registration activities for use of SSG&PM. Assess the efficacy and safety of miltefosine
combinations for East Africa.
New treatments for HIV/VL co-infection for Africa
Objective: Identify and deliver a safe and highly effective treatment for VL in HIV co-infected
patients that will improve long-term survival of these patients.
SSG&PM - Sodium Stibogluconate/Paromomycin Combination Therapy
Objectives: Facilitate implementation of and access to SSG&PM in key endemic areas of East
Africa by supporting registration of paromomycin (PM) and facilitate uptake with local
partners. Monitor safety and effectiveness post-implementation in a pharmacovigilance
study.
FOR FILARIAL DISEASES
Flubendazole macrofilaricide
Objective: Determine the potential of flubendazole as a pre-clinical macro-filaricide
candidate for preventive treatment of onchocerciasis and lymphatic filariasis in Loa loa coendemic regions.
FOR PAEDIATRIC HIV
Two ‘4-in-1’ LPv/r-based fixed-dose combinations
Objective: Develop two fixed-dose combinations of the protease inhibitor (PI)-based
paediatric antiretroviral (ARV) regimen of lopinavir/ritonavir (LPV/r) with either one of two
NRTI backbones, 3TC/ABC or 3TC/ZDV. The ‘4-in-1’ treatment for infants and young children
will be formulated in taste-masked granules.
RTV Superbooster for HIV/TB co-infection Paediatric HIV
Objective: Develop a stand-alone ritonavir (RTV) booster formulation to be added to the
optimized LPV/r-based paediatric ARV regimen to counteract the negative drug-drug
interactions between protease inhibitors (PIs) and rifampicin-containing tuberculosis
treatments.
FOR MALARIA
ASAQ - Artesunate/Amodiaquine Fixed-Dose Combination
Objectives: Continue to facilitate implementation of ASAQ FDC in all countries where it could
benefit patients and where the combination is recommended in national treatment
guidelines. Participate in Risk Management Plan in Africa. Diversify ASAQ suppliers, by
facilitating transfer of technology.
ASMQ - Artesunate/Mefloquine Fixed-Dose Combination
Objectives: Continue to facilitate implementation of and access to ASMQ FDC in South East
Asia and Latin America by obtaining registration authorizations. Assess efficacy of ASMQ FDC
in Africa.
The Drugs for Neglected Diseases initiative (DNDi) is a patient needs-driven, not-for-profit
research and development organization that develops safe, effective, and affordable
treatments for neglected diseases that afflicts millions of the world’s poorest people,
notably human African trypanosomiasis (sleeping sickness), leishmaniasis, Chagas disease,
paediatric HIV, filarial, and malaria.
DNDi’s primary objective is to:
-
Deliver 11 to 13 new treatments by 2018 for targeted neglected diseases and
establish a strong R&D portfolio that addresses patients’ treatment needs
In doing this, DNDi has two further objectives:
-
Use and strengthen capacities in disease endemic countries via project
implementation.
-
Raise awareness about the need to develop new drugs for neglected diseases and
advocate for increased public responsibility.
DNDi Africa
c/o Centre for Clinical Research
Kenya Medical Research Institute
P.O. Box 20778
KNH 00202 Nairobi
Kenya
Tel: +254 20273 0076
DNDi DRC
Av. Révolution N. 04
Quartier Socimat
La Gombe, Kinshasa
Democratic Republic of the Congo
Tel: +243 81011 81 31