Today at the Neglected Tropical Diseases Meeting of the International Society for Infectious Diseases (ISID-NTD) in Boston, the Drugs for Neglected Diseases initiative (DNDi) announced the first research and development project in its new helminth infection drug portfolio to address unmet needs of patients in Africa and Asia. The project will assess the potential of the drug flubendazole to treat a highly neglected subset of helminth infections, notably co-infection of two of the three filarial diseases: onchocerciasis (river blindness) and lymphatic filariasis (LF; elephantiasis), in co-infection with loiasis (African eyeworm or Loa loa). Existing treatments are inadequate and in some cases life-threatening. The project is supported by a grant from The Bill & Melinda Gates Foundation.
While remaining fully committed to kinetoplastid diseases (sleeping sickness, leishmaniases, and Chagas disease) DNDi is expanding its drug portfolio to include helminth infections, focusing specifically on filariasis, because in patients co-infected with filariasis and loa loa, the standard treatment of ivermectin, alone or in combination with albendazole, can result in brain dysfunction, coma, and potentially death. The objective is to assess and reformulate flubendazole, which has proven highly active against adult filarial worms in animals and humans, into a safe, highly efficacious, and field-adapted macrofilaricidal drug candidate.
If successful, flubendazole would be highly useful for case management and in mass drug administration (MDA) programs to treat, control, and eliminate filarial infections, regardless of parasitic worm life stage. Current drugs primarily kill young worms whereas a macrofilaricide would kill adult worms.
“DNDi is focusing on developing a safe macrofilaricide – to kill the adult worms – with no severe adverse reactions,” said Dr Shing Chang, Director of R&D at DNDi. “Such a drug could be used as an alternative preventive treatment with a major public health impact.”
In addition to addressing the specific and urgent needs of co-infected patients, a new macrofilaricide could significantly reduce treatment cycles even for areas that are not burdened by co-infection, since it would no longer be necessary to wait until the adult worm dies, which can take up to 12 years. It could reduce the current MDA treatment cycle to approximately 2 to 3 years, making the diseases easier to control.
“The first step of this project is to assess the safety profile in pre-clinical studies to further reformulate flubendazole and develop a safe, highly efficacious, and field-adapted macrofilaricidal drug candidate,” explains Dr. Charles MacKenzie of Michigan State University, who was involved in early work on flubendazole. “Flubendazole is the only macrofilaricide candidate on the horizon that has demonstrated positive in vivo results.”
DNDi is partnering with Michigan State University in the US, and McGill University in Canada, for the pharmacodynamic studies; the generic pharmaceutical company Advinus Therapeutics, in India, for the toxicology and the pharmacokinetics studies; and Drugabilis and Bertin Pharma, France, for the pre-formulation and formulation of the drug, respectively.
“Without new tools adapted to the needs of patients in the poorest and remote areas of the world it will be difficult, if not impossible, to eliminate some of the most common neglected tropical diseases,” said Dr. Bernard Pécoul, Executive Director of DNDi. “To achieve sustainable control and potential elimination of helminth infections, we need to both improve implementation of existing tools and develop better drugs for patients in whom current treatments do not work.”
The initial investigations by DNDi to assess its helminth drug portfolio were made possible with the financial support of Doctors Without Borders/Médecins Sans Frontières. This pre-clinical flubendazole project is funded by The Bill & Melinda Gates Foundation.
What are filarial diseases?
These diseases are caused by worms and are highly prevalent in the poorest regions of the world:
• 128 million people are infected with lymphatic filariasis (LF) mainly in Western and Central Africa and South-East Asia
• 26 million people are infected with onchocerciasis with one million people suffering from vision impairments or blindness as a result
• Number of people at risk of loiasis is unknown: 11 major African countries are endemic.
While not fatal in themselves, they cause chronic conditions and life-long disabilities.
Current treatments and impact on Loa loa co-infected patients
Filarial diseases are currently treated with the microfilaricide ivermectin. However, in people co-infected with Loa loa, the standard treatment of ivermectin, alone or in combination with albendazole, can:
• Engender encephalopathy or brain dysfunction
• Potentially lead to death
Over 14 million people are at high risk of these severe adverse effects due to treatments used in areas of co-infection. Safe and effective treatment for these areas represents an urgent and unaddressed need.
About Drugs for Neglected Diseases initiative (DNDi)
DNDi is a not-for-profit research and development organization working to deliver new treatments for neglected diseases, in particular human African trypanosomiasis, leishmaniasis, Chagas disease, malaria, and, with the recent expansion of its portfolio, specific helminth-related infections and pediatric HIV. DNDi was established in 2003 by Doctors Without Borders/Médecins Sans Frontières (MSF), the Oswaldo Cruz Foundation from Brazil, the Indian Council for Medical Research, the Kenya Medical Research Institute, the Ministry of Health of Malaysia, and the Pasteur Institute of France. The WHO/TDR program serves as a permanent observer. Since 2003, DNDi has delivered four treatments: two fixed-dose anti-malarials (ASAQ and ASMQ), NECT (nifurtimox-eflornithine combination therapy) for late-stage sleeping sickness, and SSG&PM (sodium stibogluconate & paromomycin combination therapy) for visceral leishmaniasis in Africa.
• Violaine Dällenbach, DNDi Geneva, office: +41 22 906 92 47, mobile:+41 79 424 14 74; email: firstname.lastname@example.org
• Oliver Yun, DNDi North America, office: +1-646-616-8681, mobile: +1-646-266-5216; email: email@example.com