by Walker M, Hamley JID, Milton P, Monnot F, Pédrique B, Basanez M-G. Nature Communications 2020, 11: 2685. doi: 10.1038/s41467-020-16442-y

Summary: The treatments used in mass drug administration for Lymphatic filariasis and onchocerciasis are predominantly active against the microfilarial progeny of adult worms. New treatments are needed, and several therapies and regimens are currently in (pre-)clinical testing. Clinical trial simulators have not been widely applied to neglected tropical diseases, where their resource-saving payoffs could be highly beneficial. The authors use an individual-based onchocerciasis transmission model that projects trial outcomes of a hypothetical drug that kills adult worms. They identify key design decisions that influence the power of clinical trials and discuss how clinical trial simulators help to inform target product profiles.

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DNDi aims to deliver a safe, effective, affordable, and field-adapted drug that can kill adult filarial worms (a ‘macrofilaricide’) and be used for prevention or individual treatment.

DNDi current filaria portfolio includes:

R&D discovery stage iconDiscovery

  • Screening: With a portfolio of four potential treatments for people with onchocerciasis, DNDi has now ended its active screening programme for filaria. Some 530 compounds have been screened in partnership with Salvensis, Merck Sharp & Dohme, University of North Carolina, AbbVie, and others. In 2019, DNDi announced the launch of a large public-private partnership called the Helminth Elimination Platform (HELP), a new multidisciplinary consortium working to identify new treatments against ‘nematode’ worms, including onchocerciasis, lymphatic filariasis, hookworm, and whipworm.

R&D translation stage iconTranslation

  • Macro-filaricide CC6166: DNDi and Celgene (now part of Bristol-Myers Squibb) have signed an agreement covering pre-clinical and Phase I for a potentially macrofilaricidal compound known as CC6166. Celgene will cover all pre-clinical, Phase I, and CMC activities, while DNDi will provide expertise and know-how.
  • Oxfendazole: With funding from the European Union’s Horizon 2020 research and innovation programme, the Helminth Elimination Platform (HELP) will conduct a Phase I trial and continue late pre-clinical activities for oxfendazole.
  • TylAMac (ABBV-4083): Phase I studies have shown that TylAMac is safe and well-tolerated. DNDi is now preparing for a Phase II proof-of-concept study in the Democratic Republic of Congo. A hospital in Masi-Manimba that has long been one of the principal clinical sites for DNDi’s sleeping sickness studies has already been selected as one site for the study. Entirely renovated by DNDi for sleeping sickness trials, the site is again being upgraded by DNDi, with staff trained to run trials for river blindness.
  • Emodepside: With Phase I studies complete, preparations are underway to run a Phase II clinical trial (including safety and dose ranging and regimen selection) in Hohoe, Ghana. DNDi is renovating the site and will identify an additional site in the country for this study.

Photo credit: Junior Diatezua Kannah – DNDi

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“HELP consortium develops new drugs against parasitic worm infections”

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Ein neues Konsortium bestehend aus Forschungsinstituten, Universitäten, gemeinnützigen Organisationen und Pharmaunternehmen hat sich zusammengeschlossen, um neue Medikamente gegen Infektionen verursacht durch parasitäre Würmer (Helminthen) zu entwickeln. Zu diesen Krankheiten zählen die Flussblindheit und lymphatische Filariose sowie Infektionen mit Haken- und Peitschenwürmern. Fast eine Milliarde Menschen weltweit sind betroffen.

Diese neue multidisziplinäre Plattform – die “Helminth Elimination Platform” (HELP) – wird im Rahmen des Forschungs- und Innovationsprogramms Horizon 2020 der Europäischen Union finanziert und läuft bis September 2024. HELP wird vom Schweizerischen Tropen- und Public Health-Institut (Swiss TPH) geleitet und involviert eine gemeinnützige Forschungs- und Entwicklungsorganisation (R&D), die Drugs for Neglected Diseases initiative (DNDi), sowie die Pharmaunternehmen Bayer Animal Health und Celgene. Weitere Partner europäischer und afrikanischer akademischer Einrichtungen sind das Universitätsklinikum Bonn, Deutschland, das Muséum National d’Histoire Naturelle Paris, Frankreich, sowie das Ifakara Health Institute, Tansania, und die Universität Buea, Kamerun.

‘Diese parasitären Wurminfektionen betreffen Millionen von Menschen, aber die Forschung und Entwicklung hinkt anderen vernachlässigten Tropenkrankheiten weit hinterher,’ sagt Prof. Jennifer Keiser, Leiterin der Helminth Drug Development Unit am Swiss TPH und Koordinatorin des Konsortiums. ‘Durch das Zusammenbringen von Experten in der pharmazeutischen Entwicklung mit Gesundheitsfachleuten im Gebiet der Wurmerkrankungen werden wir die leere Medikamentenpipeline füllen und auch neue Medikamente entwickeln können, die gegen eine oder mehrere dieser beeinträchtigenden Krankheiten wirken.’

Das HELP-Konsortium wird an Nematodenwürmern arbeiten, zu denen sowohl die Filarien, welche Flussblindheit (Onchozerkose), Loiose und lymphatische Filariose verursachen, als auch Darmhelminthen wie Haken- und Peitschenwurm gehören, welche durch kontaminierten Boden übertragen werden. Effizientere, sicherere und erschwinglichere Behandlungen sind sowohl für Flussblindheit erforderlich, die zu einer Erblindung und einem lähmenden Juckreiz der Haut führen kann, als auch für Infektionen mit bodenübertragenen Helminthen, die Bauchschmerzen, Durchfall und erhebliche Wachstumsverzögerung verursachen können.

Das HELP-Konsortium wird Aktivitäten von der Entdeckung bis zur klinischen Entwicklung von Medikamenten durchführen. Verbindungsklassen mit validierten Wirkstofftargets in parasitologischen und präklinischen Studien in der Veterinärmedizin werden für die Anwendung am Menschen evaluiert. Darüber hinaus werden Oxfendazol und Oxantel-Pamoat, zwei gut charakterisierte Verbindungen, in frühen klinischen Studien untersucht. HELP wird auch zum Kapazitätsaufbau in Forschung und Entwicklung in den betroffenen Ländern beitragen und zwei klinische Phase-I-Studien in Afrika durchführen.

Dieses Projekt wird im Rahmen des Grant Agreements Nr. 815628 aus dem Forschungs- und Innovationsprogramm der Europäischen Union Horizon 2020 finanziert.

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Photo credit: DNDi

A new consortium of research institutes, universities, not-for-profit organizations, and pharmaceutical companies has teamed up to develop novel drugs for infections caused by parasitic worms (helminths), a debilitating group of diseases that includes river blindness, lymphatic filariasis, as well as infection with hookworm and whipworm, which together affect close to a billion people.

Called the Helminth Elimination Platform (HELP), this new multidisciplinary platform is funded through the European Union’s Horizon 2020 research and innovation programme and will run to September 2024. HELP is led by the Swiss Tropical and Public Health Institute (Swiss TPH), and comprises not-for-profit research and development (R&D) organization, Drugs for Neglected Diseases initiative (DNDi), and pharmaceutical companies, Bayer Animal Health and Bristol-Myers Squibb (formerly Celgene). Partnering European and African academic institutions are the University Hospital Bonn, Germany, and Muséum National d’Histoire Naturelle Paris, France, as well as the Ifakara Health Institute, Tanzania, and the University of Buea, Cameroon.

‘These gastrointestinal or tissue helminth diseases affect millions of people, yet R&D lags behind that of other neglected tropical diseases, said Professor Jennifer Keiser, Head of the Helminth Drug Development Unit at Swiss TPH, and Consortium Coordinator. By bringing together experience in pharmaceutical development and translational medicine with disease specialists, we will bolster the empty anthelminthic drug pipeline, and put us on the path towards curative drugs that target one or more of these debilitating parasitic worm infections.’

The HELP consortium will work on ‘nematode’ worms, which include both the filarial worms that cause river blindness (onchocerciasis), loiasis, and lymphatic filariasis, and intestinal helminths like hookworm and whipworm, which are transmitted through contaminated soil. More efficacious, safe, and affordable treatments are needed for river blindness, which can cause blinding and debilitating itching of the skin, as well as for infections with soil-transmitted helminths, which can cause abdominal pain, diarrhoea, and considerable growth retardation.

‘We’re hoping to develop desperately needed new treatments for at least one – and because these parasites are related, possibly several – of these diseases, by bringing together this unprecedented combination of expertise in one group,’ said Sabine Specht, Head of Filarial Diseases, DNDi, and co-application of the HELP consortium.

The HELP consortium will undertake activities ranging from drug discovery to development. Compound classes with validated drug targets in parasitological and preclinical studies in veterinary medicine will be evaluated for application in humans. Moreover, oxfendazole and oxantel pamoate, two well characterized compounds, will be studied in early clinical testing. HELP will also contribute to capacity building of affected countries to conduct R&D for these diseases by translational medicine, and lead two clinical first-in-human phase I trials in Africa.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 815628.

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About Swiss TPH

The Swiss Tropical and Public Health Institute (Swiss TPH) is a world-leading institute in global health with a particular focus on low- and middle-income countries. Associated with the University of Basel, Swiss TPH combines research, services, and education and training at local, national, and international levels. About 850 people from 80 nations work at Swiss TPH focusing on infectious and non-communicable diseases, environment, society, and health as well as health systems and interventions. www.swisstph.ch

About DNDi

The Drugs for Neglected Diseases initiative (DNDi) is a not-for-profit research and development organization working to deliver new treatments for neglected diseases – notably leishmaniasis, sleeping sickness, Chagas disease, specific filarial infections, and mycetoma – as well as treatments for neglected patients, particularly those living with paediatric HIV and hepatitis C. Since its inception in 2003, DNDi and its partners have delivered eight innovative treatments to improve the quality of life and health of patients. www.dndi.org

About University of Buea

The University of Buea is a state University in Cameroon, created in 1993. Scientists at the University of Buea work on tropical diseases, notably filariasis. Their work combines experimental models of infection (preclinical research) to clinical trial,  and  epidemiology. They developed animal models for loaisis for both screening and counter screening of compounds against loaisis, lymphatic filariasis,  and onchocerciasis. www.ubuea.cm

About University Hospital Bonn

The Institute for Medical Microbiology, Immunology and Parasitology at the Universitätsklinikum Bonn is internationally renowned for its work in tropical medicine, specifically for pioneering a new drug treatment for filariasis. The new treatment exploits the symbiosis between the filarial nematodes and bacterial endosymbionts called Wolbachia, which are susceptible to some classes of antibiotics. www.ukbonn.de

 

About Ifakara Health Institute (IHI)

Ifakara Health Institute (IHI) is a leading health research organization in Africa, with a strong track record of developing, testing, and validating innovations for health. We are driven by a core strategic mandate for research, training, and services. The institute’s work spans across the full research lifecycle from basic science to policy and translation. IHI’s work is organized in three research departments, six research units, and seven technical units. The research departments are: Environmental Health & Ecological Sciences, Interventions & Clinical Trials, and Health Systems, Impact Evaluation & Policy. The research units are: Grants and Contracts, Training & Capacity Building, Laboratories, Data Systems and Platforms, Vector Control Product Testing, and Chronic Diseases Clinics. The technical units, which are supporting research (our primary activity), are: Internal Audit, Knowledge Management and Communications, Finance Management, Human Resources, Procurement Management, Branch Management and Information & Communication Technology. We have three major offices in Tanzania (Ifakara, Bagamoyo, & Dar es Salaam). www.ihi.or.tz

About Muséum National d’Histoire Naturelle

The Muséum National d’Histoire Naturelle is a research establishment, educational institution and museum rolled into one, a crossroads of knowledge with collections, a variety of sites open to the public and laboratories. One of them is dedicated to parasitology and has a long history in the study of filariasis. www.mnhn.fr

 

About Bayer Animal Health

Based in Germany and a business unit of Bayer AG, Bayer Animal Health is the #5 animal health company globally with revenues of €1.5 billion in 2018. It offers a broad range of products, with a particularly strong position in the field of parasiticides for companion animals, as well as parasiticides and anti-infectives for the treatment of infectious diseases in livestock. Bayer Animal Health sells products in over 120 countries and has over 3,500 employees worldwide. www.animalhealth.bayer.com

Media contacts

DNDi
media@dndi.org

Ilan Moss
Tel.: +1 646 266 5216
imoss@dndi.org

Bayer Animal Health
Christine Wunderlich
Tel.: +49 2173 38 5061
christine.wunderlich1@bayer.com

Photo credit: DNDi

The Drugs for Neglected Diseases initiative (DNDi) has been awarded $29.2 million to accelerate the development of innovative new drugs for patients in sub-Saharan Africa with sleeping sickness (human African trypanosomiasis – $15 million) and river blindness (onchocerciasis – $14.2 million) by the Bill & Melinda Gates Foundation These two parasitic diseases could be eliminated if new patient care tools are brought to bear.

Announced today, these grants will run from 2020 until 2023 and will help deliver a single-dose cure for sleeping sickness, a terrifying and fatal disease, and greatly aid efforts to develop a short-course treatment for the millions of people at risk of river blindness in Central and West Africa.

‘Both river blindness and sleeping sickness require innovative drugs to improve patient care or achieve elimination,’ said Dr Bernard Pécoul, Executive Director of DNDi. ‘There has been great progress for these two diseases in recent years, with the delivery of fexinidazole, the first all-oral treatment for sleeping sickness developed by DNDi and Sanofi, and the approval in the US of moxidectin for river blindness. Nevertheless, the needs remain acute, and reaching the goal of elimination requires innovation into better, field-adapted tools.’

The financial support will help develop:

New tools to address debilitating filarial diseases and that will shorten the time to onchocerciasis elimination and enable test-and-treat strategies:

  • River blindness is transmitted by the bite of an infected blackfly and causes severe itching, skin lesions, and eventually blindness. An estimated 20.9 million people are infected by the disease worldwide. The current approach to eliminating river blindness is based on the mass distribution of ivermectin, which has been tremendously successful in reducing disease prevalence. But these programs need to be repeated for 10-12 years as current treatments only kill the juvenile worms that cause river blindness, but not the adult worms, which can live more than 10 years in the human body.
  • DNDi aims to develop a safe, effective, affordable, and field-adapted ‘macrofilaricidal’ drug that can kill adult worms that cause river blindness. This could be used for individual patient treatment – current approaches are largely preventative targeting the larval stages only – with the potential for use as preventive chemotherapy to accelerate the elimination of river blindness in Africa in areas that are difficult to treat.
  • In 2018-9, DNDi and partners successfully progressed two new chemical compounds to first-in-human Phase I clinical studies: emodepside with Bayer Pharmaceuticals, and ABBV-4083 with AbbVie and the Liverpool School of Tropical Medicine. Thanks to this renewed financial support, DNDi aims to demonstrate a proof-of-concept for efficacy, safety, and tolerability for the two compounds.

The first single-dose oral treatment for sleeping sickness to support sustainable elimination of the disease:

  • Sleeping sickness is transmitted by the tsetse fly. The parasite attacks the central nervous system, causing severe neurological disorders, convulsions, and coma, and the disease is nearly always fatal without treatment. While cases are currently declining, 8.5 million people live in areas at moderate to very high risk in sub-Saharan Africa, particularly in the Democratic Republic of Congo (DRC), which is home to two-thirds of all cases.
  • In 2018-9, DNDi and partners, in particular Sanofi, delivered the first all-oral treatment for sleeping sickness, fexinidazole, that is currently being implemented in endemic countries. Fexinidazole eliminates the need for systematic hospitalization of patients and will improve the management of sleeping sickness patients, and facilitate the integration of sleeping sickness treatment into health systems. But a second all-oral, and importantly single-dose treatment, acoziborole, is now being tested in Phase II/III clinical studies in DRC and Guinea. Acoziborole is the first new chemical entity from DNDi’s own lead optimization program to have entered clinical development.
  • If successful, acoziborole would bring a simple, safe, and effective treatment that – together with a rapid diagnostic test – could be administered at point of diagnosis. This important feature would be a game-changer for sustainable elimination of the disease.

Both these investments build on previous financial support to DNDi’s earlier-stage R&D activities in filarial diseases and sleeping sickness projects from the Bill & Melinda Gates Foundation.

‘We are extremely grateful to the Bill & Melinda Gates Foundation for its long-standing trust over the past 12 years, our close partnership, and its renewed support to our mission to improve the quality of life and the health of millions of people living with these diseases,’ said Dr Pécoul.

About DNDi

The Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patient needs-driven, not-for-profit research and development (R&D) organization that develops safe, effective, and affordable treatments for the millions of people across the world affected by neglected diseases, notably human African trypanosomiasis (sleeping sickness), leishmaniasis, Chagas disease, filarial infections, mycetoma, paediatric HIV, and hepatitis C. Since its inception in 2003, DNDi has delivered eight new treatments: two fixed-dose antimalarials (ASAQ and ASMQ); nifurtimox-eflornithine combination therapy (NECT) for late-stage sleeping sickness; sodium stibogluconate and paromomycin (SSG&PM) combination therapy for visceral leishmaniasis in Africa; a set of combination therapies for visceral leishmaniasis in Asia; paediatric dosage forms of benznidazole for Chagas disease; a ‘super-booster’ therapy for children co-infected with HIV and TB; and fexinidazole, the first all-oral drug for sleeping sickness.

Media contacts

Ilan Moss, DNDi Communications Manager, DNDi North America
Mobile: +1-646-266-5216
E-mail: imoss@dndi.org

DNDi Press Manager
E-mail: media@dndi.org

Photo credit: Xavier Vahed-DNDi

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Efforts to eliminate river blindness, a debilitating disease affecting millions in Africa, will be hampered by another parasitic infection known as Loiasis, or ‘African eye worm’, according to a study published in Clinical Infectious Diseases.

While the World Health Organization (WHO) has targeted the elimination of river blindness in most African countries by 2025, researchers from Erasmus MC, University Medical Center Rotterdam in the Netherlands, and the Drugs for Neglected Diseases initiative (DNDi) have estimated that over 4 million people in West and Central Africa will still be infected with the disease in 2025 in areas where African eye worm is endemic.

In their modelling study, the researchers also found that 90% of these people will live in areas currently not covered by treatment programmes for river blindness, posing a major challenge to the elimination of this disease.

River blindness is transmitted by the bite of an infected blackfly and causes severe itching, skin lesions, and eventually blindness. African eye worm gets its name from its most infamous tell-tale sign: the visible passing of the Loa loa worm through the eye. Individuals with a very high amount of Loa loa larvae (microfilariae) in the blood are at risk of life-threatening complications if they receive ivermectin, a drug for river blindness.

Mass drug administration programmes of ivermectin need to be repeated for 10-12 years or more, as these treatments only kill the juvenile filarial worms that cause river blindness, and adult worms can live more than 10 years in the human body. Because of the risk of dangerous side effects, ivermectin cannot be safely used in areas co-endemic for river blindness and African eye worm and mass drug administration programmes have not been started in some of these areas

The current approach to preventing river blindness based on mass drug administration of ivermectin has been extraordinarily successful,’ says Sabine Specht, Head of Filarial Clinical Programme at DNDi. ‘But this study supports that alternative treatment strategies will be needed if we want to eliminate the disease, including the development of entirely new tools that offer a rapid and safe cure for river blindness.

DNDi aims to develop a safe, effective, affordable, and field-adapted ‘macrofilaricidal’ drug that can kill adult filarial worms and be used for individual patient treatment and to support the elimination of river blindness in Africa in areas that are difficult to treat.

About DNDi

The Drugs for Neglected Diseases initiative (DNDi) is a not-for-profit research and development organization working to deliver new treatments for neglected diseases – notably leishmaniasis, sleeping sickness, Chagas disease, specific filarial infections, and mycetoma – as well as treatments for neglected patients, particularly those living with paediatric HIV and hepatitis C. Since its inception in 2003, DNDi and its partners have already delivered eight innovative treatments to improve the quality of life and health of patients. www.dndi.org

Media contacts

DNDi North America, attending ASTMH 2019
Ilan Moss
+1 646 266 5216
imoss@dndi.org

DNDi Switzerland
media@dndi.org

Photo credit: Neil Brandvold-DNDi