Research for new drugs for elimination of onchocerciasis in Africa

Abstract

Onchocerciasis is a parasitic, vector borne disease caused by the filarial nematode Onchocerca volvulus. More than 99% of the population at risk of infection live in Africa. Onchocerciasis control was initiated in West Africa in 1974 with vector control, later complemented by ivermectin mass drug administration and in the other African endemic countries in 1995 with annual community directed treatment with ivermectin (CDTI.) This has significantly reduced infection prevalence. Together with proof-of-concept for onchocerciasis elimination with annual CDTI from foci in Senegal and Mali, this has resulted in targeting onchocerciasis elimination in selected African countries by 2020 and in 80% of African countries by 2025. The challenges for meeting these targets include the number of endemic countries where conflict has delayed or interrupted control programmes, cross-border foci, potential emergence of parasite strains with low susceptibility to ivermectin and co-endemicity of loiasis, another parasitic vector borne disease, which slows down or prohibits CDTI implementation. Some of these challenges could be addressed with new drugs or drug combinations with a higher effect on Onchocerca volvulus than ivermectin. This paper reviews the path from discovery of new compounds to their qualification for large scale use and the support regulatory authorities provide for development of drugs for neglected tropical diseases. The status of research for new drugs or treatment regimens for onchocerciasis along the path to regulatory approval and qualification for large scale use is reviewed. This research includes new regimens and combinations of ivermectin and albendazole, antibiotics targeting the O. volvulus endosymbiont Wolbachia, flubendazole, moxidectin and emodepside and discovery of new compounds.

Keywords: Africa; Discovery; Drug development; Elimination; Implementation research; Onchocerciasis.

Fig. 1

Conceptual framework for onchocerciasis elimination. CMFL - community microfilarial load. From: (African Programme for Onchocerciasis Control (APOC) 2010b).

Fig. 2

Simulation of the trend in prevalence after ivermectin treatment for different pre-control endemicity levels. The simulation was done with the programme ONCHOSIM (Plaisier et al., 1990, Remme et al., 1990). CMFL - community microfilarial load. MF - microfilariae. The geographic coverage and treatment coverage assumed are 100% and 70%, respectively. APOC recommends at least 80% therapeutic coverage for elimination of onchocerciasis. From: (African Programme for Onchocerciasis Control (APOC) 2010b).

Fig. 3

Trends in prevalence of people with detectable levels of skin microfilariae and community microfilarial load. CMFL - community microfilarial load. Mf - microfilariae. From: (African Programme for Onchocerciasis Control (APOC) 2010b). Prevalence refers to prevalence of people with levels of skin microfilariae detectable when two snips of skin are obtained and examined microscopically for presence of microfilariae, not to prevalence of infection.

Fig. 4

Stages, terminology and historical success rates during research of new drugs. Discovery: Testing of thousands of compounds in computer models, in vitro and in animal models with emphasis on evaluating whether the compounds have the desired efficacy. Pre-clinical development: Testing of compounds in vitro and in animal models with emphasis on evaluating the toxicity. On average around 5 of 250 compounds entering pre-clinical development are progressed to clinical development, i.e. are tested in humans. It was estimated that it takes 3–6 years to identify a compound that can enter clinical development. Clinical development consists of three phases. Phase 1 studies occur typically in small groups of healthy volunteers. Out of 3–7 compounds tested in Phase 1 studies, 2–5 compounds enter Phase 2 studies. Phase 2 studies are typically the first studies in people who have the disease intended to be treated. Out of 2–5 compounds tested in Phase 2 studies, 1–2 enter Phase 3 studies. Phase 3 studies are typically conducted in ≥1000 people. Of 1–2 compounds tested in Phase 3 studies, one has the properties which result in submission for marketing approval by the US FDA. * Failure rates based on Congress of the United States, Congressional Budget Office, Research and Development in the Pharmaceutical Industry, October 2006 (http://www.cbo.gov/ftpdocs/76xx/doc7615/10-02-DrugR-D.pdf, accessed 16 January 2016) ** Failure rate based on estimate of International Federation of Pharmaceutical Manufacturer’s Association (IFPMA) presented to the WHO Expert Working Group on Funding R&D for Diseases of the Developing World (http://www.who.int/phi/IFPMA_FundingR&D_Jan09.ppt, access 16 January 2016).