Onchocerciasis drug development: from preclinical models to humans

Abstract

Twenty diseases are recognized as neglected tropical diseases (NTDs) by World Health Assembly resolutions, including human filarial diseases. The end of NTDs is embedded within the Sustainable Development Goals for 2030, under target 3.3. Onchocerciasis afflicts approximately 20.9 million people worldwide with > 90% of those infected residing in Africa. Control programs have made tremendous efforts in the management of onchocerciasis by mass drug administration and aerial larviciding; however, disease elimination is not yet achieved. In the new WHO roadmap, it is recognized that new drugs or drug regimens that kill or permanently sterilize adult filarial worms would significantly improve elimination timelines and accelerate the achievement of the program goal of disease elimination. Drug development is, however, handicapped by high attrition rates, and many promising molecules fail in preclinical development or in subsequent toxicological, safety and efficacy testing; thus, research and development (R&D) costs are, in aggregate, very high. Drug discovery and development for NTDs is largely driven by unmet medical needs put forward by the global health community; the area is underfunded and since no high return on investment is possible, there is no dedicated drug development pipeline for human filariasis. Repurposing existing drugs is one approach to filling the drug development pipeline for human filariasis. The high cost and slow pace of discovery and development of new drugs has led to the repurposing of “old” drugs, as this is more cost-effective and allows development timelines to be shortened. However, even if a drug is marketed for a human or veterinary indication, the safety margin and dosing regimen will need to be re-evaluated to determine the risk in humans. Drug repurposing is a promising approach to enlarging the pool of active molecules in the drug development pipeline. Another consideration when providing new treatment options is the use of combinations, which is not addressed in this review. We here summarize recent advances in the late preclinical or early clinical stage in the search for a potent macrofilaricide, including drugs against the nematode and against its endosymbiont, Wolbachia pipientis.

Co-Administration of Adjuvanted Recombinant Ov-103 and Ov-RAL-2 Vaccines Confer Protection against Natural Challenge in A Bovine Onchocerca ochengi Infection Model of Human Onchocerciasis

“…Epidemiological modelling suggests elimination efforts based exclusively on MDA will not achieve disease elimination [7], whilst the consensus amongst experts (~70%) is that additional measures are required to eliminate human onchocerciasis [8]. The recent licencing of the macrocyclic lactone moxidectin for use as an additional microfilaricidal treatment is promising [9][10][11], whilst efforts to identify and evaluate safe drugs targeting adult worms (macrofilaricides) are ongoing [12,13].…”

Corallopyronin A: antimicrobial discovery to preclinical development

“…35 The lengthy therapy interval of 4-5 weeks and the contraindications for pregnant and breastfeeding women, as well as children below the age of 8 years led to the search for novel, faster acting drugs active against Wolbachia. 34,36 COR A constitutes one of these novel agents currently in the preclinical phase with the aim to develop it as a treatment for human larial infections (Fig. 1).…”

Surveillance for Onchocerciasis-Associated Epilepsy and OV16 IgG4 Testing of Children 6–10 Years Old Should Be Used to Identify Areas Where Onchocerciasis Elimination Programs Need Strengthening

“…Several new promising drugs for the treatment of onchocerciasis are being tested in clinical trials [ 11 , 12 ], of which moxidectin was shown to reduce and maintain low skin microfilarial density for longer than ivermectin [ 13 ]. Macrofilaricides, currently only in an early phase of development, will be needed to drastically reduce the elimination time of onchocerciasis [ 11 , 12 ]. However, today none of these new drugs are available for mass drug administration programmes.…”