Research on moxidectin was initiated by TDR in the late 1990s with support of the Onchocerciasis Control Programme (OCP) and the African Programme for Onchocerciasis Control (APOC), which worked with TDR on research required to advance their objectives.
Data from TDR sponsored research in in vitro and animal models of onchocerciasis and lymphatic filariasis showed that it was more effective than ivermectin against the parasites. Experimental data from research conducted by Fort Dodge Animal Health for moxidectin's use against animal parasites suggested that moxidectin might be safe enough for mass treatment. Based on these data, the clinical development was initiated in collaboration with the pharmaceutical company Wyeth, the owner of moxidectin at the time, and with support of OCP and APOC.
Moxidectin development objective
Moxidectin was evaluated to see whether it is safe enough for use in mass treatment and can reduce parasite transmission faster than ivermectin, i.e. reduce the number of years of interventions required to meet criteria for stopping treatment.
If that is the case, moxidectin could be particularly valuable in post-conflict countries in Africa where community-directed treatment with ivermectin (CDTI) has not yet been implemented or only recently.
TDR-funded research since initiation of moxidectin development and recent APOC surveys of onchocerciasis prevalence in areas with more than 10 years of CDTI suggest that the impact of ivermectin on onchocerciasis transmission may be larger than originally anticipated and that 10-25 years of annual community-directed treatment with ivermectin (CDTI) (depending on the proportion of population treated and endemicity) may permanently interrupt transmission of the parasite in a given endemic zone. Should this be confirmed, these areas could discontinue CDTI - provided that there is no risk of 're-importing' the parasite through infected flies or people from surrounding areas, in the same country or across the border, because these areas belong to the same transmission zone (i.e. an area sharing a parasite population).
Moxidectin could, therefore, also be beneficial to accelerate progress towards elimination of parasite transmission in areas that need to 'catch up' with neighbouring areas which have benefitted from lower pre-control endemicity levels, earlier implementation of CDTI, CDTI with higher coverage (percentage of the population which took ivermectin) or CDTI with lower levels of non-compliance (percentage of people who took ivermectin rarely or never). This would allow criteria for stopping treatment across the whole transmission zone to be met earlier and onchocercia and community, health system and donor resources to be redirected towards other health priorities.
Moxidectin development for onchocerciasis to date
All pre-clinical pharmacology and toxicology studies and six studies in healthy volunteers (Phase 1 studies), as well as the first study in humans infected with O. volvulus (Phase 2 study in Ghana) as well as the pivotal study in humans infected with O. volvulus (Phase 3 study in Liberia, Democratic Republic of the Congo and Ghana), have been completed.
The external expert committee (Special Project Team, SPT) which advises TDR on the development of moxidectin, met in December 2010 to review data from the Phase 1 studies and the Phase 2 study data, and recommended continuing development of moxidectin. The Phase 2 study data were discussed in March 2011 by the Technical Consultative Committee (TCC) of APOC which also recommended continuation of moxidectin development.
In September 2011, TDR and APOC convened another external advisory committee (EAC) to review the Phase 2 data in light of the new data on the effect of CDTI on onchocerciasis transmission and resulting onchocerciasis control needs, taking into account other events impacting the development of moxidectin. The EAC recommended that WHO continue moxidectin development while the search for a license holder and donor is being conducted. The recommendations of the EAC were presented in September 2011 to the APOC TCC, which endorsed them.
The search for a new donor had become necessary because Wyeth, the company with which TDR initiated moxidectin development, had been acquired by Pfizer which discontinued the collaboration on moxidectin in July 2011. In 2013, Medicines Development for Global Health (MDGH), a not-for-profit global health company, contacted TDR about moxidectin which they were evaluating for potential development for scabies. After due diligence review of all data from moxidectin studies available to TDR, MDGH decided in 2014 to assume sponsorship of moxidectin to register it for onchocerciasis, make it available to onchocerciasis endemic countries and develop it for other neglected infectious diseases such as scabies.
MDGH raised 10 Million US$ from the Global Health Investment Fund, initiated discussions with the US FDA on a 'New Drug Application' (NDA) for moxidectin, re-established manufacturing of moxidectin tablets for human use and prepared the NDA submission to the US FDA. On 12 December 2017, the US FDA informed MDGH that it had awarded priority review designation to the NDA.
Research capacity built and ready for new projects
As is typical for TDR sponsored research projects in disease endemic countries, research capacity strengthening in the countries where the project is implemented was an integral part of the moxidectin project. More infrastructure building than usual was required for the Phase 3 study since part of this study was to be conducted in areas in Liberia and the Democratic Republic of the Congo (DRC), which were recovering from recent conflicts and had no clinical research capacity. The project created three new clinical research centres in Liberia (1 centre) and DRC (2 centres) and strengthened a centre in Ghana that had been created with TDR support in 1977. The building, equipment and skilled staff provided through the moxidectin project have since contributed to other research for control of onchocerciasis and lymphatic filariasis. Organizations and researchers interested in conducting studies in these countries can find the available resources and contact information in the publication below.