@article{c3c40c6c12f34dbbaeea1f6232030677,
title = "The pipeline for drugs for control and elimination of neglected tropical diseases: 1. Anti-infective drugs for regulatory registration",
abstract = "The World Health Organization {\textquoteleft}Ending the neglect to attain the Sustainable Development Goals: A road map for neglected tropical diseases 2021–2030{\textquoteright} outlines the targets for control and elimination of neglected tropical diseases (NTDs). New drugs are needed to achieve some of them. We are providing an overview of the pipeline for new anti-infective drugs for regulatory registration and steps to effective use for NTD control and elimination. Considering drugs approved for an NTD by at least one stringent regulatory authority: fexinidazole, included in WHO guidelines for Trypanosoma brucei gambiense African trypanosomiasis, is in development for Chagas disease. Moxidectin, registered in 2018 for treatment of individuals ≥ 12 years old with onchocerciasis, is undergoing studies to extend the indication to 4–11-year-old children and obtain additional data to inform WHO and endemic countries' decisions on moxidectin inclusion in guidelines and policies. Moxidectin is also being evaluated for other NTDs. Considering drugs in at least Phase 2 clinical development, a submission is being prepared for registration of acoziborole as an oral treatment for first and second stage T.b. gambiense African trypanosomiasis. Bedaquiline, registered for tuberculosis, is being evaluated for multibacillary leprosy. Phase 2 studies of emodepside and flubentylosin in O. volvulus-infected individuals are ongoing; studies for Trichuris trichuria and hookworm are planned. A trial of fosravuconazole in Madurella mycetomatis-infected patients is ongoing. JNJ-64281802 is undergoing Phase 2 trials for reducing dengue viral load. Studies are ongoing or planned to evaluate oxantel pamoate for onchocerciasis and soil-transmitted helminths, including Trichuris, and oxfendazole for onchocerciasis, Fasciola hepatica, Taenia solium cysticercosis, Echinococcus granulosus and soil-transmitted helminths, including Trichuris. Additional steps from first registration to effective use for NTD control and elimination include country registrations, possibly additional studies to inform WHO guidelines and country policies, and implementation research to address barriers to effective use of new drugs. Relative to the number of people suffering from NTDs, the pipeline is small. Close collaboration and exchange of experience among all stakeholders developing drugs for NTDs may increase the probability that the current pipeline will translate into new drugs effectively implemented in affected countries. Graphical Abstract: [Figure not available: see fulltext.]",
keywords = "Acoziborole, Bedaquiline, Drug development, Emodepside, Fexinidazole, Flubentylosin, Fosravuconazole, Implementation research, JNJ-64281802, Moxidectin, Neglected topical diseases, Oxantel pamoate, Oxfendazole",
author = "Pfarr, {Kenneth M.} and Krome, {Anna K.} and Issraa Al-Obaidi and Hannah Batchelor and Michel Vaillant and Achim Hoerauf and Opoku, {Nicholas O.} and Kuesel, {Annette C.}",
note = "Funding Information: Onchocerciasis: The UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR) initiated research on moxidectin in the late 1990s, in consultation and with the support of the Onchocerciasis Control Programme in West Africa (OCP) and the African Programme for Onchocerciasis Control (APOC). Clinical development for onchocerciasis and lymphatic filariasis (LF) was supported by the WHO/TDR-funded in vitro and animal pharmacology studies as well as the non-clinical safety studies for veterinary use registration provided by Fort Dodge Animal Health to WHO/TDR for external expert assessment. Clinical development for onchocerciasis was initiated in collaboration with Wyeth Pharmaceuticals. The development plan was informed by {\textquoteleft}scientific advice{\textquoteright} from the EMA in view of obtaining an EMA positive {\textquoteleft}scientific opinion{\textquoteright} through the Article 58 of Regulation (EC) No. 726/2004 procedure in the context of cooperation with WHO (now referred to as EU-M4all). For a {\textquoteleft}Scientific Opinion{\textquoteright}, the EMA assesses drugs not intended for marketing in the European Union according to the same criteria used for drugs for the European market. A positive {\textquoteleft}Scientific Opinion{\textquoteright} facilitates WHO prequalification and registration in endemic countries. Following acquisition of Wyeth by Pfizer and Pfizer{\textquoteright}s withdrawal from the collaboration agreement WHO and Wyeth had concluded, TDR completed the Phase 3 study on its own (last participant visit May 2012, database lock and unblinding December 2013). In 2014, WHO licensed all moxidectin-related data at its disposal to Medicines Development for Global Health (MDGH), a not-for-profit Australian Health Charity. MDGH raised funding for all activities required for a {\textquoteleft}New Drug Application{\textquoteright} (NDA) to the US FDA by leveraging the prospect of a {\textquoteleft}Priority Review Voucher{\textquoteright} []. The US FDA approved an 8 mg moxidectin dose for treatment of onchocerciasis in individuals ≥ 12 years old. US FDA review summaries and the moxidectin label are available []. Funding Information: Clinical studies demonstrating the efficacy of oxantel pamoate against T. trichiura date back to the 1970s and were recently reviewed together with the available non-clinical data []. The data support development of oxantel pamoate for approval by a stringent regulatory authority. The Helminth Elimination Platform (HELP) consortium, formed in 2019 to develop drugs for STH and onchocerciasis, is pursuing this with European Union funding (European Union{\textquoteright}s Horizon 2020 research and innovation programme grant agreement no. 815628). Studies should include not only oxantel mono-treatment arms but also two or three drug combination treatment arms [, ] to inform both regulatory approval and WHO guidelines and country policies. Funding Information: Flubentylosin has emerged from discovery programmes at the Anti-Wolbachia Consortium funded by the Bill and Melinda Gates Foundation since 2007 [, , ] and the pharmaceutical company AbbVie Inc. (North Chicago, IL, USA). Studies in Litomosoides sigmodontis mice and Mongolian gerbil models showing that flubentylosin reduced Wolbachia levels by ≥ 99.9% [] encouraged progression into development. The results of Phase 1 studies conducted by AbbVie justified preparation of a Phase 2 study. The Phase 2 study investigating the safety, efficacy and pharmacokinetics of 7 or 14 days of dosing with TylAMac alone or in combination with albendazole, ivermectin or albendazole plus ivermectin started recruitment in 2021 (PACTRI: PACTR202104600961505, CTI: NCT04913610). The study is sponsored by AbbVie and conducted in collaboration between DNDi and researchers in DRC. Funding Information: A Phase 1 multiple ascending dose study of LXE408 was completed in September 2021 and a Phase 2 study in patients with visceral leishmaniasis is planned (Clinical Trials Registry-India identifier: CTRI/2022/03/040775). The Drugs for Neglected Diseases initiative (DNDi) concluded a collaboration and license agreement in early 2022 with Novartis to develop LXE408 as a potential oral treatment for visceral leishmaniasis. The development is financially supported by Wellcome [] . Publisher Copyright: {\textcopyright} World Health Organization 2023.",
year = "2023",
month = mar,
day = "1",
doi = "10.1186/s13071-022-05581-4",
language = "English",
volume = "16",
journal = "Parasites and Vectors",
issn = "1756-3305",
publisher = "BioMed Central Ltd.",
number = "1",
}