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Collaboration for innovation: Establishment of a pan-nematode drug development platform

Periodic Reporting for period 1 - HELP (Collaboration for innovation: Establishment of a pan-nematode drug development platform)

Reporting period: 2019-09-01 to 2021-02-28

Among Neglected Tropical Diseases (NTDs), infections with nematodes constitute the largest proportion, with an estimated 1.8 billion infected individuals worldwide and over 5 billion people living in endemic countries at risk of further infections. To target helminth elimination, a drug research and development (R&D) pipeline is an urgent need to provide new chemotherapeutics that effectively eliminate or sterilize adult worms, thus creating the paradigm shift necessary to reach the 2030 sustainable development goals (SDGs) on Good Health and Well-being.

The Helminth Elimination Platform (HELP) project aims to establish an R&D pipeline for anthelmintic drug development with a focus on onchocerciasis (filarial infections) and soil-transmitted helminths (STH) infections, which are among the leading NTDs. The project is supported by a consortium of eight international public and private partners including the Swiss Tropical and Public Health Institute (Switzerland, the Coordinator), the Drugs for Neglected Diseases initiative (Switzerland), the University Hospital Bonn (Germany), the National Museum of Natural History (France), the University Of Buea (Cameroon), the Ifakara Health Institute (Tanzania), Bayer Animal Health GmbH (now Elanco Animal Health Inc., Germany) and Celgene Management Sàrl (now Bristol Myers Squibb, Switzerland). To attain its ambitious goal and be able to deliver new highly efficacious drugs as soon as possible, HELP intervenes at different stages of drug development and specifically aims to:

• Identify candidates with the best profile from compounds preselected in late drug discovery stage and provided by the industrial partners. To this end, the compounds are tested against STH and filarial worms in in vitro and in vivo drug efficacy studies.
• Progress the compounds with the best profile through standard pre-clinical studies and advance Corallopyronin A (CorA), a novel compound with proven efficacy against filariae and superiority to the gold standard doxycycline, towards phase 1 clinical trials.
• Conduct two phase 1 clinical trials with oxfendazole and oxantel pamoate under current regulatory guidelines to eventually allow for filing with a regulatory authority.

With this strategy, the consortium will establish a much-needed drug R&D pipeline, the importance of which is two-fold. It will indeed i) advance the development of treatment options for STH infections for which there is currently neither a drug with good efficacy against all species nor any prospects on the horizon; and ii) propose a pipeline of drug candidates for treating onchocerciasis, especially should current clinical candidates fail in upcoming clinical trials.

The consortium therefore expects to make a strong positive impact on the society including the reduction of disease burden in endemic countries and their social and economic consequences, given the fact that helminth infections strongly affect mental, physical and economic human development. The resulting novel broad-spectrum treatment options will bring benefits to the patients and the community at large improving their health and quality of life.
The HELP project aims to establish, fill and advance a R&D pipeline for antihelminthics at different phases including late stages of drug discovery, pre-clinical development and early stages of clinical development.

- Late stages of drug discovery:
Preselected compounds were provided by the industrial partners Celgene and Bayer Animal Health and their efficacy was tested in vitro on different helminths by the academic partners Swiss TPH, UKB and MNHN. Promising candidates were identified with high in vitro activity against both soil-transmitted helminths and filariae, and consequently found to qualify for in vivo drug efficacy testing. In vivo testing was initiated with some of these qualifying compounds.

- Pre-clinical development:
Activities are planned to start in reporting period 2 (RP2), in which compounds from the previous phase with the best profile will be progressed through standard pre-clinical studies. Of note, UKB has started preparatory work in RP1 to produce CorA according to Good Manufacturing Practice before GLP-Toxicology and Safety studies can be initiated in RP2.

- Early stages of clinical development:
Upon a complete analysis of the Oxfendazole global development landscape and pathway for clinical development, Swiss TPH together with partners DNDi and IHI have been preparing the Phase I clinical trial for Oxfendazole, resulting in the generation of essential study documents including study protocol, case report forms and informed consent forms. These documents are part of the submission packages that will be sent to the relevant ethics and regulatory authorities in early RP2 for approval.
Swiss TPH together with DNDi conducted a complete data review for oxantel pamoate resulting in the assembly of a Briefing Book and a subsequent meeting with the regulatory authority Swissmedic to obtain a scientific advice on the suitability of the further non-clinical and clinical development of the drug.

In addition, RP1 also included work performed by DNDi and partners for the dissemination of the HELP-related activities. The dissemination and communication activities carried out in RP1 comprise the creation and population of the HELP website, a press release, the publication of non-scientific and non-peer reviewed articles (e-news), a continuous social media posting activity on the partners accounts, some communication campaigns, and communications on the HELP project during conferences.

Furthermore, with respect to the ethics requirements, Swiss TPH developed a data protection policy, evaluated the ethics risks underlying the data processing activities of the project, and produced the opinion that, upon analysis as of end of August 2020, a data protection impact assessment should not be conducted.

The HELP project was continuously managed and coordinated in RP1 to ensure implementation of the work plan, accurate communication between the key project players for an adequate start and undertaking of the tasks set out in the work packages, and overall a smooth running of the project and compliance with the EC regulations.
This section is not applicable for our first Reporting Period (RP1) as the HELP project is still in the early stages of development. We will be able to report actual progress that goes beyond the state-of-the-art and towards the achievement of the set out objectives together with socio-economic and societal impacts in the 2nd period report (month 36).
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