Safety, tolerability, and pharmacokinetics of the novel antiviral compound ARN-75039 against Lassa fever in West African countries

Lassa fever (LF) is an acute febrile illness caused by Lassa virus (LASV) and associated with bleeding, organ failure, and shock. The virus reservoir is the commensal rodent Mastomys natalensis. LF outbreaks have been reported in several West African countries (Guinea, Liberia, Nigeria, Sierra Leone), with the main foci being in Nigeria. Challenges in the clinical care of patients are multiple due to the limited availability of LF molecular diagnostics, the risk for nosocomial transmission, and the limited treatment options. There are currently no safe and effective treatment options available for LF, except ribavirin, a drug with concerning toxicity and the efficacy of which is debated. With current standard of care including ribavirin and supportive treatments, at least 12% of patients hospitalised for LF still die. The clinical development and accessibility of effective treatment options would be a game-changer towards reducing mortality associated with this disease and limiting its socio-economic impact. The list of promising candidates includes 4 drugs at different stages of development. Among them is ARN-75039, a new compound that has shown an interesting efficacy and safety profile on a rodent model of LF. The INTEGRATE consortium builds on a more than 15 years lasting highly successful collaboration between leading European and West African research and health care institutions focusing on the joint priority to better understand, manage, and combat LF in West Africa. The aim of the INTEGRATE project is to establish a GCP-compliant adaptive seamless phase II/III platform clinical trial in West Africa (Nigeria and other countries) to assess the efficacy, safety, tolerability and pharmacokinetics (PK) of repurposed and novel drug candidates for the treatment of LF, given along with optimized standard of care. The INTEGRATE platform will conduct the first randomized controlled trials ever conducted to evaluate the treatment of LF. The objective of this proposal, is to conduct, within the INTEGRATE platform, a Phase II randomized, controlled, unblinded trial evaluating the safety, tolerability and (PK) of ARN-75039 compared to the standard of care drug (SCD), currently being ribavirin. The evaluated treatment arms will be:- ARN-75039 (dosage 1) + standard supportive care- ARN-75039 (dosage 2) + standard supportive care [if the Phase I suggests that there is a need to evaluate two dose regimens]- Ribavirin (control group) + standard supportive care The ARN-75039 dosages tested in this Phase II will be chosen according to the results of the Phase I study currently in progress. This Phase II trial will be conducted at the two main Nigerian clinical trial sites: the Federal Medical Centre of Owo (FMCO) and the Irrua Specialist Teaching Hospital (ISTH). The primary endpoint will be a composite defined as the proportion of participants presenting clinical aggravation between Day0 (D0) and D14. Clinical aggravation will be defined as the occurrence of death or of at least one new organ dysfunction not present on D0. It will serve to select the best dose regimen for further evaluation in the Phase III. Secondary endpoints will include PK, safety and tolerability endpoints. The total sample size for this Phase II will be 87 hospitalized adults with a positive LASV RT-PCR (ARN-75039: dosage 1 n=29, dosage 2 n=29; SCD n=29). This study will rely on a collaboration of experts from several disciplines, including researchers and coordinators from ALIMA (France and Dakar), the University of Bordeaux (France), the PAC-CI program team (Ivory Coast), BNITM (Germany), FMCO and ISTH (Nigerian clinical trial sites), Aix-Marseille University (France) and Arisan Therapeutics (USA). This study will provide for the first time data on safety and tolerability profile of ARN-75039 for the treatment of hospitalized patients with LF. These results will allow the scientific community to move forward regarding the clinical development of effective treatment options for LF, and deciding to continue or not with a Phase III evaluation for this molecule