Study placed on FDA full clinical hold on 03JUN2026; enrollment and study drug administration are suspended pending resolution

This multicenter, randomized, open-label Phase 2 clinical trial evaluates the safety, tolerability, and virologic efficacy of ARN-75039, a novel oral antiviral, for treating Lassa fever in hospitalized adults in West Africa. The study is conducted within the INTEGRATE platform and compares two oral dose regimens of ARN-75039 (100 mg BID and 50 mg BID) with intravenous ribavirin, the locally mandated standard of care.

Approximately 135 participants with RT-PCR-confirmed Lassa virus infection will be enrolled and randomized 1:1:1 to receive ARN-75039 high dose, ARN-75039 low dose, or ribavirin for 10 days, followed by safety and efficacy follow-up through Day 28. The primary objectives are to assess safety and tolerability and to evaluate antiviral activity, as measured by the change in slope of Lassa virus RT-PCR cycle threshold (Ct) values from Day 1 to Day 10, in participants with low baseline viral load Ct values. Secondary objectives include additional virologic, pharmacokinetic, and clinical outcome assessments, including time to viral clearance, symptom resolution, organ failure, and mortality.

ARN-75039 is a small-molecule viral entry inhibitor targeting the Lassa virus glycoprotein complex and has demonstrated potent antiviral activity and favorable safety and pharmacokinetic profiles in preclinical models and Phase 1 clinical studies. This study aims to inform dose selection and support further clinical development of ARN-75039 as a potential treatment for Lassa fever.

This Phase 2, randomized, open-label, controlled clinical trial, conducted under the INTEGRATE platform, evaluates the safety, tolerability, antiviral activity, and pharmacokinetics of ARN-75039 in adults hospitalized with RT-PCR-confirmed Lassa fever. The trial is conducted at specialized treatment centers in West Africa that have established capacity for Lassa fever diagnosis, inpatient management, and pharmacovigilance. It operates under coordinated African and U.S. regulatory oversight.

Participants are randomized 1:1:1 to receive one of three interventions for a 10-day inpatient treatment period: a high-dose oral regimen of ARN-75039, a low-dose oral regimen of ARN-75039, or intravenous ribavirin administered according to the locally mandated "Irrua regimen." Randomization is stratified by Lassa virus lineage and baseline viral load, as measured by RT-PCR cycle threshold (Ct) values. All participants receive optimized supportive care consistent with INTEGRATE platform standards and local site capabilities.

ARN-75039 is a novel, orally administered small-molecule antiviral that inhibits viral entry by targeting the Lassa virus glycoprotein complex and blocking membrane fusion. The dose regimens evaluated in this study were selected based on preclinical efficacy data, translational pharmacology, and Phase 1 clinical studies demonstrating favorable safety, tolerability, and pharmacokinetic profiles. The study incorporates an initial loading phase followed by tapered twice-daily dosing to rapidly achieve and maintain plasma concentrations associated with antiviral activity while preserving tolerability.

The primary efficacy analysis focuses on the change in slope of Lassa virus RT-PCR Ct values between Day 1 and Day 10 in participants with low baseline Ct values, reflecting viral load dynamics during acute infection. Additional virologic assessments include time to first RT-PCR result below the lower limit of quantification, time to undetectable viral RNA, and longitudinal changes in Ct value across predefined time points. Lineage-specific and baseline viral load-stratified analyses are planned to characterize antiviral effects across circulating Lassa virus variants.

Safety assessments include continuous monitoring of treatment-emergent adverse events, serious adverse events, laboratory abnormalities, vital signs, and clinically significant changes in electrocardiograms and physical examinations. Adverse events are graded using standardized criteria and reviewed by an independent Data and Safety Monitoring Board operating under the INTEGRATE master protocol. Clinical outcome measures include mortality, organ failure, need for intensive care-level support, and time to symptom resolution and hospital discharge.

Pharmacokinetic sampling is performed in participants receiving ARN-75039 to characterize systemic exposure, including peak and trough concentrations, area under the concentration-time curve, half-life, and apparent clearance. These data will support pharmacokinetic/pharmacodynamic modeling to define further exposure-response relationships and inform dose optimization for future studies.

Exploratory objectives include evaluating viral genomic sequences from selected post-dose samples to assess the potential emergence of resistance-associated mutations, and detailed monitoring of Lassa fever-related symptoms and biomarkers to support the development of future composite clinical endpoints.

Participants are followed for 28 days from treatment initiation, including the inpatient dosing period and post-treatment follow-up assessments. Study conduct adheres to International Council for Harmonisation Good Clinical Practice guidelines and applicable national and international regulatory requirements. The results of this study are intended to support further clinical development and potential regulatory approval of ARN-75039 for the treatment of Lassa fever.

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for enrollment:

• Age ≥ 18 years
• Hospitalized with clinical disease consistent with Lassa fever
• Positive plasma Lassa virus RT-PCR at screening
• Requires hospitalization for Lassa fever per local clinical guidelines
• Able to provide written informed consent, or consent provided by a legally authorized representative.

Exclusion Criteria:

Participants will be excluded if they meet any of the following criteria:

• Pregnant (confirmed by positive urine pregnancy test in women of childbearing potential)
• Receipt of specific drug therapy for Lassa fever (e.g., ribavirin, direct antivirals, or host-directed therapies including corticosteroids) within 15 days before enrollment
• Prior vaccination against Lassa fever
• History of severe gastrointestinal disease
• History of chronic generalized pruritus
• History of severe chronic liver disease
• History of severe cardiac disorder

Sex and Reproductive Criteria

• Women of childbearing potential must have a negative pregnancy test at screening
• Breastfeeding is not permitted during the treatment period and early follow-up
• Participants must agree to comply with protocol-defined contraception requirements

May currently be shared in cases of compassionate use.

This study is conducted without masking. Participants, care providers, investigators, and some outcomes assessors are aware of the treatment assignments. Viremia and PK assessors will be masked.