Influenza continues to pose a significant global health burden, with seasonal outbreaks causing substantial morbidity and mortality. Current antiviral therapies, such as neuraminidase inhibitors and M2 inhibitors, face challenges like drug resistance and variable efficacy. ADC189, a novel cap-dependent endonuclease (CEN) inhibitor structurally related to baloxavir marboxil, emerges as a potential therapeutic candidate. This study evaluates ADC189’s preclinical antiviral activity, pharmacokinetics, and safety in a first-in-human phase I trial. Preclinical results demonstrate potent inhibition of influenza polymerase activity across multiple strains, including oseltamivir-resistant variants, and robust efficacy in murine models. Phase I data reveal favorable pharmacokinetic profiles, prolonged half-life, and no food-related absorption interference, supporting its development as a single-dose oral therapy for influenza.

ADC189’s active metabolite, ADC189-107, exhibits inhibitory activity comparable to baloxavir against both wild-type and PA I38T mutant influenza polymerases. In vitro assays using luciferase reporters and cytopathic effect inhibition confirm broad-spectrum antiviral potency against laboratory, zoonotic, and clinical influenza strains, with EC50 values ranging from 0.24 to 15.64 nmol/L. In H1N1-infected mice, prophylactic ADC189 administration prevented weight loss, reduced lung viral titers to undetectable levels, and achieved 100% survival, outperforming oseltamivir. Therapeutic dosing at 1–10 mpk significantly prolonged survival and lowered viral loads in a dose-dependent manner. These findings highlight ADC189’s potential as a preventive and therapeutic agent, particularly against severe influenza infections.

The phase I trial involved 47 healthy volunteers in single ascending dose (SAD) and food effect (FE) cohorts. Pharmacokinetic analysis showed dose-proportional exposure increases, with mean maximum plasma concentrations (Cmax) rising from 18.09 ng/mL (15 mg) to 181.90 ng/mL (90 mg). The terminal elimination half-life (T1/2) ranged between 76.69 and 98.28 hours, supporting once-daily dosing. Food intake did not significantly alter Cmax, AUC, or T1/2, indicating flexibility in administration. Safety assessments revealed mild adverse events, primarily hypotension and transient laboratory abnormalities, with no serious adverse events or dose-dependent toxicity.

ADC189’s preclinical and clinical profiles align with baloxavir marboxil but suggest potential advantages. Its deuterated structure may enhance metabolic stability, as evidenced by sustained plasma concentrations exceeding inhibitory thresholds for viral replication. Synergistic effects with oseltamivir in vitro further support combination strategies for resistant strains. The long T1/2​ and consistent exposure across weight groups suggest reliable efficacy without dose adjustments. These attributes position ADC189 as a promising candidate for managing seasonal and pandemic influenza, particularly in regions where baloxavir access is limited.

Limitations include the study’s focus on healthy volunteers, necessitating further trials in infected populations to confirm therapeutic efficacy. Additionally, while ADC189-107 demonstrated reduced activity against PA I38T mutants, the clinical relevance of this resistance requires monitoring in real-world settings. Future research should explore ADC189’s impact on viral transmission and its efficacy in high-risk populations, such as immunocompromised individuals.

In summary, ADC189 demonstrates potent antiviral activity, favorable pharmacokinetics, and a strong safety profile. Its ability to inhibit diverse influenza strains, coupled with a long half-life and food-independent absorption, underscores its potential as a convenient, single-dose treatment. These findings warrant advancing ADC189 to phase II trials to evaluate clinical efficacy and further assess its role in mitigating influenza-related morbidity and mortality.
DOI: 10.1007/s11684-024-1115-1