ADC189 shows promise as a single-dose treatment for influenza

ADC189 shows promise as a single-dose treatment for influenza

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

The active metabolite of ADC189, 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 inhibitory effect inhibition confirm broad-spectrum antiviral efficacy 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 virus titers to undetectable levels, and achieved 100% survival, outperforming oseltamivir. Therapeutic dosage at 1-10 MPK significantly prolonged survival and reduced viral load in a dose-dependent manner. These results demonstrate the potential of ADC189 as a preventative and therapeutic agent, particularly against severe influenza infections.

The Phase I study involved 47 healthy volunteers in a single dose (SAD) and food effect (FE) cohort. Pharmacokinetic analysis showed dose-proportional increases in exposure with mean maximum plasma concentrations (Cmax) from 18.09 ng/ml (15 mg) to 181.90 ng/ml (90 mg). The terminal elimination half-life (T1/2) ranged from 76.69 to 98.28 hours and supported once daily dosing. Food intake did not change significantlyCMax, AUC, orT1/2, indicating flexibility in administration. Safety assessments revealed mild adverse events, mainly hypotension and transient laboratory abnormalities, with no serious adverse events or dose-related toxicity.

The preclinical and clinical profiles of ADC189 are consistent with baloxavir marboxil but suggest potential benefits. Its deuterated structure may improve metabolic stability, such as sustained plasma concentrations exceeding inhibition thresholds for viral replication. Synergistic effects with oseltamivir in vitro further support combination strategies for resistant strains. The long oneT1/2 and consistent exposure across weight groups suggest reliable efficacy without dosage adjustments. These characteristics position ADC189 as a promising candidate for the management of seasonal and pandemic influenza, particularly in regions where baloxavir access is limited.

Limitations include the study's focus on healthy volunteers, requiring further studies in infected populations to confirm therapeutic efficacy. However, while ADC189-107 showed reduced activity against PA i38T mutants, the clinical relevance of this resistance requires monitoring in real-world settings. Future research should examine the effects of ADC189 on viral transmission and its effectiveness 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 various influenza strains, coupled with a long half-life and food independence, highlights its potential as a convenient single-dose treatment. These findings ensure progress with ADC189 trials in Phase II trials to assess clinical efficacy and further evaluate its role in mitigating influenza-related morbidity and mortality.

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