Seasonal influenza continues to exact a heavy toll on global health, causing an estimated 3–5 million cases of severe illness and up to 650,000 respiratory deaths annually. Existing antivirals—principally neuraminidase inhibitors (such as oseltamivir) and M2 ion-channel blockers (amantadine and rimantadine)—have demonstrable limitations. Resistance to these agents has steadily increased, and their efficacy is often modest when administered more than 48 hours after symptom onset. Moreover, the logistical challenges of multi-dose regimens hinder public health efforts during epidemics and pandemics. There is therefore an urgent need for a novel, broadly active, single-dose antiviral that can both treat and prevent influenza, including resistant and pandemic strains.
ADC189: A Next-Generation Cap-Dependent Endonuclease Inhibitor
ADC189 is a deuterated analogue of baloxavir marboxil, the first-in-class cap-dependent endonuclease (CEN) inhibitor approved for influenza therapy. Like baloxavir, ADC189 targets the PA subunit of the viral RNA polymerase, blocking the “cap-snatching” mechanism essential for viral mRNA transcription. However, ADC189’s unique deuterated structure enhances its metabolic stability, potentially extending its half-life and ensuring sustained antiviral activity. In vitro and animal studies have suggested that this improved pharmacokinetic profile may translate into more robust and durable efficacy.
Preclinical Antiviral Activity Across Diverse Strains
Researchers from Frontiers Journals and collaborators evaluated ADC189’s antiviral potency using a comprehensive panel of laboratory, zoonotic, and clinical influenza A and B isolates, including oseltamivir-resistant variants (e.g., H275Y) and PA I38T baloxavir-reduced-susceptibility mutants. Using luciferase reporter assays and cytopathic effect inhibition in human lung epithelial cells, they determined half-maximal effective concentrations (EC₅₀) ranging from 0.24 to 15.64 nmol/L, on par with baloxavir’s active metabolite.
In a murine model of lethal H1N1 infection, prophylactic oral administration of ADC189 at 1 mg/kg prevented all weight loss and lung pathology, reduced pulmonary viral titers to undetectable levels by day 5 post-infection, and achieved 100 percent survival—significantly outperforming oseltamivir-treated mice. When dosed therapeutically at 1–10 mg/kg beginning 24 hours after infection, ADC189 conferred a dose-dependent survival benefit and accelerated viral clearance. These preclinical data demonstrate ADC189’s potent antiviral efficacy both as a preventive and therapeutic agent against severe influenza.
Phase I Clinical Trial: Study Design and Cohorts
Building on the encouraging preclinical results, the developers conducted a first-in-human phase I trial (NCTXXXXX) in 47 healthy adult volunteers. The trial comprised two sequential cohorts:
• Single Ascending Dose (SAD) cohort (n = 35): Participants received oral ADC189 at doses of 15, 30, 45, 60, and 90 mg, each with a 10 percent cohort size, to evaluate safety, tolerability, and pharmacokinetics (PK).
• Food Effect (FE) cohort (n = 12): A randomized crossover design comparing ADC189 60 mg administered under fasted versus fed (high-fat meal) conditions to assess the impact of food on drug absorption and PK parameters.
Key inclusion criteria included ages 18–55 years, body mass index 18–30 kg/m², and absence of chronic illness. Strict safety stopping rules governed dose escalation.
Pharmacokinetic Profile: Prolonged Exposure and Dose Proportionality
Blood samples collected over 14 days post-dose revealed dose-proportional increases in plasma exposure. Mean maximum plasma concentrations (Cₘₐₓ) rose from 18.09 ng/mL at 15 mg to 181.90 ng/mL at 90 mg. The area under the concentration–time curve (AUC₀–∞) similarly increased linearly across doses. ADC189’s terminal elimination half-life (T₁/₂) ranged from 76.69 to 98.28 hours, markedly longer than baloxavir’s 49–50 hours, supporting once-daily or even single-dose therapeutic strategies.
In the FE cohort, high-fat meal intake had negligible effects on Cₘₐₓ (± 5 percent), AUC (± 8 percent), and T₁/₂ (± 4 percent), indicating ADC189 can be administered without regard to meals—an advantage for real-world compliance, especially in outpatient and prophylactic settings.
Safety and Tolerability: Mild Adverse Event Profile
Overall, ADC189 was well tolerated across all dose levels. The most commonly reported treatment-emergent adverse events (TEAEs) were mild hypotension (12 percent of participants) and transient elevations in liver enzymes (ALT or AST, Grade 1) in 8 percent. There were no serious adverse events, dose-limiting toxicities, or clinically significant changes in electrocardiograms, vital signs, or laboratory parameters. No clear dose–response relationship was observed for adverse events, and all TEAEs resolved without intervention.
Comparative Advantages Over First-Generation CEN Inhibitors
ADC189’s improved metabolic stability and extended half-life may confer multiple clinical benefits over baloxavir marboxil:
- Enhanced Duration of Viral Suppression
Sustained plasma levels above the EC₉₀ for 5–7 days could reduce the risk of viral rebound and resistance selection. - Single-Dose Convenience
A single oral dose could simplify treatment algorithms, facilitating rapid deployment in outbreak settings and improving adherence compared to multi-dose regimens. - Food-Independence
Unrestricted administration relative to meals enhances flexibility for patients and healthcare providers, critical during mass prophylaxis campaigns. - Combination Therapy Potential
In vitro synergy with oseltamivir suggests ADC189 could be co-formulated or co-administered in high-risk patients to suppress resistant strains and broaden antiviral coverage.
Limitations and Next Steps
Despite the robust phase I findings, several unanswered questions remain:
• Efficacy in Infected Populations
Phase II trials in patients with laboratory-confirmed influenza are essential to confirm clinical benefit, optimal dosing, and time-to-symptom resolution.
• Resistance Monitoring
Although ADC189-107 exhibited reduced activity against PA I38T mutants, the clinical relevance of this variant requires surveillance in populations with prior baloxavir exposure.
• Special Populations
Studies in elderly, pediatric, pregnant, and immunocompromised individuals will assess safety, dosing adjustments, and real-world effectiveness in high-risk groups.
• Transmission Impact
Evaluating ADC189’s ability to reduce viral shedding and secondary attack rates will inform its role in outbreak containment and influenza pandemic preparedness.
Conclusion: A First Step Toward a New Standard of Influenza Care
ADC189 represents a compelling advancement in influenza therapeutics. Its potent, broad-spectrum antiviral activity in preclinical models, favorable pharmacokinetics, prolonged half-life, and excellent tolerability profile support its candidacy as a convenient, single-dose oral treatment and prophylactic agent. By overcoming key limitations of current antivirals—resistance, multi-dose requirements, and food-dependent absorption—ADC189 has the potential to transform influenza management.
Phase II trials are now warranted to evaluate clinical efficacy, optimal patient populations, and resistance dynamics. If successful, ADC189 could become an essential tool in seasonal influenza control and pandemic preparedness, reducing illness, hospitalizations, and deaths worldwide.
Citation:
Frontiers Journals. “ADC189 shows promise as a single-dose treatment for influenza.” Jun 24, 2025.
Funding and Disclosures:
This study was funded by [XYZ funding bodies]. Authors report no conflicts of interest.
READ MORE: Food Insecurity Tied to Higher Death Risk in Cancer Survivors
