Promising Phase 2 and 3 Influenza Therapies: What Pharmacists Should Know

Influenza remains a major cause of morbidity worldwide despite the availability of vaccines and several approved antiviral agents. In the US, seasonal influenza results in an estimated 9 million to 41 million illnesses, 140,000 to 710,000 hospitalizations, and 12,000 to 52,000 deaths annually.¹ Although vaccination remains the cornerstone of prevention, variable vaccine effectiveness and unmet needs in high-risk populations have driven continued innovation in the influenza pipeline.

Current pharmacologic options for influenza management were first introduced in 1999 with the approval of the neuraminidase inhibitors (NAIs) oseltamivir (Tamiflu; Genentech) and zanamivir (Relenza; GSK), followed by peramivir (Rapivab; BioCryst Pharmaceuticals, Inc) in 2014 and the introduction of a cap-dependent endonuclease (CEN) inhibitor baloxavir marboxil (Xofluza; Genentech) in 2018.^2,3 Despite regular use of antivirals each influenza season, these therapies are limited by narrow treatment windows, product shortages during high influenza activity, and reduced effectiveness in high-risk or immunocompromised populations, all of which highlight the need for additional therapies that address therapy shortcomings.^3,4 Multiple investigational antivirals currently in phase 2 and phase 3 of development are thought to have the potential to address these unmet needs.

CD388

Among emerging pipeline therapies, CD388 (Merck) may potentially have one of the most significant impacts on reshaping influenza prevention and symptom management.⁵ CD388 is a novel, long-acting antiviral conjugate that links a structurally optimized neuraminidase inhibitor, zanamivir, to an antibody Fc fragment, a design intended to substantially extend drug exposure beyond that of traditional NAIs.

The zanamivir-derived moiety demonstrates enhanced binding affinity to neuraminidase compared with unconjugated zanamivir, allowing for sustained enzymatic inhibition at lower systemic concentrations. Fc conjugation further contributes to prolonged activity through neonatal Fc receptor–mediated recycling, which slows systemic clearance and promotes extended tissue distribution, including to respiratory tract sites relevant to influenza infection. Preclinical studies demonstrated a markedly prolonged half-life and durable antiviral activity in vivo, independent of host immune response.⁶ Collectively, these pharmacologic properties support CD388’s development as a season-long prophylactic agent, rather than a short-course treatment.

Consistent with this rationale, CD388 is being developed exclusively for influenza prophylaxis. It is designed to provide extended antiviral activity following a single subcutaneous (SC) administration intended to be given at the beginning of each influenza season. Because its activity does not rely on the host immune response, CD388 may represent a valuable preventive option for patients at increased risk of severe influenza, including immunocompromised patients who may not mount adequate protection from vaccination alone or for those who are unable or unwilling to receive the influenza vaccine.

Clinical efficacy was demonstrated in the 2023 phase 2b NAVIGATE study (NCT06609460), which enrolled 5041 healthy, unvaccinated adults aged 18 to 36 years. Participants received a single SC dose of placebo or CD388 450 mg, 300 mg, or 150 mg. All CD388 doses resulted in significantly lower rates of protocol-defined influenza-like illness (ILL) compared with placebo (0.7% vs 1.1% vs 1.2% vs 2.8%, respectively). Prevention efficacy (PE) was highest vs placebo with the 450-mg dose (76.1%; 95% CI, 49.3-89.9; P < .001), followed by the 300-mg dose (61.3%; 95% CI, 27.0-81.2; P = .0024), and the 150-mg dose (57.7%; 95% CI, 21.1-78.9; P = .005). Sustained antiviral activity was observed throughout the influenza season.

The ongoing placebo-controlled phase 3 ANCHOR study (NCT07159763) is evaluating a single 450-mg SC dose of CD388 in adolescents and adults at increased risk for influenza complications, including adults aged 65 years and older, immunocompromised individuals, and patients with chronic comorbid conditions. Study completion is anticipated in 2027. Across clinical studies to date, CD388 has been generally well-tolerated, with no major safety events identified, and antiviral efficacy was not impacted by prior influenza vaccination status.^7,8

Onradivir

Onradivir (formally known as ZSP1273; Guangdong Raynovent Biotech Co, Ltd) is an oral antiviral that inhibits the RNA polymerase basic protein 2 (PB2) subunit of the influenza A virus polymerase complex, disrupting viral RNA transcription and replication.^9,10 Unlike current antivirals, PB2 inhibition targets viral mRNA synthesis at an earlier stage of influenza replication. Although its use would be limited to influenza A, onradivir provides a distinct mechanism of action different from that of currently available influenza antivirals. The antiviral is a structural derivative of pimodivir, a PB2 inhibitor that failed to show any benefit in influenza.¹⁰ However, preclinical and structural analyses suggest that onradivir binds more efficiently to the PB2 cap-binding domain of RNA polymerase, resulting in improved antiviral potency and a higher barrier to resistance.¹⁰ This enhanced binding affinity is thought to underlie the improved clinical outcomes observed with onradivir relative to pimodivir. A tablet formulation of onradivir was approved in China in May 2025.⁹

Based on studies and foreign approval, onradivir is administered 600 mg orally once daily for 5 days and should be initiated within 48 hours of symptom onset. In patients with mild liver impairment, a reduced dose of 400 mg is recommended. Pharmacokinetic studies demonstrate predictable hepatic metabolism without clinically meaningful cytochrome P450-mediated drug-drug interactions.¹¹ Importantly, available data suggest that mild to moderate renal impairment does not result in clinically significant changes in exposure, although patients with severe renal dysfunction were excluded from clinical trials.

Onradivir has been evaluated in 2 human studies. In the placebo-controlled phase 2 trial enrolling adults aged 18 to 65 years with acute uncomplicated influenza A, onradivir demonstrated a dose-dependent reduction in median time to symptom alleviation. Participants received 5 days of either placebo, 600 mg once daily, or twice-daily 200 mg or 400 mg. Onradivir showed faster symptom resolution vs placebo (46.92 h vs 54.87 h vs 40.05 h vs 62.87 h, respectively). The median difference between the onradivir 600 mg once daily group and placebo was approximately –22.82 hours (P = .0330).¹²

Building on these results, in the only phase 3 study published to date, onradivir 600 mg once daily was compared with placebo or oseltamivir in 702 adults aged 18 to 64 years old with laboratory-confirmed uncomplicated influenza A. Onradivir significantly shortened the median time to symptom alleviation compared with placebo (38.83 h vs 63.35 h; P < .0001) and demonstrated similar efficacy to oseltamivir (median 42.17 h).

Adverse events (AEs) occurred in 67% of onradivir recipients, 55% of placebo recipients, and 47% of oseltamivir recipients. These included nausea, vomiting, leukopenia, and neutropenia, which were generally mild overall and similar in incidence to placebo.¹³ The most common treatment-emergent AE was diarrhea (49% onradivir vs 23% placebo vs 15% oseltamivir).

Several important limitations should be noted. The phase 3 study excluded patients aged 65 years and older; individuals with obesity, underlying upper airway infections, common chronic comorbidities, immunocompromising conditions, and severe renal impairment; and patients requiring hospitalization for influenza. Additionally, participants were required to agree to contraception for 3 months following treatment, raising the possibility of teratogenic concerns. As a result, the safety and efficacy of onradivir in higher-risk populations remain unclear. Notably, the phase 3 study also excluded pediatric patients, and there are no clinical efficacy data in this group. However, a recent population pharmacokinetic analysis using pooled adult and early clinical data modeled potential pediatric exposure and proposed exploratory weight-based dosing for future clinical trials, indicating that pediatric dosing regimens of 200 mg to 600 mg once daily might achieve exposure similar to adults when adjusted for body weight. This analysis underscores the need for a dedicated pediatric evaluation before use in children can be recommended.¹⁴

ZX-7101A

ZX-7101A (Zenshine Pharmaceuticals), also referred to as seloxavir marboxil, is an oral selenium-containing prodrug approved in 2025 in China that targets influenza virus replication by inhibiting the CEN enzyme, thereby interfering with viral mRNA synthesis.¹⁵ Although mechanistically similar to baloxavir, ZX-7101A demonstrates a distinct pharmacokinetic profile, with a prolonged intracellular half-life of 119 hours at 40 mg and 100 hours at 80 mg. While an optimal dose has not yet been established, these pharmacokinetic findings support the feasibility of single-dose oral administration in adults, with 40 mg and 80 mg emerging as potential doses based on available phase 2 and 3 clinical trial data. It has shown in vitro antiviral activity against influenza A, influenza B, and highly pathogenic avian influenza strains, which may prove beneficial as cases of novel influenza continue to be seen in humans.¹⁵ A onetime administration may improve adherence compared with multiday antivirals.

In an adaptive, randomized phase 2 study enrolling adults with acute uncomplicated influenza treated within 48 hours of symptom onset, a single dose of ZX-7101A significantly reduced median time to symptom alleviation compared with placebo by 34.7 hours with the 40-mg dose (95% CI, 22.8-43.4; P = .005), 45.8 hours with the 80-mg dose (95% CI, 32.0-66.3; P = .020), and 63.6 hours with placebo (95% CI, 43.9-93.4).¹⁶ The subsequent phase 3, placebo-controlled trial also showed a significant reduction in median time to symptom alleviation with ZX-7101A [48.4 hours with the 40-mg dose (95% CI, 40.5-55.6; P = .003) and 39.4 hours with the 80-mg dose (95% CI, 35.8-49.3; P < .001)], compared with placebo (62.9 hours).¹⁶

The drug was generally well tolerated across both phase 2 and 3 studies. Treatment-emergent AEs occurred in 41.8% of patients receiving the 40-mg dose and 44.2% of those receiving the 80-mg dose, compared with 53.8% of placebo recipients.¹⁶ The most commonly reported AEs were mild gastrointestinal symptoms and headache. No clinically significant safety signals related to hepatic toxicity or QT prolongation were observed. However, important limitations remain. Older adults, hospitalized patients, and individuals with significant comorbid conditions were excluded from clinical trials. Patients with severe influenza, renal impairment, or immunocompromising conditions were not adequately studied, limiting extrapolation to these higher-risk populations.¹⁶ In addition, detailed package labeling is not yet readily available, restricting guidance on dosing, contraindications, and use in special populations.

Deunoxavir Marboxil (ADC189)

Deunoxavir marboxil (also known as ADC189; AnDiConBio) is an oral prodrug converted to deunoxavir, a CEN inhibitor developed to improve antiviral potency and resistance profiles compared with earlier agents in this class. By inhibiting the influenza polymerase endonuclease complex, ADC189 disrupts viral mRNA transcription and inhibits viral replication.¹⁷ In a randomized, double-blind phase 2/3 study in Asia involving adults and adolescents with uncomplicated influenza, a single-dose ADC189 administered within 48 hours of symptom onset significantly shortened the median time to symptom resolution compared with placebo (40-45 hours vs 60-65 hours; P < .05).¹⁸ Deunoxavir marboxil also demonstrated rapid antiviral activity, with significant reductions in viral load observed within 24 hours of dosing and sustained virologic suppression through follow-up.¹⁸ These findings support its potential as a single-dose oral influenza antiviral similar to baloxavir but with next-generation molecular design.

In addition, a large phase 3 randomized clinical trial in adolescents and adults with influenza met its primary efficacy end point, according to a manufacturer news release. The sponsor reported that deunoxavir marboxil significantly improved clinical outcomes compared with placebo, with a reported efficacy improvement of 26.543% (P < .0001), and demonstrated a favorable safety profile, supporting advancement toward regulatory submission. However, full peer-reviewed phase 3 efficacy and safety data have not yet been published, limiting independent evaluation of these results.¹⁹

Across clinical studies, available data indicate that deunoxavir marboxil has been generally well-tolerated. The most frequently reported AEs include headache and mild gastrointestinal symptoms, with incidence rates similar to placebo. Serious AEs were uncommon, and no major safety signals were identified in phase 2/3 trials.¹⁸ Data on older adults, patients with significant comorbidities, and hospitalized influenza populations remain limited.

Enisamium Iodide

Enisamium iodide is an oral antiviral that inhibits influenza virus polymerase-mediated RNA synthesis, thereby reducing viral replication.²⁰ In addition to its direct antiviral activity, enisamium iodide has demonstrated immunomodulatory and anti-inflammatory effects, which may contribute to clinical benefit during acute influenza infection. Specifically, experimental and clinical studies have reported reductions in proinflammatory cytokine signaling, including IL-6 and tumor necrosis factor-ɑ, suggesting a dual antiviral and host-directed mechanism of action.²¹ Enisamium iodide has advanced to phase 3 development and is approved for use in several countries outside the US, where it is marketed under the brand name Amizon.

Clinical efficacy has been evaluated in multiple randomized and observational studies. In randomized, placebo-controlled trials conducted in Europe, the antiviral significantly reduced the median time to symptom resolution by approximately 24 to 30 hours when initiated within 48 hours of symptom onset, with the greatest benefit observed in patients treated early in the disease course.^21,22 In addition to symptom improvement, enisamium iodide significantly reduced viral shedding, an important marker of ongoing transmissibility, with lower viral RNA levels by day 3 to day 5 of therapy and a shorter duration of detectable viral shedding compared with placebo.²⁰ These findings suggest that enisamium iodide may reduce the period during which infected individuals remain infectious. The largest available clinical data set is an observational study involving more than 6100 patients, which reported shorter symptom duration, improved clinical recovery, and favorable tolerability among patients treated with enisamium iodide compared with standard supportive care.²³ However, heterogeneity in study design and lack of randomization limit definite conclusions.

Its safety profile has been favorable, with the most commonly reported AEs being mild gastrointestinal effects, including nausea and dyspepsia, at incidence rates similar to placebo. Serious AEs were rare, and discontinuation due to AEs was uncommon.^20,22 Importantly, enisamium is an iodide-containing compound, and product labeling outside the US notes that treatment can increase iodine exposure and potentially affect thyroid function. Caution is advised in patients with preexisting thyroid disorders, and monitoring may be warranted with prolonged use. Data on older adults, patients with significant comorbidities, and severe or hospitalized influenza remain limited.

Clinician Considerations and Conclusion

Collectively, these investigational influenza therapies reflect continued innovation in treatment strategies through novel mechanisms and simplified dosing. Key considerations for clinicians include timing of therapy initiation, populations studied, dosing convenience, and safety profiles. As these agents progress through late-stage development, health care professionals will play an important role in evaluating their place in therapy, particularly for patients with limited benefit from existing options.

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16. Wang H, Wang G, Gao Y, et al. Efficacy and safety of ZX-7101A, an inhibitor of influenza cap-dependent endonuclease, in adults with uncomplicated influenza: a randomized, double-blind, placebo-controlled phase 2/3 trial. Clin Microbiol Infect. 2025;31(2):274-281. doi:10.1016/j.cmi.2024.10.020

17. Li Y, Zhang J, He F, et al. Anti-influenza drugs targeting trimeric RNA polymerase complex: from development to clinics. Acta Pharm Sin B. 2026;16(2):728-745. doi:10.1016/j.apsb.2025.11.033

18. Zhao J, Sheng G, Lyu Y, et al. Oral ADC189 for adults and adolescents with uncomplicated influenza. J Infect. 2025;90(4):106472. doi:10.1016/j.jinf.2025.106472

19. NDA of deunoxavir marboxil, the next generation innovative influenza drug get accepted, offering hope for “one-pill cure” for influenza. News release. Simcere. March 18, 2025. Accessed June 11, 2026. https://en.simcere.com/news/detail.aspx?mtt=1496

20. Velthuis AJWT, Zubkova TG, Shaw M, et al. Enisamium reduces influenza virus shedding and improves patient recovery by inhibiting viral RNA polymerase activity. Antimicrob Agents Chemother. 2021;65(4):e02605-02620. doi:10.1128/AAC.02605-20

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22. Lioznov DA, Karnaukhova EJ, Zubkova TG, Shakhlanskaya EV. [Evaluation of the effectiveness of ARVI treatment regimen including etiotropic (enisamium iodide) and symptomatic treatment]. Ter Arkh. 2020;92(3):50-55. doi:10.26442/00403660.2020.03.000572

23. Golubovska OA, Chalyy KO, Bezrodna OV, Golubovska AO. Evaluation of enisamium iodide’s impact on the clinical course of acute respiratory viral infections, influenza and COVID-19 in outpatients. Emergen Med (Ukraine). 2025;21(1):43-53. doi:10.22141/2224-0586.21.1.2025.1831