Xocova (ensitrelvir) / Shionogi - LARVOL DELTA

Successful Treatment of Persistent and Relapsing COVID-19 with Ensitrelvir in a Patient with Obinutuzumab-Induced Long-Term B-Cell Depletion: A Case Report. (PubMed, Reports (MDPI)) - "Compared with remdesivir and molnupiravir, ensitrelvir achieves higher rates of SARS-CoV-2 antigen clearance and a more favorable viral shedding profile. Case Presentation: A 67-year-old Japanese man with follicular lymphoma had received obinutuzumab plus bendamustine, followed by obinutuzumab maintenance therapy...Three months prior to the current admission, the patient developed coronavirus disease 2019 (COVID-19) and was treated with a 10-day course of remdesivir and dexamethasone... Ensitrelvir may be an effective therapeutic option for the treatment of persistent or refractory COVID-19 in immunocompromised patients. Clinicians should recognize that patients treated with obinutuzumab may remain immunosuppressed for several years after therapy."

Journal • Follicular Lymphoma • Hematological Malignancies • Infectious Disease • Lymphoma • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • CRP

ENSITRELVIR EXPOSURE IN COVID-19 PATIENTS ON HEMODIALYSIS (PROTECT-HD) (ISN-WCN 2026) - "No treatment-emergent adverse events, hospitalizations, or severe COVID-19–related complications were observed.Conclusion Ensitrelvir exposure and pharmacokinetics were not affected by dialysis and was associated with favorable antiviral and clinical responses in participants on hemodialysis with mild COVID-19. These findings support that ensitrelvir can be used without any dose adjustments for patients on dialysis and be an important treatment option for this population.This abstract was also submitted to the 95th Annual Meeting of the Japan Society for Infectious Diseases, Western Japan Regional Meeting."

Clinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Ensitrelvir treatment of COVID-19 across multiple global phase III trials resulted in reduced culture positivity and RNA copy number with minimal viral rebound (ESCMID Global 2026) - No abstract available

P3 data • Infectious Disease • Novel Coronavirus Disease

Optimization of pyridopyrimidinedione derivatives as non-covalent SARS-CoV-2 3CL protease inhibitors. (PubMed, Bioorg Med Chem Lett) - "This study aimed to explore the structure-activity relationships (SAR) of non-covalent inhibitors of the SARS-CoV-2 3CL protease (3CLpro) and to develop more potent inhibitors starting from ensitrelvir, a potent non-peptide small-molecule 3CLpro inhibitor discovered by Shionogi & Co., Ltd...In particular, compound 18f demonstrated a balance of potent activity, high solubility, and excellent metabolic stability. Its favorable pharmacokinetics were also confirmed in rat PK tests, suggesting that this compound offers promise as a new therapeutic agent."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Characterization of the Cross-Resistance of SARS-CoV‑2 Main Protease Inhibitors, Ibuzatrelvir, Ensitrelvir, and Nirmatrelvir. (PubMed, ACS Pharmacol Transl Sci) - "Notably, the recombinant SARS-CoV-2 virus containing the Mpro L50F/E166A/L167F triple mutant is highly resistant to all three drugs in the antiviral plaque assay. These findings underscore the challenge posed by E166 mutations and highlight the need for resistance-resistant Mpro inhibitors as future therapeutics."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Optimal preclinical models for human dose projection of SARS-CoV-2 small molecule direct-acting antivirals. (PubMed, Antiviral Res) - "We assessed the minimal efficacious concentrations in these models of both ensitrelvir (ETV) and nirmatrelvir (NTV) co-dosed with ritonavir (Paxlovid) and compared this to clinical human data. Overall, we recommend applying a factor of 4-fold to the in vitro 90% effective concentration (EC90) for a conservative estimate of human efficacious exposure and recommend validation using K18-hACE2 mice. These insights are critical for guiding the development of effective SARS-CoV-2 therapeutics and optimizing clinical trial design."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Outpatient Treatment of Confirmed COVID-19: A Living, Rapid Review for the American College of Physicians (Version 3). (PubMed, Ann Intern Med) - "125 mg of ensitrelvir may not reduce time to recovery and may result in no difference in serious adverse events (both low CoE) but may increase adverse events (44.2% vs. 24.8%; low CoE)...Simnotrelvir-ritonavir reduces time to recovery (-35.8 median hours; high CoE) and probably increases adverse events (28.9% vs. 21.6%; moderate CoE). There was no difference in recovery between molnupiravir and favipiravir (high CoE) and nirmatrelvir-ritonavir and molnupiravir (low CoE)...American College of Physicians. (PROSPERO: CRD420251029146; OSF: https://osf.io/ywp6u)."

Journal • Review • Infectious Disease • Novel Coronavirus Disease

Analysis of Ibuzatrelvir's Activity Against SARS-CoV-2 Circulating Variants and In Vitro Resistance Mutations. (PubMed, Antiviral Res) - "Cross-resistance testing revealed that this double substitution retained susceptibility to remdesivir and also conferred resistance to nirmatrelvir. Ibuzatrelvir and nirmatrelvir remained active against viruses containing the ensitrelvir-specific resistance Mpro substitution M49L. The sustained efficacy of ibuzatrelvir against circulating variants, combined with the low prevalence of the E166V substitution, supports its continued evaluation in phase 3 studies."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Treatment Duration of Each Anti-COVID-19 Agent Used in a Tertiary Hospital in Japan. (PubMed, Cureus) - "Four anti-COVID-19 agents, nirmatrelvir/ritonavir (Nir/r), ensitrelvir (ESV), molnupiravir (MPV), and remdesivir (RDV), have been used in Japan for adult patients, and their clinical effectiveness, especially treatment duration and reduction of viral antigen titers, was investigated. However, the treatment durations differed significantly: 4.09 days with Nir/r, 4.76 days with ESV, 4.74 days with MPV, and 5.08 days with RDV. These data suggest that the anti-viral activity of each anti-COVID-19 agent may differ in clinical use."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Persistent COVID-19 in Patients With Hematological Malignancies: A Focused Review in the Omicron Era. (PubMed, Clin Lymphoma Myeloma Leuk) - "We carried out a comprehensive literature review of Omicron pCOVID-19 occurring in HM patients, compiled the scattered evidence, and provide practical recommendations which can be of guide to clinicians. Main topics discussed within this review include efficacy of vaccinations in HM patients, risk factors for developing pCOVID-19 (B-cell depleting agents, bendamustine + rituximab therapy, bispecific T-cell engagers, etc.), treatment of pCOVID-19 including extended/sequential/combination therapy incorporating antivirals (nirmatrelvir/ritonavir, remdesivir, molnupiravir, and ensitrelvir) and convalescent plasma/intravenous immunoglobulin therapy, monitoring pCOVID-19 with reverse transcription (RT)-PCR, and optimal target cycle threshold values as goals of therapy."

Clinical • Journal • Review • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Combination Therapy With Ensitrelvir and Remdesivir Versus Antiviral Monotherapy in Patients Receiving Anti-CD20 Monoclonal Antibody Therapy: A Retrospective Cohort Study. (PubMed, Cureus) - "Conclusions Combination therapy with ensitrelvir and remdesivir was associated with lower long-term mortality and viral burden in patients with COVID-19 who had received anti-CD20 monoclonal antibody therapy. However, these results are based on a small retrospective cohort and should be interpreted as hypothesis-generating; larger prospective studies are needed to determine whether this association reflects a true therapeutic effect."

Journal • Monotherapy • Retrospective data • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors. (PubMed, Adv Sci (Weinh)) - "The highly conserved 3C-like protease (3CLpro) in coronaviruses, together with the well-established druggability, makes it an ideal target for broad-spectrum antiviral therapeutics. Here, the inhibitory activity of approved 3CLpro inhibitors, including nirmatrelvir, ensitrelvir, and simnotrelvir, against fifteen 3CLpros is first reported by enzymatic assays...Moreover, it effectively inhibits nirmatrelvir-resistant 3CLpro mutants and demonstrates broad-spectrum antiviral efficacy in cells. These findings suggest an important rule that a small, non-cyclic P2 segment and a P4 segment with a suitable size are preferred by the design of ultra-broad-spectrum 3CLpro inhibitors, and provide a proof-of-concept guide for developing broad-spectrum antivirals as potential pan-CoV therapeutics."

Journal • Infectious Disease • Novel Coronavirus Disease

A patent review of Mpro protease inhibitors for the treatment of COVID-19 infections (2020 - present). (PubMed, Expert Opin Ther Pat) - "Clinically advanced agents including nirmatrelvir, ensitrelvir, simnotrelvir, zevotrelvir and leritrelvir are highlighted alongside structurally novel leads and broad-spectrum candidates. A number of Mpro inhibitors have progressed into preclinical and clinical stages, underscoring the rapid advancement in this field. The accumulation of structural knowledge, chemical diversity and mechanistic insight has laid a robust foundation for future antiviral development and may further enhance the utility of Mpro inhibitors against evolving coronaviruses."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • SPECC1

Identification and characterization of a SARS-CoV-2 M pro G23 deletion ensitrelvir-resistant mutant. (PubMed, bioRxiv) - "The clinical use of SARS-CoV-2 antiviral drugs is increasingly challenged by the emergence of drug-resistant mutants. Thus, there is a pressing need to identify and characterize antiviral escape SARS-CoV-2 variants, particularly for FDA-approved antivirals. Our study addresses this by employing a luminescent attenuated virus platform (Δ3a7b-Nluc WT) to safely identify and characterize resistance mutations without the concern of using virulent forms of SARS-CoV-2. Using this safe approach, we have identified a G23 deletion (G23del) in SARS-CoV-2 M pro , which mediates resistance to ensitrelvir in vitro and in vivo . Importantly, while G23del was able to confer more than 1,000-fold increased resistance to ensitrelvir, SARS-CoV-2 containing G23del remained sensitive to other M pro (nirmatrelvir) and RdRp (remdesivir) inhibitors. Altogether, this study demonstrates the feasibility of using Δ3a7b-Nluc to safely identify and characterize drug resistant viruses without the..."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • SPECC1

A SARS-CoV-2 Mpro mutation conferring ensitrelvir resistance paradoxically increases nirmatrelvir susceptibility. (PubMed, Nat Commun) - "Structural analyses reveal critical conformational changes in the catalytic loop (Ile136-Val148) and β-hairpin loop (Cys22-Thr26), directly influencing inhibitor binding selectivity. These results highlight differential resistance profiles of Mpro inhibitors, supporting potential sequential or alternative use of nirmatrelvir and ensitrelvir in patients requiring prolonged antiviral treatment."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Development of a Cell-Based Recombinant Green Fluorescent Protein Assay System for Generalized Discovery of Viral Protease Inhibitors. (PubMed, ACS Pharmacol Transl Sci) - "For proof of concept, we validated this method using two well-characterized SARS-CoV-2 3CLpro inhibitors, GC376 and ensitrelvir, to demonstrate its applicability for inhibitor screening. Our results indicate that the DIFF-rGFP assay is a safe, efficient, and reliable platform for identifying viral protease inhibitors with potential applications in accelerating antiviral drug discovery."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE): Shionogi Protease Inhibitor (Ensitrelvir) (clinicaltrials.gov) - P3 | N=602 | Terminated | Sponsor: University of Minnesota | Active, not recruiting ➔ Terminated; DSMB closed due to futility.

Trial termination • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Coronaviruses main proteases and their inhibitors. (PubMed, Enzymes) - "Recent efforts in drug discovery have led to the development of a wide spectrum of Mpro inhibitors, including covalent peptidomimetics (e.g., nirmatrelvir) and non-covalent small molecules with enhanced pharmacological profiles, such as ensitrelvir. Ongoing research is exploring prodrug strategies, advanced delivery systems, and combinatorial regimens that integrate Mpro inhibitors with other antivirals to achieve synergistic effects and suppress resistance. This chapter provides a comprehensive overview of the current landscape of Mpro-targeted therapeutics and emphasizes their potential role in future pandemic preparedness."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Durations of Fever and Other Symptoms among COVID-19 Outpatients Administered Ensitrelvir During the 2023 Japanese XBB Epidemic Period. (PubMed, J Infect Chemother) - "Ensitrelvir significantly shortened fever and symptom durations in mild to moderate COVID-19 outpatients. Patients with higher fever or more symptoms may benefit, even with repeated COVID-19 vaccination."

Journal • Fatigue • Infectious Disease • Novel Coronavirus Disease • Otorhinolaryngology

Research to evaluate safety and impact of long COVID intervention with Ensitrelvir for National Cohort (RESILIENCE Study): A protocol for a randomized, double-blind, placebo-controlled trial. (PubMed, PLoS One) - "This study was registered with the Japan Registry of Clinical Trials on February 16, 2024 (jRCTs051230184, https://jrct.mhlw.go.jp/en-latest-detail/jRCTs051230184)."

Clinical • Journal • Novel Coronavirus Disease

SAFETY AND EFFICACY OF ENSITRELVIR IN PATIENTS WITH MILD-TO-MODERATE SARS-COV-2 INFECTION: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS (CHEST 2025) - "Ensitrelvir is effective in reducing viral load, especially in the short term compared to placebo. The 125 dose of Ensitrelvir appears to be more effective with fewer adverse effects, making it a potentially safer choice. Although the 250 mg dose may offer slightly greater efficacy, it is associated with a higher risk of adverse events."

Retrospective data • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease • Respiratory Diseases

SARS-CoV-2 Mpro inhibitor ensitrelvir: asymmetrical cross-resistance with nirmatrelvir and emerging resistance hotspots. (PubMed, Emerg Microbes Infect) - "However, the second most frequent substitution, E166H, conferred high resistance to nirmatrelvir, but not to ensitrelvir. This comparative resistance analysis can inform COVID-19 treatment strategies and contribute to pandemic preparedness."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Comparative effectiveness of antiviral treatment on household transmission of SARS-CoV-2: a retrospective cohort study using administrative data. (PubMed, BMC Infect Dis) - "Household transmission rates were not statistically different among three different outpatient oral antiviral agents. Hospitalization was associated with a trend toward lower transmission rates, possibly due to physical isolation."

Clinical • HEOR • Journal • Retrospective data • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases

Beyond ritonavir-boosted nirmatrelvir: the case for ensitrelvir in COVID-19 treatment. (PubMed, Lancet Infect Dis) - No abstract available

Journal • Infectious Disease • Novel Coronavirus Disease

Antiviral efficacy of oral ensitrelvir versus oral ritonavir-boosted nirmatrelvir in COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial. (PubMed, Lancet Infect Dis) - P2 | "Both ensitrelvir and nirmatrelvir accelerate oropharyngeal SARS-CoV-2 viral clearance. Ensitrelvir is an effective alternative to currently available antivirals in treating COVID-19. Although COVID-19 is now generally a mild disease, it still causes substantial morbidity, particularly in vulnerable groups, and new variants or other coronaviruses could still emerge with pandemic potential. Safe effective and affordable antivirals are needed, and these are best assessed initially in pharmacometric platform trials assessing viral clearance."

Journal • P2 data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases