Xocova (ensitrelvir) / Shionogi - LARVOL DELTA

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

The Same and Not the Same: Discovery of S-892216, A Second-Generation Nonpeptidic Covalent 3CL Protease Inhibitor for Oral COVID-19 Therapeutics. (PubMed, J Med Chem) - "Targeting the 3CLpro main protease has been successful in identifying clinical agents; however limited options exist, and improvements are still required to have broader clinical utility. Utilizing the established central scaffold to develop ensitrelvir, both noncovalent and covalent modes of action were leveraged using structural knowledge to identify S-892216 as a potential best-in-class reversible covalent nonpeptidic 3CLpro inhibitor with a superior preclinical profile for treatment of COVID-19 and future pandemic preparedness."

Journal • Infectious Disease • Novel Coronavirus Disease

Clinical rebound after ensitrelvir treatment for COVID-19 (ERS 2025) - "While clinical rebound rates for similar agents, such as nirmatelvir/ritonavir, have been reported to range from 6% to 24%, clinical rebound rates associated with ensitrelvir are unclear. Clinical rebound of COVID-19 after ensitrelvir treatment is rare, likely due to its long plasma half-life, and is generally mild with favorable outcomes."

Clinical • Cardiovascular • Diabetes • Hypertension • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease

Design, synthesis and biological evaluation of novel quinazolinedione derivatives as non-covalent SARS-CoV-2 3CL protease inhibitors. (PubMed, Bioorg Med Chem Lett) - "With the aim of creating novel non-covalent 3CLpro inhibitors, we planned a scaffold hopping transformation starting with ensitrelvir, which was discovered by Shionogi...The newly discovered compound has shown good results in terms of metabolic stability and oral absorption in rat PK studies. It is expected to be a good lead compound for finding superior 3CLpro inhibitors."

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 | Active, not recruiting | Sponsor: University of Minnesota | Recruiting ➔ Active, not recruiting | N=1500 ➔ 602

Enrollment change • Enrollment closed • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Ensitrelvir suppresses prolonged olfactory abnormalities derived from SARS-CoV-2 infection in hamsters. (PubMed, Antiviral Res) - "In conclusion, our study indicates that chronic inflammation may occur in the nasal turbinates over a long period post-SARS-CoV-2 infection, leading to smell disorder onset in a hamster model. Early ensitrelvir treatment post-infection suppressed inflammation in the nasal turbinates and prevented smell disorder onset."

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

Efficacy of Oral Antivirals and Combination Therapy with Remdesivir in Hematological Patients with COVID-19. (PubMed, J Infect Chemother) - "Nir/Rit and Ens may exhibit superior antiviral efficacy compared to RDV in COVID-19 patients with underlying hematological malignancies. Combination therapy needs to be considered for patients with high risk of severe disease or persistent infection, and in cases where a rapid therapeutic response is urgently required for the management of the underlying malignancy."

Journal • Hematological Disorders • Hematological Malignancies • Infectious Disease • Novel Coronavirus Disease • Oncology

Ensitrelvir (ESV) Population Pharmacokinetics (PK) in Nonhospitalized Adults with COVID-19 (IDWeek 2025) - No abstract available

Clinical • PK/PD data • Infectious Disease • Novel Coronavirus Disease

Clearance of Infectious Virus in COVID-19 Patients Treated with Ensitrelvir Across Vaccination Status, Age, and Risk Subgroups: Exploratory Analyses from the SCORPIO-HR Study (IDWeek 2025) - No abstract available

Clinical • Infectious Disease • Novel Coronavirus Disease

FDA Accepts Shionogi’s Ensitrelvir NDA as the First Oral Therapy for the Prevention of COVID-19 Following Exposure (Businesswire) - "The FDA has set an action date of June 16, 2026 under the Prescription Drug User Fee Act (PDUFA)....The NDA is supported by results from the global, double-blind, randomized, placebo-controlled Phase 3 Study, SCORPIO-PEP, which studied ensitrelvir as post-exposure prophylaxis (PEP). If approved, ensitrelvir would be the first and only oral therapy for the prevention of COVID-19 following exposure to an infected individual."

FDA filing • PDUFA • Novel Coronavirus Disease

Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE): Shionogi Protease Inhibitor (Ensitrelvir) (clinicaltrials.gov) - P3 | N=1500 | Recruiting | Sponsor: University of Minnesota | Trial completion date: Jul 2025 ➔ Dec 2025 | Trial primary completion date: Jul 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

CROI 2025: Acute and Postacute COVID-19. (PubMed, Top Antivir Med) - "Results of the SCORPIO-PEP (Stopping COVID-19 Progression With Early Protease Inhibitor Treatment-Postexposure Prophylaxis) study indicated that the protease inhibitor ensitrelvir is effective for postexposure prophylaxis...In addition, numerous studies improved our understanding of the long-term consequences of SARS-CoV-2 infection, including immunologic, metabolic, cardiovascular, neurologic, and other clinical sequelae. The application of new and more specific case definitions in research studies of long COVID provided new insights into the epidemiology and pathogenesis of this condition, although data on therapeutics from randomized clinical trials are still lacking."

Clinical • Journal • Cardiovascular • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Efficacy and safety of Ensitrelvir in asymptomatic or mild to moderate COVID-19: a systematic review and meta-analysis of randomized controlled trials. (PubMed, Infection) - "Ensitrelvir effectively reduces viral load in COVID-19 patients, but its safety profile raises concerns due to significant adverse effects. The benefits must be carefully weighed against the risks, and further research is needed to confirm its role in treatment and to find ways to mitigate these adverse effects."

Journal • Retrospective data • Review • Hypertriglyceridemia • Infectious Disease • Novel Coronavirus Disease • Pain • Respiratory Diseases