Xocova (ensitrelvir) / Shionogi - LARVOL DELTA

SCORPIO-PEP: Phase 3 Study of S-217622 in Prevention of Symptomatic SARS-CoV-2 Infection (clinicaltrials.gov) - P3 | N=3701 | Completed | Sponsor: Shionogi | N=2387 ➔ 3701

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

Reduction of Infectious SARS-CoV-2 and Viral Titer with Ensitrelvir: A Pooled Analysis of SCORPIO-SR and SCORPIO-HR Trials (IDWeek 2026) - No abstract available

Retrospective data • Infectious Disease • Novel Coronavirus Disease

Brain Microstructural Disorganization as a Potential Mechanism of post-COVID-19 Condition and the Onset-suppressive Effects of Ensitrelvir Revealed by Advanced Diffusion MRI–based Translational Research (IDWeek 2026) - No abstract available

Metastases • Infectious Disease • Novel Coronavirus Disease

Ensitrelvir Suppresses Fatigue-like Symptoms Derived from SARS-CoV-2 Infection in Hamsters (IDWeek 2026) - No abstract available

Infectious Disease • Novel Coronavirus Disease

Early Pre-Symptomatic Treatment with Ensitrelvir Among PCR-Positive, SARS‑CoV‑2–Exposed and Infected Household Contacts: SCORPIO‑PEP Subpopulation Analysis (IDWeek 2026) - No abstract available

Clinical • Infectious Disease • Novel Coronavirus Disease

Ensitrelvir for Covid-19 Postexposure Prophylaxis. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • Infectious Disease • Novel Coronavirus Disease

Ensitrelvir for Covid-19 Postexposure Prophylaxis. (PubMed, N Engl J Med) - No abstract available

Journal • Infectious Disease • Novel Coronavirus Disease

Dimerization and Ligand Binding Rewire Allosteric Networks in SARS-CoV-2 Main Protease. (PubMed, Biophys J) - "For each of these states, we simulated MPro in the apo state, as well as bound to a natural peptide substrate (nsp 15/16), the covalent inhibitor nirmatrelvir (Paxlovid) and the noncovalent inhibitor ensitrelvir (Xocova). Together, these findings define how correlated motion networks couple active-site dynamics to dimerization and ligand binding, providing molecular insight into the principles governing allosteric regulation in MPro. This framework highlights potential avenues for developing antivirals that target not only the catalytic site but also the communication pathways sustaining dimer stability and enzymatic function."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

XOCOVA® (ensitrelvir). (PubMed, Clin Ther) - No abstract available

Journal

Slowly exchanging bound states of SARS-CoV-2 3CLpro-inhibitor complexes revealed by 19F NMR. (PubMed, Struct Dyn) - "Using 19F NMR spectroscopy, we characterize a slow-exchange conformational equilibrium in both the covalent nirmatrelvir (NMV) and noncovalent ensitrelvir (ENS) complexes of 3CLpro. These dynamics are not readily explained by available crystal structures or conventional microsecond molecular dynamics simulations, suggesting that in solution the inhibited enzyme samples alternative, energetically accessible conformations that are not fully represented in the crystal lattice. This study highlights the utility of solution-state 19F NMR for quantifying low-energy conformational states relevant to drug-target energetics and inhibitor design."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A phase 3 Study of ensitrelvir in japanese participants aged 6-11 years with SARS-CoV-2 infection. (PubMed, J Pediatric Infect Dis Soc) - "In children aged 6 to <12 years with mild-to-moderate COVID-19 treated with ensitrelvir, we observed a favorable safety profile, adult-matched plasma concentration-time profile, and a greater reduction in viral RNA vs placebo. Ensitrelvir represents a potential treatment option for underserved pediatric patients with mild-to-moderate COVID-19."

Journal • P3 data • Cough • Infectious Disease • Novel Coronavirus Disease • Pediatrics • Respiratory Diseases

Structural basis for the inhibition of HKU8 main protease by nirmatrelvir and ensitrelvir. (PubMed, Biochem Biophys Res Commun) - "These findings provide crucial information on the effectiveness of Mpro-targeting antivirals cross different species and highlight the S2 subsite as a key determinant for their activity. It may help the design of next-generation broad-spectrum antivirals against CoVs."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Ensitrelvir in hospitalized patients with COVID-19 who were moderately to severely immunocompromised: a single-center cohort study. (PubMed, Ther Adv Infect Dis) - "IPTW-adjusted 28-day mortality was 4.2% with ensitrelvir and 10.7% with remdesivir (hazard ratio 0.39; 95% CI 0.04-3.64). In this small, single-center exploratory cohort, ensitrelvir was associated with low mortality, although comparison with remdesivir should be interpreted cautiously given treatment selection, treatment switching, and limited sample size."

Journal • Immunology • Infectious Disease • Novel Coronavirus Disease

Ensitrelvir. (PubMed, Am J Health Syst Pharm) - No abstract available

Journal

Ensitrelvir (Xocova) for post-exposure prophylaxis of COVID-19. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Infectious Disease • Novel Coronavirus Disease

Efficacy and safety of Ensitrelvir in COVID-19 patients: a systematic review and meta-analysis with focus on viral clearance and RNA change. (PubMed, Eur J Clin Pharmacol) - "This systematic review and meta-analysis support Ensitrelvir efficacy and safety in promoting rapid viral clearance and greater reduction in viral RNA in mild-to-moderate or asymptomatic COVID-19 patients, justifying its integration into outpatient treatment protocols while emphasizing the need for further large-scale, variant-inclusive studies to validate and extend these findings."

Clinical • Journal • Retrospective data • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Decoding Enzyme-Inhibitor Kinetic Mechanisms by Isothermal Titration Calorimetry: The Case of SARS-CoV-2 3CLpro. (PubMed, Anal Chem) - "The inhibition of SARS-CoV-2 main protease (3CLpro) with ML300, X77, Nirmatrelvir, and Ensitrelvir was used as a benchmark. Equilibrium ITC binding measurements on wild-type and mutant 3CLpro variants provided independent validation, revealing distinct affinity and thermodynamic parameters that complemented the inferred inhibitory pathway. These results establish inverse single-injection kinetic ITC as a robust and versatile analytical platform for dissecting complex enzyme inhibition mechanisms, supporting the rational optimization of next-generation SARS-CoV-2 3CLpro inhibitors, and offering broad applicability in drug discovery."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

PRISM-Gen: A physics-informed multi-fidelity framework for broad-spectrum coronavirus mpro inhibitor discovery. (PubMed, Comput Biol Chem) - "Applied to 4136 generated candidates, the pipeline identifies 36 broad-spectrum-consistent inhibitor candidates whose top-ranked members exhibit predicted worst-case binding energies comparable to those of the non-covalent reference inhibitor ensitrelvir under identical docking conditions, while sharing no Bemis-Murcko scaffolds with nirmatrelvir, ensitrelvir, or GC376. Retrospective analysis demonstrates that replacing GEM's continuous moderation with a conventional hard electronic cutoff would eliminate 48.0% of candidates, including 55.6% of the final 36 molecules, disproportionately depleting scaffold diversity. These results establish that continuous, physics-informed electronic moderation integrated within a multi-fidelity generative pipeline can recover structurally novel chemotypes that binary exclusion filters would irreversibly discard - a design principle applicable to generator-agnostic molecular discovery workflows."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Matching-adjusted comparison of the effectiveness and safety of Ensitrelvir versus Remdesivir for high-risk, hospitalized patients with non-severe COVID-19 in Japan. (PubMed, J Infect Chemother) - "In this multicenter cohort of hospitalized high-risk patients with mild to moderate COVID-19 able to receive oral therapy, no significant differences were observed between ESV and RDV in the matched cohort of patients with mild disease. ESV may represent a feasible oral alternative in selected high-risk patients able to receive oral therapy."

Journal • Infectious Disease • Novel Coronavirus Disease

Identification and characterization of a SARS-CoV-2 Mpro G23 deletion ensitrelvir-resistant mutant. (PubMed, mBio) - "Importantly, while G23del was able to confer ~1,000-fold increased resistance to ensitrelvir, a Δ3a7b-Nluc containing G23del remained sensitive to other Mpro (nirmatrelvir) and RdRp (remdesivir) inhibitors. Altogether, this study demonstrates the feasibility of using Δ3a7b-Nluc WT to safely identify and characterize drug-resistant viruses without the biosafety concern of using virulent WT SARS-CoV-2 and advance the design of next-generation antiviral drugs."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Shionogi Announces FDA Approval of XOCOVA (ensitrelvir), the First and Only Oral Option to Help Prevent COVID-19 Following Exposure (Businesswire) - "Approval is based on SCORPIO-PEP, the only Phase 3 study of an oral antiviral to meet the primary endpoint of preventing symptomatic COVID-19 following exposure to an infected individual...The approval occurred ahead of the Prescription Drug User Fee Act (PDUFA) action date of June 16, 2026."

FDA approval • Novel Coronavirus Disease

Successful Management of Severe COVID-19 in a Kidney Transplant Recipient Safe Co-Administered Tacrolimus and Ensitrelvir: A Case Report. (PubMed, Reports (MDPI)) - "Case Presentation: The patient had been taking tacrolimus (TAC) (2.5 mg/day), mycophenolate mofetil (1000 mg/day), and prednisone (5 mg/day) since his kidney transplant 7 years earlier. Twenty days before admission, he tested positive for SARS-CoV-2 antigen and was administered molnupiravir for 5 days...Combination therapy of ESV and TAC was feasible in kidney transplant recipients with dose adjustment. The use of other anti-inflammatory drugs should also be considered."

Journal • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • Transplantation • IL6R

Cross-resistance patterns in SARS-CoV-2 against 3CL protease inhibitors. (PubMed, Nat Commun) - "Here, we report the pathways to resistance for atilotrelvir and simnotrelvir, two 3CL protease inhibitors used for COVID-19 treatment, and ibuzatrelvir, a compound in late-stage clinical development...Moreover, viral inhibition assays demonstrate that there is not only strong cross-resistance between the emerged viruses against these three molecules, but also against two additional widely used antivirals, nirmatrelvir and ensitrelvir, as well. Cellular assays highlight S144A, E166A, and E166V as mediating broad resistance, with E166V having the strongest effects. These results have important clinical implications, including the need to carefully consider cross-resistance properties in salvage therapy and combination treatment, as well as emphasizing the need for the further development of SARS-CoV-2 antivirals with differing modalities."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Early-Phase Oral Antiviral Use and Post-COVID-19 Condition in Outpatients. (PubMed, JAMA Netw Open) - "Oral antiviral use (ensitrelvir, nirmatrelvir, or molnupiravir) at enrollment vs no antiviral use. In this cohort study of outpatients with COVID-19, early oral antiviral use was associated with a lower risk of PCC. These findings suggest that early antiviral treatment may help mitigate long-term consequences of SARS-CoV-2 infection."

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

Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts. (PubMed, N Engl J Med) - P3 | "Ensitrelvir administered to household contacts of a patient with Covid-19 within 72 hours after symptom onset in the index patient was effective in preventing Covid-19 in the contacts. (Funded by Shionogi; SCORPIO-PEP Japan Registry for Clinical Trials number, jRCT2031230124; ClinicalTrials.gov number, NCT05897541.)."

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