Author: Tachibana, Yuki ; Akiyama, Toshiyuki ; Tanaka, Satoru ; Hirai, Keiichiro ; Nobori, Haruki ; Tomida, Yutaka ; Taoda, Yoshiyuki ; Uehara, Shota ; Nakahara, Kenji ; Unoh, Yuto ; Kato, Teruhisa ; Kawashima, Sho ; Sako, Yusuke ; Sugiyama, Shuichi ; Yamamoto, Shiho

COVID-19, an infectious disease caused by SARS-CoV-2, first identified in Wuhan, China, in 2019 and rapidly spread around the world. In response to this worldwide crisis, the research and development of antiviral drugs advanced together with vaccines, and several medications are currently being used for treatment. This study aimed to explore the structure-activity relationships (SAR) of non-covalent inhibitors of the SARS-CoV-2 3CL protease (3CL^pro) and to develop more potent inhibitors starting from ensitrelvir, a potent non-peptide small-molecule 3CL^pro inhibitor discovered by Shionogi & Co., Ltd. Although a previously reported dihydrofuran-ring-fused tricyclic compound 1 exhibited high antiviral activity, there were issues with its metabolic stability and solubility. Therefore, we focused on compound 2, which has a pyridopyrimidinedione scaffold, and tried to optimize its structure. Here we report compounds that have improved antiviral activity while maintaining enzyme inhibitory activity and enhanced solubility. 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.

19 May 2026·JOURNAL OF VIROLOGY

SARS-CoV-2 3CLpro mutations T21I and E166A confer differential resistance to simnotrelvir, bofutrelvir, and ensitrelvir

Article

Author: Kuang, Wenhua ; Liu, Wen ; Shang, Weijuan ; Shao, Qiang ; Zhang, Yumin ; Zhang, Leike ; Su, Haixia ; Xu, Yechun ; Wang, Chenchen ; Nie, Tianqing ; Chen, Lu

ABSTRACT:

Inhibiting the catalytic activity of 3CLpro is a mainstream strategy to block coronavirus replication. However, the appearance of SARS-CoV-2 3CLpro resistance to protease inhibitors raises concerns for effective therapies. In this work, we first investigated the resistance profile of simnotrelvir, an approved anti-SARS-CoV-2 drug that targets 3CLpro. We found that the T21I/E166A mutations in 3CLpro equally emerged when SARS-CoV-2 was passaged in the HEK293T-hACE2 cells with increasing concentrations of simnotrelvir. The SARS-CoV-2 isolate carrying 3CLpro T21I/E166A (SARS2-T21I/E166A) showed cross-resistance to simnotrelvir, nirmatrelvir, and ensitrelvir, but not significant resistance to bofutrelvir. Biochemical and cellular assays confirmed that 3CLpro T21I/E166A was associated with the differential resistance to these protease inhibitors. Crystallographic structural analysis indicated that the alanine substitution disrupted hydrogen bonding interactions surrounding the γ-lactam rings (P1) of the inhibitors, which is similar to the model rebuilding observed with the previously reported E166V mutation. However, in contrast to the valine substitution, the alanine substitution resulted in a more spacious S2 subsite, thereby causing stronger interaction between the P1 and residues F140 and Ser1 of protomer B. Further computational simulations demonstrated that the covalent binding of bofutrelvir preserves strong binding affinity despite modifications in the S2 subsite caused by the E166A mutation, suggesting that inhibitors containing an aldehyde warhead may partially overcome resistance. Notably, both simnotrelvir and bofutrelvir exhibited therapeutic efficacy against the SARS2-T21I/E166A variant in K18-hACE2 mice. These findings advance our understanding of the resistance profiles and mechanistic underpinnings of SARS-CoV-2 3CLpro and underscore the necessity for diversified antiviral therapeutic strategies.

IMPORTANCE:

Considering that the nirmatrelvir-resistant SARS-CoV-2 has emerged in immunocompromised patients who received long-term Paxlovid therapy, it is essential to investigate the response of resistance 3CLpro mutants to various protease inhibitors. Simnotrelvir, a novel inhibitor targeting SARS-CoV-2 3CLpro, has been authorized for the treatment of mild-to-moderate COVID-19 in China and has treated over 1 million patients. However, the resistance profile of simnotrelvir to SARS-CoV-2 remains unknown. Here, we identified that 3CLpro with T21I/E166A mutations confers resistance to simnotrelvir and showed cross-resistance to nirmatrelvir and ensitrelvir, but not bofutrelvir. More importantly, we further revealed that E166A showed a novel resistance mechanism to both the covalent inhibitors consisting of a γ-lactam ring and non-covalent inhibitors like ensitrelvir, which is different from that of E166V previously reported. In contrast, bofutrelvir maintains high affinity to T21I/E166A, suggesting that inhibitors with aldehyde warhead can partly neutralize the resistance.

02 May 2026·INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES

Impact of Early Oral Antiviral Use for Outpatients With COVID-19 on Healthcare Utilization and Recovery (ANCHOR-02).

Article

Author: Kinoshita, Masahiro ; Murayama, Hiroyuki ; Monma, Eiji ; Yoden, Takahiro ; Morikawa, Nobuyuki ; Nakagawa, Hidemitsu ; Takahashi, Yusaku ; Higa, Hikari ; Shintani, Ayumi ; Nishiguchi, Sho ; Kudo, Naoko ; Maeda, Yohei ; Kakii, Bumpachi ; Asami, Sadaharu ; Hibino, Makoto ; Higashiue, Shinichi

OBJECTIVES:

To evaluate the associations of early-phase oral antivirals with recovery in outpatients with COVID-19, regardless of baseline risk for severe disease, during the SARS-CoV-2 Omicron JN.1-/KP.3-dominant epidemic era.

METHODS:

This nationwide, multi-institutional (51 acute-care hospitals in Japan), prospective, registry-based cohort study enrolled outpatients aged ≥12 years with laboratory-confirmed COVID-19 within 5 days of symptom onset (February 1-October 31, 2024). Participants were compared between those with and without oral antiviral use at enrollment (ensitrelvir, nirmatrelvir, or molnupiravir) for medical re-consultation, failure to return to usual health, and work productivity and activity impairment through Day 28. Analyses were conducted among participants with complete baseline covariates and valid Day 28 outcome assessments and were adjusted for pre-specified baseline covariates.

RESULTS:

Baseline characteristics were generally comparable between groups (efficacy analysis population: antiviral n=2271; no antiviral n=5768). Overall re-consultation rates tended to be lower in the antiviral group (adjusted risk ratio [aRR] 0.93; 95% CI 0.83-1.04). Antiviral use was associated with lower rates of failure to return to usual health (aRR 0.76; 95% CI 0.70-0.82) and with improvements in presenteeism, overall work impairment, and activity impairment.

CONCLUSIONS:

Early-phase oral antiviral use was associated with more favorable patient-reported and functional recovery outcomes, with a trend toward reduced healthcare utilization. These findings may have broader societal implications beyond traditional virological and disease progression endpoints.

News (Medical) associated with Ensitrelvir Fumaric Acid

01 Jun 2026

·www.fiercepharma.com

Shionogi's COVID antiviral Xocova passes muster with FDA as post-exposure preventative

The FDA delivered its green light more than two weeks early, with the agency originally slated to weigh in on Shionogi’s Xocova application by June 16. After a prior misfire in demonstrating its protease inhibitor ensitrelvir’s potential as a COVID-19 treatment for U.S. patients, Shionogi has secured an FDA green light for the medicine in the prevention setting.Sold under the Xocova moniker—and available in Japan since 2022—Shionogi’s oral drug has been cleared for post-exposure prophylaxis (PEP) of COVID-19 in U.S. adults and adolescents ages 12 and older following contact with someone who has COVID.With the FDA's sign-off, Xocova has earned the distinction of becoming the first oral drug approved in the U.S. to protect against COVID after exposure, Shionogi noted in a June 1 press release. The drug is taken over five days, beginning with three tablets on day one and just one tablet on the following four. The FDA delivered its green light more than two weeks early, with the agency originally slated to weigh in on Shionogi’s Xocova application by June 16. Beyond currently approved COVID-19 vaccines from Pfizer-BioNTech, Moderna and Novavax, the U.S. has also cleared antiviral treatments in Pfizer’s Paxlovid, Gilead’s Veklury and Merck & Co.’s Lagevrio, all for treatment after symptom onset. Shionogi’s drug, meanwhile, “has the potential to benefit anyone who does not want to get COVID-19,” Frederick Hayden, M.D., professor emeritus of clinical virology at the University of Virginia School of Medicine, said in the company’s release. Aside from use among households, Xocova could offer an appealing prophylactic option in other exposure incidents, including outbreaks in nursing homes and care facilities, and after travel-related contact, Hayden added. The FDA’s approval hinges on Shionogi’s SCORPIO-PEP trial, in which Xocova curbed the risk of symptomatic COVID-19 by 67% in uninfected people following exposure to someone infected, through 10 days, as weighted against placebo. Shionogi’s trial enrolled 2,387 participants who had a negative local screening test for the SARS-CoV-2 virus and no symptoms at enrollment after being exposed to an infected person in their household. The company’s primary analysis relied on 2,041 household contact participants with a lab-confirmed negative test at baseline. The Osaka-headquartered company noted that its antiviral was generally well tolerated, with headache, diarrhea and cough the most common side effects among patients on Xocova. “Xoxova is the first and only oral option clinically proven to help prevent symptomatic COVID-19 after exposure among study participants regardless of vaccination status or baseline immunity from prior infection,” Nathan McCutcheon, president and CEO of Shionogi’s U.S. arm, said in a statement. With the drug, “people who are exposed to COVID-19 can act early to help protect themselves,” he added. While the heyday of COVID-19 vaccine and drug sales has long waned—as evinced by Pfizer and Moderna’s ongoing earnings pressures—Shionogi feels Xocova still has an important niche to fill as the disease remains highly transmissible. Up to 47% of people who live with someone infected with COVID risk developing it themselves, Shionogi reckons, pointing to CDC estimates that there were some 3.8 million to 12.4 million new COVID cases in the U.S. from the beginning of last October to May 23, 2026. These infections led to hundreds of thousands of outpatient visits, some 240,000 hospitalizations and between 13,000 and 42,000 deaths, according to the data. In Shionogi’s home country of Japan, Xocova also holds a post-exposure prophylaxis approval. The antiviral was originally greenlit under an emergency nod there as a COVID-19 treatment in November 2022 before securing a full approval in that setting in early 2024. The medication is also available in Singapore. With its protection nod, Shionogi has found a new niche in the U.S. market for Xocova, which disappointed in the late-stage SCORPIO-HR trial back in May 2024. In the study, the antiviral failed to chart a statistically significant reduction in time to sustained resolution of 15 common COVID symptoms. That performance caused the study to miss its primary endpoint. Shionogi leadership admitted at the time that the data were mixed, but they stood behind their asset’s potential and pledged to continue working with regulators to make ensitrelvir more broadly available. Shionogi clarified in its approval announcement Monday that Xocova is cleared as a preventative and not on offer as a COVID treatment in the U.S.

Drug ApprovalVaccineEmergency Use AuthorizationClinical Result

01 Jun 2026

·firstwordpharma.com

Biopharma bites: Setbacks for Fulcrum, Praxis, while Shionogi, Moderna make infectious disease strides

Fulcrum ends development of sole clinical candidate, pociredirPraxis' vormatrigine falls short in pivotal seizure studyShionogi gets FDA nod for oral COVID-19 preventativeCEPI promises Moderna up to $50M for Ebola vaccine development Agios nabs Oscotec's SYK inhibitor Fulcrum ends development of sole clinical candidate, pociredirFulcrum Therapeutics' shares crashed close to 50% during after-hours trading on Monday after disclosing it has discontinued its sickle cell disease asset — and only clinical programme — pociredir. The company is planning to launch a comprehensive review to identify any "strategic alternatives" such as a merger, acquisition or business combination.The decision to bin pociredir, an oral small molecule EED inhibitor, was driven by feedback from the FDA. According to Fulcrum, the US regulator had "heightened" concerns about the candidate's risk-benefit profile due to a high rate of secondary haematologic malignancies observed with a mechanistically similar drug, Tazverik (tazemetostat), which Ipsen withdrew from markets in March. Though the two drugs are directed against different targets — pociredir targets EED and Tazverik targets EZH2 — they are both within the PRC2 complex. carries equivalent malignancy risk regardless of the specific subunit engaged.Feedback from the FDA "left no viable regulatory path forward for further clinical development of pociredir," Fulcrum said. The company is now significantly reducing its operating expenses to preserve capital; as of March 31, it had $333.3 million in cash on-hand. Praxis' vormatrigine falls short in pivotal seizure study Praxis Precision Medicines' focal onset seizure (FOS) hopeful vormatrigine has failed the Phase II/III POWER1 study, the company said Monday. The sodium channel inhibitor and functional state modulator did not lead to a statistically significant reduction from baseline in monthly seizure frequency as compared with placebo. Still, the company — whose shares slipped about 10% during after-hours trade Monday — isn't giving up on vormatrigine yet. CEO Marcio Souza said Praxis was "encouraged by the signal we saw on the higher dose arm, the low discontinuation rate and solid safety profile," adding that the drugmaker is taking "some time to review these results to ensure we have the best path forward for developing vormatrigine and the ongoing POWER2 study." The Phase III POWER2 trial is the second registrational study evaluating vormatrigine in adults with FOS; it's expected complete in the second half, with topline results due in 2027.Shionogi gets FDA nod for oral COVID-19 preventativeThe FDA on Monday approved Shionogi's oral antiviral Xocova (ensitrelvir) for post-exposure prophylaxis (PEP) of COVID‑19 in adults and children aged 12 and up to prevent infection after coming into contact with someone who has the disease. The approval, which came ahead of Xocova's June 16 PDUFA date, covers a five-day treatment regimen for the SARS-CoV-2 main protease inhibitor. Three tablets are taken on the first day, following exposure, and one tablet is taken on days two through five. Xocova's green light is based on the results of the Phase III SCORPIO-PEP trial, which involved 2387 participants. The PEP treatment significantly reduced the risk of symptomatic COVID-19 by 67% in uninfected individuals following exposure to an infected individual after 10 days, compared with placebo. According to Shionogi, SCORPIO-PEP is the first and only Phase III study of an oral antiviral to meet the primary endpoint of preventing COVID-19 following exposure.CEPI promises Moderna up to $50M for Ebola vaccine development The Coalition for Epidemic Preparedness Innovations (CEPI) is "urgently" backing the development of three Ebola vaccine candidates to combat the viral disease outbreak in the Democratic Republic of the Congo, committing about $60 million in total to the venture. Moderna said Monday that CEPI has pledged up to $50 million to support preclinical development and Phase I testing of its mRNA vaccine candidate. The funds will also go towards manufacturing so the asset can quickly move into large-scale Phase II/III trials if the early safety and immunogenicity data come back positive. The International AIDS Vaccine Initiative will also receive financial support from CEPI to work on a Bundibugyo vaccine candidate, as will the University of Oxford. Agios nabs Oscotec's SYK inhibitor Agios Pharmaceuticals licensed exclusive, global rights to cevidoplenib, a next-generation, oral spleen tyrosine kinase (SYK) inhibitor, from South Korea-based drugmaker Oscotec. It plans to launch a Phase III trial evaluating the drug in patients with immune thrombocytopenia (ITP) in the first half of 2028."Cevidoplenib is a next-generation SYK inhibitor uniquely designed to potentially offer improved tolerability and durability compared to first-generation SYK inhibitors," Agios CEO Brian Goff said in a company release Monday. "Backed by clinically meaningful Phase II data, we believe cevidoplenib has the opportunity to become a best-in-class treatment option for ITP."Under the deal, Oscotec will receive $25 million upfront and is eligible for up to $140 million in development and regulatory milestones across up to three indications in the US and Europe, as well as commercial milestone payments and royalties ranging from high single-digit to mid-teen. The firm also has an option to license exclusive development and commercialisation rights to cevidoplenib in South Korea after the Phase III trial reads out.

VaccinePhase 3Phase 2Clinical ResultLicense out/in

01 Jun 2026

·www.shionogi.com

(Corrections) Shionogi Announces FDA Approval of XOCOVA® (ensitrelvir), the First and Only Oral Option to Help Prevent COVID-19 Following Exposure

Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.) hereby announces that there have been corrections made to the above-mentioned disclosure material released on June 1, 2026, at 9:20 a.m. (JST). Note that no corrections have been made to numerical data. 1. Details of corrections From page 4 onward, duplicated content in the main text and the References section were identified and has been removed. 2. Reason for corrections This was due to the discovery that certain portions of the disclosed English-language material, including the main text and the References section, contained duplicated content. ・The content, including the main text and the References section, was duplicated throughout the section beginning “OSAKA, Japan, June 1, 2026 – …” on page 4 through to “*Literature search conducted in May 2026” on page 7. ・Reference numbers 19 through 34 were erroneously included. ・The duplicated content from the section beginning “OSAKA, Japan, June 1, 2026 – Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, PhD; hereinafter “Shionogi”) announced that the U.S. Food and Drug Administration (FDA) has approved XOCOVA® (ensitrelvir)” on page 4 through to “*Literature search conducted in May 2026” on page 7 has been removed. ・Reference numbers 19 through 34 have been removed. Please refer to the attached corrected version for the full text Press Release (Corrected Version) Shionogi Announces FDA Approval of XOCOVA® (ensitrelvir), the First and Only Oral Option to Help Prevent COVID-19 Following Exposure 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* XOCOVA offers a new approach to help prevent COVID-19 by blocking viral replication during the critical window between exposure and COVID-19 symptom onset1,2 OSAKA, Japan, June 1, 2026 – Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, PhD; hereinafter “Shionogi”) announced that the U.S. Food and Drug Administration (FDA) has approved XOCOVA® (ensitrelvir), an oral antiviral, for post-exposure prophylaxis (PEP) of COVID‑19 in adults and adolescents 12 years of age and older following contact with an individual who has COVID-19.3 This approval introduces the first and only oral option to help prevent COVID-19 after exposure in the current therapeutic landscape, addressing a critical gap in prevention. XOCOVA is a five-day oral regimen with three tablets taken on day one and one tablet taken on days two through five.3 The approval occurred ahead of the Prescription Drug User Fee Act (PDUFA) action date of June 16, 2026. “The FDA approval of XOCOVA provides an important new approach to preventing COVID-19, which continues to impact lives. COVID-19 can become severe and even when mild or moderate, it can worsen or exacerbate chronic conditions or trigger new ones, including long COVID,” said Frederick Hayden, MD, Richardson Professor Emeritus of Clinical Virology and Professor Emeritus of Medicine, University of Virginia School of Medicine. “Ensitrelvir inhibits viral replication, helping protect people who have been exposed to COVID-19 from developing illness. The PEP strategy has the potential to benefit anyone who does not want to get COVID-19. It could be useful not only in household settings but also in other exposure circumstances, such as outbreaks in nursing homes, chronic or acute care facilities and following travel-related exposures.” The approval is based on positive results from 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.* XOCOVA significantly reduced the risk of symptomatic COVID-19 by 67% in uninfected individuals following exposure to an infected individual through Day 10 compared with placebo(ensitrelvir n=1,030; placebo n=1,011). 3,4 Overall, XOCOVA was generally well tolerated, with similar rates of adverse events across groups (15.1% in the XOCOVA group (n=1,190) and 15.5% in the placebo group (n=1,187)).4 The most common adverse events (regardless of causality) occurring in greater than or equal to 1% of the XOCOVA group and at a greater frequency compared to placebo were headache, diarrhea, and cough. 3 There were no reports of altered taste (dysgeusia) attributed to XOCOVA in the trial.4,5 Results from the SCORPIO-PEP trial were published in the New England Journal of Medicineon May 14, 2026. “The FDA approval of XOCOVA is an exciting new chapter in the Shionogi antiviral story, which includes innovative medicines that have changed the way we manage other viruses including HIV and influenza,” said Nathan McCutcheon, President and CEO, Shionogi Inc. “XOCOVA is the first and only oral option clinically proven to help prevent symptomatic COVID-19 after exposure among study participants regardless of vaccination status or baseline immunity from prior infection. With XOCOVA, people who are exposed to COVID-19 can act early to help protect themselves.” The impact of this matter on the consolidated financial results for the fiscal year ending March 2027 has already been reflected in the earnings forecast announced on May 12, 2026. The Ongoing Impact of COVID-19 COVID-19 remains highly transmissible, driven by Omicron and its subvariants, and up to 47% of people living with an infected individual may develop COVID-19.6 The U.S. Centers for Disease and Control estimates that between October 1, 2025 and May 23, 2026 there were 3.8-12.4 million new cases in the U.S., resulting in 800,000 – 2.3 million outpatient visits, 120,000 – 240,000 hospitalizations and 13,000 - 42,000 deaths.7 Beyond acute infection, COVID-19 can have lasting impacts. People diagnosed with COVID-19 had increased rates of both new and worsening neurologic, cardiovascular, respiratory, and renal conditions during the year following infection.8-17 COVID-19 also disproportionately affects older adults with greater risk for severe illness and death in close-community settings, such as long-term care facilities.18 About SCORPIO-PEP The global, double-blind, randomized, placebo-controlled Phase 3 study, SCORPIO-PEP, assessed the safety and efficacy of XOCOVA as post-exposure prophylaxis for COVID-19. The study included 2,387 study participants aged 12 years and older with a negative local screening test for SARS-CoV-2 infection and no symptoms at the time of enrollment, who were exposed to a person living in their household with symptomatic COVID-19. The primary analysis included 2,041 household contact participants with a central laboratory-confirmed negative SARS-CoV-2 test at baseline. The trial was conducted from June 2023–September 2024. More than 99% of household contacts tested positive for antibodies against SARS-CoV-2 N (nucleocapsid) or S (spike) proteins, indicating that nearly all had evidence of previous SARS-CoV-2 infection or vaccination, or both. Study participants were randomly assigned at a 1:1 ratio to receive XOCOVA (375 mg on day 1 and 125 mg on days 2-5) or placebo, once daily, and began treatment within 72 hours of when the household member with COVID-19 began showing symptoms. Participants then continued XOCOVA (125 mg) or placebo for five days. SCORPIO-PEP is the first and only Phase 3 study of an oral antiviral to meet the primary endpoint of preventing COVID-19 following exposure to an infected individual. About XOCOVA XOCOVA® (ensitrelvir) is a SARS-CoV-2 main protease inhibitor created through joint research between Hokkaido University and Shionogi. SARS-CoV-2 has an enzyme called the main protease, which is essential for the replication of the virus. XOCOVA suppresses the replication of SARS-CoV-2 by selectively inhibiting the main protease. XOCOVA is approved in the U.S. and Japan for post-exposure prophylaxis of COVID‑19 in adults and adolescents 12 years of age and older following contact with an individual who has COVID-19. XOCOVA received emergency regulatory approval in Japan in November 2022 and full approval in March 2024 for the treatment of COVID-19 based on results from SCORPIO-SR, a Phase 3 study conducted in Asia during the Omicron-dominant phase of the pandemic. Results from this study were published in JAMA Network Open. XOCOVA is not approved for the treatment of COVID-19 in the U.S. About Shionogi Inc. Shionogi Inc. is a U.S. subsidiary of Shionogi & Co., Ltd., a global research‑driven pharmaceutical company committed to bringing to market the best possible medicines to aid the health and well-being of the patients we serve. Our global expertise in infectious disease began in the 1950s and in addition to discovering and developing multiple innovative antibiotics, today our global portfolio includes an antibiotic for the treatment of serious Gram‑negative bacterial infections, antivirals for COVID-19, HIV and influenza and a therapeutic for rare fungal infections. Our U.S. infectious disease franchise includes both approved and investigational novel anti-infectives, and investigational antivirals for COVID-19 and RSV. In parallel, we are advancing a U.S. rare disease franchise that includes an approved therapy for amyotrophic lateral sclerosis (ALS), along with clinical programs in Fragile X syndrome, Jordan’s syndrome, and Pompe disease. We are also pursuing research in additional high‑unmet need therapeutic areas, including oncology, acute ischemic stroke, sleep apnea, and other quality of life areas. Learn more at shionogi.com. About Shionogi & Co., Ltd. Shionogi & Co., Ltd. is a 148-year-old global, research-driven pharmaceutical company headquartered in Osaka, Japan, that is dedicated to bringing benefits to patients based on its corporate philosophy of “supplying the best possible medicine to protect the health and wellbeing of the patients we serve.” The company currently markets products in several therapeutic areas including anti-infectives, pain, CNS disorders and cardiovascular diseases. Shionogi’s research and development currently targets two therapeutic areas: infectious diseases and diseases with unmet medical needs in pain/CNS, including Alzheimer’s disease, oncology, rare diseases, and sleep apnea. For more information on Shionogi & Co., Ltd., please visit https://www.shionogi.com/global/en. Forward-Looking Statements This announcement contains forward-looking statements. These statements are based on expectations in light of the information currently available, assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from these statements. Risks and uncertainties include general domestic and international economic conditions such as general industry and market conditions, and changes of interest rate and currency exchange rate. These risks and uncertainties particularly apply with respect to product-related forward-looking statements. Product risks and uncertainties include, but are not limited to, completion and discontinuation of clinical trials; obtaining regulatory approvals; claims and concerns about product safety and efficacy; technological advances; adverse outcome of important litigation; domestic and foreign healthcare reforms and changes of laws and regulations. Also for existing products, there are manufacturing and marketing risks, which include, but are not limited to, inability to build production capacity to meet demand, lack of availability of raw materials and entry of competitive products. The company disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events or otherwise. For Further Information, Contact: U.S. Media: ShionogiCommunications@shionogi.com SHIONOGI Website Inquiry Form: https://www.shionogi.com/global/en/contact.html Shionogi Europe Press Office: pressoffice@shionogi.eu *Literature search conducted in May 2026 References: 1. Kawashima S, Matsui Y, et al. Ensitrelvir is effective against SARS-CoV-2 3CL protease mutants circulating globally. Biochem Biophys Res Commun. 2023;645:132-136. doi:10.1016/j.bbrc.2023.01.040. 2. Kuroda T, Nobori H, et al. Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo. J Antimicrob Chemother. 2023;78(4):946-952. doi:10.1093/jac/dkad027. 3. XOCOVA® (ensitrelvir) Prescribing Information. Available from: https://www.shionogi.com/content/dam/shionogi/si/products/pdf/xocova.pdf. Accessed May 30, 2026. 4. Hayden FG, Shinkai M, et al. Ensitrelvir for COVID-19 postexposure prophylaxis in household contacts. N Engl J Med. 2026;394(19):1905-1915. doi:10.1056/NEJMoa2509306. 5. Hayden FG, Shinkai M, et al. Ensitrelvir for COVID-19 postexposure prophylaxis in household contacts. Supplementary Appendix. N Engl J Med. 2026;394(19). Available from: https://www.nejm.org/doi/suppl/10.1056/NEJMoa2509306/suppl_file/nejmoa2509306_appendix.pdf. 6. Posfay-Barbe KM, Wagner N, et al. SARS-CoV-2 transmission dynamics in households with children, Los Angeles, California. Front Pediatr. 2021;9:752993. doi:10.3389/fped.2021.752993. 7. Centers for Disease Control and Prevention [Internet]. Preliminary estimates of COVID-19 burden for 2024-2025. 2026. Available from: https://www.cdc.gov/covid/php/surveillance/burden-estimates.html. 8. Centers for Disease Control and Prevention [Internet]. Long COVID basics. 2026. Available from: https://www.cdc.gov/long-covid/about/index.html. 9. Xie Y, Xu E, et al. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28(3):583-590. doi:10.1038/s41591-022-01689-3. 10. Xie Y, Xu E, et al. Risks of mental health outcomes in people with COVID-19: a cohort study. BMJ. 2022;376:e068993. doi:10.1136/bmj-2021-068993. 11. Srivastava S, Garg I. Post-COVID-19 infection: long-term effects on liver and kidneys. World J Meta-Anal. 2021;9(3):220-233. doi:10.13105/wjma.v9.i3.220. 12. Tenforde MW, Kim SS, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March-June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(30):993-998. doi:10.15585/mmwr.mm6930e1. 13. Graham EL, Clark JR, et al. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized COVID-19 “long haulers.” Ann Clin Transl Neurol. 2021;8(5):1073-1085. doi:10.1002/acn3.51350. 14. Kwok WC, Chau CH, et al. Outcomes among patients with chronic obstructive pulmonary disease after recovery from COVID-19 infection of different severity. Sci Rep. 2024;14(1):13881. doi:10.1038/s41598-024-64670-9. 15. Conway SE, Healy BC, et al. COVID-19 severity is associated with worsened neurological outcomes in multiple sclerosis and related disorders. Mult Scler Relat Disord. 2022;63:103946. doi:10.1016/j.msard.2022.103946. 16. Chen IW, Chang LC, et al. Association between COVID-19 and the development of chronic kidney disease in patients without initial acute kidney injury. Sci Rep. 2025;15(1):10924. doi:10.1038/s41598-025-96032-4. 17. Sax PE, Draica F, et al. New onset conditions, exacerbations and worsening of underlying conditions following COVID-19 infection [poster presentation]. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 2026; Denver, CO, United States. 18. Gravenstein S, Cooke C, et al. Current impact of COVID-19 in long-term care facilities in the United States: a systematic literature review [poster presentation]. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 2026; Denver, CO, United States.

Phase 3Clinical ResultDrug ApprovalFinancial Statement

100 Deals associated with Ensitrelvir Fumaric Acid

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Approved

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Indication	Country/Location	Organization	Date
COVID-19	Japan	Shionogi & Co., Ltd.	22 Nov 2022

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Phase 2	United States	Shionogi, Inc.	09 Apr 2024
Post Acute COVID 19 Syndrome	Phase 2	United States	Shionogi, Inc.	09 Apr 2024

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT06161688 (PREVAIL-LC, CTgov)	Phase 2	Post Acute COVID 19 Syndrome \| Inflammation	40	Ensitrelvir (Ensitrelvir (S-217622))	oyzjmvmnoe(hvzfjtafgm) = certxxthis cghdwwqfzt (zojtazwbmc, svjaywwupa - kxtgijhyga) View more	-	02 Apr 2026
				Placebo (Placebo)	oyzjmvmnoe(hvzfjtafgm) = qmsyabqywh cghdwwqfzt (zojtazwbmc, zunygaqrgd - ceoputxerl) View more
NCT05041907 (PLATCOV, Pubmed \| Lancet Infect Dis)	Phase 2	COVID-19	604	Ensitrelvir	qurreefrgb(jblecquzgh) = Viral clearance following ensitrelvir was 82% faster (95% credible interval 61-104) than no study drug and 16% slower (5-25) than ritonavir-boosted nirmatrelvir. qfobquecef (rmpsyvddtw )	Positive	01 Feb 2026
				Ritonavir-boosted Nirmatrelvir
NCT05041907 (PLATCOV, Pubmed \| Lancet Infect Dis)	Phase 2	COVID-19	604	Ensitrelvir	hkwczbhayu(ldrfztunoq) = Viral clearance following ensitrelvir was 82% faster (95% credible interval 61-104) than no study drug and 16% slower (5-25) than ritonavir-boosted nirmatrelvir. arodrpioot (guweeidasi )	Positive	01 Oct 2025
				Ritonavir-boosted Nirmatrelvir
NEWS Manual	Not Applicable	COVID-19	-	Ensitrelvir	xheazilzsy(burnrjllfh) = zlusmuncot mmygwplqdl (rpdqavxjjh ) View more	Positive	20 Mar 2025
				Placebo	xheazilzsy(burnrjllfh) = vsmjektsdc mmygwplqdl (rpdqavxjjh ) View more
NCT05897541 (SCORPIO-PEP, Company_Website) Manual	Phase 3	COVID-19	-	Ensitrelvir	jcniibpxfv(akewbioddv) = omwolsncvz jmwogeanqq (jwgmkoorek ) Met View more	Positive	17 Mar 2025
				Placebo	jcniibpxfv(akewbioddv) = jgeqllojax jmwogeanqq (jwgmkoorek ) Met View more
NCT05305547 (SCORPIO-HR, Pubmed \| Clin Infect Dis)	Phase 3	COVID-19	1,888	Ensitrelvir	osleodnciy(inadfakrpw) = xlgyqdvygl pexngkdxzi (ldlvezjxkt ) View more	Negative	17 Feb 2025
				Placebo	osleodnciy(inadfakrpw) = oaqupklsse pexngkdxzi (ldlvezjxkt ) View more
NCT05305547 (SCORPIO-HR, Pubmed \| NEWS)	-	COVID-19	2,093	Ensitrelvir	rjvlvzshaf(dkbgefyyaf) = yckqauewwb niknvrieac (guuuirigch )	Negative	13 May 2024
				安慰剂	rjvlvzshaf(dkbgefyyaf) = hbdljccnfu niknvrieac (guuuirigch )

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