Hokkaido University

OSAKA, Japan, May 17, 2023 - Shionogi & Co., Ltd. (Head Office: Osaka, Japan; President and CEO: Isao Teshirogi, Ph.D.; hereinafter “Shionogi”) today announced the initiation of a Phase 1 clinical trial in Japan of S-892216, an investigational agent which is being developed as an antiviral against COVID-19, caused by SARS-CoV-2 infection. The first dose in this Phase 1 clinical trial was administered successfully and no safety concerns have been identified. S-892216 is a 3CL protease inhibitor discovered by Shionogi and its research and development is supported by Japan Agency for Medical Research and Development (AMED) under Grant Number JP21fk0108584. In addition to S-892216, Shionogi continues its extensive global development program for the novel COVID-19 oral antiviral ensitrelvir (generic name: ensitrelvir fumaric acid, Code No.: S-217622), known as Xocova® 125 mg tablet in Japan. 1-5In pre-clinical trials, S-892216 demonstrated strong antiviral effect as well as ensitrelvir. In the Phase 1 clinical trial, Shionogi will evaluate the pharmacokinetics, safety, and tolerability of this agent in healthy adults. Since the start of the COVID-19 pandemic, the emergence of new variants has often signaled the onset of a new wave of infection worldwide.6,7While the rate of severe cases of COVID-19 leading to hospitalization has decreased due to vaccination programs, natural immunity and possibly less virulent variants, COVID-19 remains an ongoing health concern and future waves of infection are likely.6,8-12Therefore, the development of additional antiviral drugs is needed. 13Shionogi is committed to the principle “Protecting people worldwide from the threat of infectious diseases” as our key focus, and is working on the realization of total care for infectious diseases. Shionogi will seek to contribute to re-establishing the safety and security of society by developing new products and services to address COVID-19, which continues to affect many individuals around the world, and continue to focus on research and development for COVID-19 so as to be prepared for the swift provision of therapeutic drugs and vaccines as necessary depending on the situation, such as the emergence of new variants or the future prevalence of the disease. Ensitrelvir (known in Japan as Xocova®), an oral antiviral drug for COVID-19 currently approved under the emergency regulatory approval system in Japan, is a 3CL protease inhibitor created through joint research between Hokkaido University and Shionogi. SARS-CoV-2 has an enzyme called 3CL protease, which is essential for the replication of the virus. Ensitrelvir suppresses the replication of SARS-CoV-2 by selectively inhibiting 3CL protease. Ensitrelvir is the first antiviral agent to show both clinical symptomatic efficacy for five typical Omicron-related symptoms (primary endpoint) and antiviral efficacy (key secondary endpoint) in a predominantly vaccinated population of patients with mild to moderate SARS-CoV-2 infection, regardless of risk factors, in the Phase 3 part of the Phase 2/3 study conducted during the Omicron-dominant phase of the epidemic. With regard to safety, most adverse events were mild in severity and no deaths were seen in the study. Among the most common treatment-related adverse events were temporary decreases in high-density lipoprotein and increased blood triglycerides, as observed in previous studies. Currently, the Phase 2b/3 part of the Phase 2/3 study targeting SARS-CoV-2 infected persons who were asymptomatic or only had mild symptoms is being conducted in Asia, mainly in Japan. Recently, the U.S. Food and Drug Administration (FDA) grantedFast Trackdesignation to ensitrelvir for COVID-19. FDAFast Trackdesignation is designed to facilitate the development and expedite the review of potential new therapies that treat serious conditions and fulfill an unmet medical need. Ensitrelvir remains an investigational drug outside of Japan and has not been approved outside of Japan. In addition, the brand name Xocova® has not been approved for use outside of Japan and pertains only to the approved drug in Japan. SHIONOGI Website Inquiry Form :https://www.shionogi.com/global/en/contact.html

Shionogi’s once-daily 3CL protease inhibitor hit on a primary endpoint in a late-stage trial as a post-exposure prophylaxis treatment for Covid-19 after failing a Phase 3 study in May. The oral antiviral, ensitrelvir, showed a statistically significant decrease in the proportion of patients with a symptomatic infection through 10 days after being exposed to household members with Covid-19 when compared to placebo. The company described the drug as well-tolerated with no new safety signals. Shionogi’s senior VP and head of clinical development Simon Portsmouth said in a statement that “there are currently no oral antiviral medications approved for post-exposure prophylactic use,” adding that “there is a need for convenient, preventive approaches to protect ourselves and those close to us from contracting SARS-CoV-2.” Ensitrelvir, marketed as Xocova and developed in a joint research collaboration with Hokkaido University, scored an emergency regulatory approval in Japan in 2022 before garnering a full approval in March for the treatment of Covid-19. But the drug failed in the NIH-partnered SCORPIO-HR study when it didn’t show a statistically significant reduction in patients being completely clear of symptoms for at least two days when the drug was given within three days of symptoms starting. However, a separate analysis showed that patients had no sign of six different symptoms for at least one day, earning a p-value of 0.05 compared to placebo. The trial showed other positives, according to the company, including a reduction from baseline in viral RNA levels and no symptomatic viral rebounds in patients.

OSAKA, Japan, June 28, 2024 - Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.; hereafter "Shionogi") announced that the newly obtained clinical data for the novel COVID-19 oral antiviral Xocova® (generic name: ensitrelvir fumaric acid, Code No.: S-217622, hereafter “ensitrelvir”) was presented at the joint conference of the 98th Annual Meeting of the Japanese Association for Infectious Diseases and the 72nd Annual Meeting of the Japanese Society of Chemotherapy, held in Japan from June 27 to 29, 2024. The summary of two new data presented at the conference is as follows. Real-world effectiveness of ensitrelvir in reducing severe outcomes in outpatients at high-risk for COVID-19 progression This was a retrospective study using the JMDC Claims Database (JMDC Inc., Tokyo, Japan), a large Japanese health insurance claims database. The study included 167,310 outpatients aged ≥18 years, who were at high-risk for severe desease and received their first COVID-19 diagnosis between November 2022 and July 2023. The primary endpoint was all-cause hospitalization during the 4-week period from the date of outpatient diagnosis and medication, comparing the ensitrelvir group and the no antiviral treatment group. As a result, the incidence of hospitalization from all causes was statistically lower by approximately 37% in the ensitrelvir group than those receiving no antiviral treatment (: 0.494% vs. 0.785%; Risk Ratio: 0.629, 95% CI: 0.420 to 0.943; The risk difference: −0.291, 95% CI: −0.494 to −0.088). These results suggest that ensitrelvir may be an effective treatment option for patients at high-risk of severe COVID-19 not only in Phase2/3 clinical trials in Japan but also in the real world, where vaccination has become widespread and the Omicron strain is prevalent. “Currently, the predominant strain of COVID-19 is the Omicron variant, and although the severity rate has decreased, there are still many patients, especially among the elderly, who become seriously ill and are hospitalized.”, said Dr. Hiroshi Mukae, Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan. “This study provides strong evidence suggesting the efficacy of ensitrelvir in reducing severe outcomes among high-risk COVID-19 patients based on real-world clinical data during the Omicron variant outbreak. However, further prospective studies are needed to confirm these findings. Early administration of ensitrelvir, which has potent antiviral effects, is expected to mitigate severe COVID-19 in high-risk patients.” This manuscript has has been published in the international peer-reviewed journal ‘Infectious Diseases and Therapy’. Safety and Effectiveness of Ensitrelvir for the Treatment of COVID-19 in Japanese Clinical Practice: Final Analysis Report from a Post-Marketing Surveillance This report was new data evaluating the effectiveness and tolerability of ensitrelvir in clinical practice in Japan. Following emergency regulatory approval from the MHLW in Japan, an ongoing post-marketing surveillance study enrolled a total of 4,125 patients. Of these patients, 3,760 were evaluated for safety and 3,638 for effectiveness. The summary of the tally is as follows. Safety: • Treatment-related adverse events were observed in 271 patients (7.2%), with the common treatment-related adverse events being diarrhea in 91 patients (2.4%), nausea in 43 patients (1.1%), and headache in 42 patients (1.1%). • Serious adverse events occurred in 3 patients (5 events) (headache, nausea, vomiting, cold sweats, generalized edema), all of which resolved within 5 days. • No occurrence of the specific identified risk anaphylaxis was confirmed. Effectiveness: • After administration of ensitrelvir, the median time to fever resolution was about 1.5 days (36.0 hours), and the median time to complete symptom disappearance was about 6.5days (156.0 hours). • Within 28 days of starting ensitrelvir treatment, 14 patients (0.4%) required hospitalization, of which 10 were due to worsening of COVID-19. • There were 2 deaths (0.1%), both believed to be related to incidental events or underlying conditions/complications. These results provide important additional evidence to the clinical trial programme by demonstrating the effectiveness of ensitrelvir in the real-world among a diverse and large group of patients. Further, these findings provide important evidence supporting the safety profile observed in the clinical trial programme. About ensitrelvir Ensitrelvir is a 3CL protease inhibitor created through joint research between Hokkaido University and Shionogi. SARS-CoV-2 has an enzyme called 3CL protease, which is essential for the replication of the virus. Ensitrelvir suppresses the replication of SARS-CoV-2 by selectively inhibiting the 3CL protease. Known as Xocova® in Japan, ensitrelvir received emergency regulatory approval in 2022 and full approval in March 2024. Ensitrelvir was approved in Singapore in November 2023 based on the Special Access Route application. Ensitrelvir remains an investigational drug outside of Japan and Singapore. In addition, the brand name Xocova® has not been approved for use outside of Japan and Singapore and pertains only to the approved drug in Japan and Singapore. About the ensitrelvir clinical program Shionogi has a robust clinical development program for ensitrelvir and is committed to making it available to populations worldwide. Shionogi evaluated the safety and efficacy of ensitrelvir through SCORPIO-SR, during the Omicron-dominant phase of the epidemic. The data from this study were recently published in JAMA Network Open. Additionally, an investigator-initiated research study is ongoing in hospitalized patients for the management of COVID-19 as part of the new Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE) platform protocol. STRIVE was developed under the auspices of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership. A further study, SCORPIO-PEP, is evaluating the safety and efficacy in the prevention of symptomatic SARS-CoV-2 infection when exposed to household contacts who are symptomatic and tested positive for SARS-CoV-2. Lastly, Shionogi is studying the safety and efficacy of ensitrelvir in Japan for children between the ages of 6 to 11 years old. About Shionogi in Infectious Disease Shionogi is committed to “Protect people worldwide from the threat of infectious diseases” with research and development of therapeutics, whilst also working towards total care through awareness building, epidemiologic monitoring, prevention, diagnosis, and addressing exacerbations, as well as treating infections directly. As SARS-CoV-2 continues to have a major impact on people’s lives and to represent a global threat, Shionogi will seek to contribute to re-establishing the safety and security of society by developing new products and services to address this pandemic. Shionogi is committed to equitable access worldwide, including by working with the Medicines Patent Pool to provide access to low- and middle-income countries (LMICs), and by strengthening its manufacturing and global supply chain. 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: SHIONOGI Website Inquiry Form: https://www.shionogi.com/global/en/contact.html