Fujita Health University

The trial met its primary and key secondary endpoints, making ensitrelvir the first antiviral agent to show both clinical symptom improvement and antiviral effect in a predominantly vaccinated population with Omicron infection. The study found that once-daily administration of ensitrelvir led to a statistically significant reduction in the time to resolution of five typical COVID-19 symptoms characteristic of Omicron, runny nose, sore throat, cough, fever and tiredness, versus placebo. More than 90% of patients in the trial had received two or more doses of the SARS-CoV-2 vaccine and patients were included regardless of risk factors for severe disease. “We’re pleased to present the data from our Phase 3 study conducted in Asia in this peer-reviewed article. These results demonstrate accelerated resolution in a range of symptoms, reinforcing the potential of ensitrelvir across multiple patient profiles,” said Takeki Uehara, senior vice president, drug development and regulatory science at Shionogi. “Additionally, ensitrelvir reduced viral RNA levels and time to first negative viral titer, suggesting it could help reduce transmission of SARS-CoV-2. This study was conducted in a largely vaccinated population that included patients infected with Omicron. The patients also had varying risk factors for severe disease. This is relevant as there is a lack of data and a need for additional treatment options for this population.” Known as Xocova in Japan, ensitrelvir received emergency regulatory approval from the Ministry of Health, Labour and Welfare in Japan for the treatment of SARS-CoV-2 infection back in 2022. googletag.cmd.push(function () { googletag.display('text-ad1'); }); In addition, the therapy was approved in Singapore in November 2023, based on the Special Access Route application, but remains an investigational drug outside of Japan and Singapore. Ensitrelvir was also granted Fast Track designation by the U.S. Food and Drug Administration. Despite vaccines and some therapeutics available to treat COVID-19, the World Health Organization has emphasized that more treatment options are still needed for the disease. “We continue to see COVID-19 surges and we need additional treatment options for more patients, irrespective of risk factors for severe disease, as the virus continues to evolve, adapt, infect and re-infect people across the world,” said Yohei Doi, professor of Medicine, Fujita Health University, Japan, and one of the study authors. “Seeing the comprehensive data from the study in Asia signals that ensitrelvir has promising potential to treat patients with many common COVID-19 symptoms.”

OSAKA, Japan--( BUSINESS WIRE )--Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.; hereafter “Shionogi”) announced the first peer-reviewed publication of the Phase 3 portion of its pivotal, double-blind, randomized, placebo-controlled Phase 2/3 study (SCORPIO-SR) in patients with mild to moderate COVID-19 in Japan, South Korea and Vietnam in JAMA Network Open. The trial met its primary and key secondary endpoints, making ensitrelvir (Generic name: ensitrelvir fumaric acid, Code No.: S-217622, hereafter “ensitrelvir”) the first antiviral agent to show both clinical symptom improvement and antiviral effect in a predominantly vaccinated population with Omicron infection regardless of risk factors.* The publication reports that treatment with once-daily ensitrelvir in the primary analysis population led to a statistically significant reduction in the time to resolution of five typical COVID-19 symptoms characteristic of Omicron (runny/stuffy nose, sore throat, cough, feeling hot or feverish, and low energy/tiredness 1 ) versus placebo (p=0.04). The median time to symptom resolution was approximately one day shorter in the 125 mg ensitrelvir group versus placebo (approximately 7 days versus 8 days, respectively). 1 Patients included in the primary analysis population were randomized less than 72 hours from symptom onset. 1 More than 90% of patients had received two or more doses of the SARS-CoV-2 vaccine and patients were included regardless of risk factors for severe disease. 1 Known as Xocova ® in Japan, ensitrelvir received emergency regulatory approval from the Ministry of Health, Labour and Welfare in Japan for the treatment of SARS-CoV-2 infection in 2022. Ensitrelvir was approved in Singapore in November 2023 based on the Special Access Route application. It remains an investigational drug outside of Japan and Singapore. Ensitrelvir was granted Fast Track designation by the U.S. Food and Drug Administration. “We’re pleased to present the data from our Phase 3 study conducted in Asia in this peer-reviewed article. These results demonstrate accelerated resolution in a range of symptoms, reinforcing the potential of ensitrelvir across multiple patient profiles. Additionally, ensitrelvir reduced viral RNA levels and time to first negative viral titer, suggesting it could help reduce transmission of SARS-CoV-2,” said Takeki Uehara, Ph.D., Senior Vice President, Drug Development and Regulatory Science at Shionogi. “This study was conducted in a largely vaccinated population that included patients infected with Omicron. The patients also had varying risk factors for severe disease. This is relevant as there is a lack of data and a need for additional treatment options for this population.” Key Secondary Endpoints The study also met its two key secondary endpoints (primary analysis population), as previously presented at the Conference on Retroviruses and Opportunistic Infections 2023. The amount of viral RNA was significantly lower on Day 4 in the 125 mg ensitrelvir group compared with placebo (least squares mean change from baseline -2.48 log 10 copies/mL versus -1.01 log 10 copies/mL, p<0.001). 1 The time to achieve first negative infectious viral titer in nasal swabs, indicating clearance of infectious virus from the upper airways, was significantly shorter in the ensitrelvir 125 mg group compared with placebo (a median time of 36.2 hours versus 65.3 hours, p<0.001). 1 This is the first study of an oral antiviral for COVID-19 in humans to show a statistically significant reduction in the time to negative infectious viral titer versus placebo.* “We continue to see COVID-19 surges and we need additional treatment options for more patients, irrespective of risk factors for severe disease, as the virus continues to evolve, adapt, infect and re-infect people across the world,” said Yohei Doi, M.D., Ph.D., Professor of Medicine, Fujita Health University, Japan, and one of the study authors. “Seeing the comprehensive data from the study in Asia signals that ensitrelvir has promising potential to treat patients with many common COVID-19 symptoms.” 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. Serious adverse events were observed in two patients, one in the 125 mg ensitrelvir group and one in the placebo group, both of which were determined to not be treatment related. 1 Of the total study population (n=1,821), 1,030 patients were randomized in less than 72 hours of disease onset. Patients were randomized to receive once-daily ensitrelvir 125 mg (375 mg on Day 1 followed by 125 mg on Days 2-5), or 250 mg (750 mg on Day 1 followed by 250 mg on Days 2-5) or placebo for five days. In the earlier Phase 2 part of the Phase 2/3 study, the 125 mg dose of ensitrelvir demonstrated statistically significant antiviral effect in patients with mild-to-moderate COVID-19 and was well-tolerated. 2 Shionogi secured emergency regulatory approval in Japan with the 125 mg dose and has proceeded with the 125 mg dose for the ensitrelvir clinical development program. 1 COVID-19 is a serious disease that can lead to a range of acute and lasting health problems, and still carries a risk of severe disease, hospitalization and death in some people. 3,4 COVID-19 has yet to settle into a predictable or stable pattern and continues to significantly impact populations, healthcare systems and economies around the world. 5,6,7,8,9 New variants continue to emerge, and future surges are likely. 5,6 Although vaccines and some therapeutics are available, the World Health Organization has emphasized that more treatment options are still needed for COVID-19. 10 About ensitrelvir 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 the 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 results of 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. Initial exploratory analyses from the Phase 2/3 study also indicated a potential for reduced risk of development of long COVID and further evaluations in this regard are still ongoing. The U.S. Food and Drug Administration (FDA) granted Fast Track designation to ensitrelvir for COVID-19. FDA Fast Track designation 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 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 Development Program As SARS-CoV-2 continuously evolves, Shionogi is studying its investigational oral antiviral, ensitrelvir, across a range of patient populations and disease severity to evaluate how ensitrelvir may address the current needs. Shionogi has a comprehensive, global clinical development program underway for ensitrelvir that includes four Phase 3 trials, including SCORPIO-HR , a trial for non-hospitalized, symptomatic COVID-19 patients who have tested positive for COVID-19. SCORPIO-HR is also evaluating the potential effect of ensitrelvir on the symptoms of long COVID. An investigator-initiated research study is also 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. 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. References Yotsuyanagi H., et al. Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients with Mild to Moderate COVID-19. JAMA Network Open. 2024. Available at: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2023.54991?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=020924 Hiroshi Mukae, et al. Efficacy and Safety of Ensitrelvir in Patients With Mild-to-Moderate Coronavirus Disease 2019: The Phase 2b Part of a Randomized, Placebo-Controlled, Phase 2/3 Study, Clinical Infectious Diseases , Volume 76, Issue 8, 15 April 2023, Pages 1403–1411, https://doi.org/10.1093/cid/ciac933 COVID-19 Death Data and Resources. The Centers for Disease Control and Prevention. Accessed January 19, 2024. Available at: https://www.cdc.gov/nchs/nvss/covid-19.htm . About COVID-19. Centers for Disease Control and Prevention. Accessed September 27, 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/your-health/about-covid-19.html Variants of the Virus. Centers for Disease Control and Prevention. Accessed September 27, 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/variants/index.html . Tracking SARS-CoV-2 variants. World Health Organization. Accessed September 27, 2023. Available at: https://www.who.int/activities/tracking-SARS-CoV-2-variants . WHO Coronavirus (COVID-19) Dashboard. The World Health Organization. Accessed September 27, 2023. Available at: https://covid19.who.int/ . Post-pandemic world economy still feeling COVID-19’s sting. United Nations. Accessed October 3, 2023. Available at: https://news.un.org/en/story/2023/05/1136727#:~:text=Prospects%20for%20a%20robust%20global,Prospects%20report%2C%20released%20on%20Tuesday . COVID-19 Surveillance After Expiration of the Public Health Emergency Declaration ― United States, May 11, 2023. Centers for Disease Control and Prevention. Accessed October 3, 2023. Available at: https://www.cdc.gov/mmwr/volumes/72/wr/mm7219e1.htm?s_mm7219e1_w . Therapeutics and COVID-19. Page 8. The World Health Organization. Accessed September 26, 2023. Available at: https://apps.who.int/iris/bitstream/handle/10665/365584/WHO-2019-nCoV-therapeutics-2023.1-eng.pdf . *Literature search conducted January 2024

Our body movements profoundly impact how our brain processes sensory information. Historically, it was believed that the brain's primary motor cortex played a key role in modulating sensory experiences during movement. However, a new study has challenged this view. By selectively inhibiting different neural pathways in the mouse brain, they discovered that regions beyond the primary motor cortex significantly influence the primary sensory cortex during movement. Our body movements profoundly impact how our brain processes sensory information. Historically, it was believed that the brain's primary motor cortex played a key role in modulating sensory experiences during movement. However, a new study led by researchers from Fujita Health University has challenged this view. By selectively inhibiting different neural pathways in the mouse brain, they discovered that regions beyond the primary motor cortex significantly influence the primary sensory cortex during movement. The brain is widely considered the most complex organ in the human body. The intricate mechanisms through which it processes sensory information and how this information affects and is affected by motor control have captivated neuroscientists for more than a century. Today, thanks to advanced laboratory tools and techniques, researchers can use animal models to solve this puzzle, especially in the mouse brain. During the 20th century, experiments with anesthetized mice proved that sensory inputs primarily define neuronal activity in the primary sensory cortices -- the brain regions processing sensory information, including touch, vision, and audition. However, over the past few decades, studies involving awake mice revealed that spontaneous behavior, such as exploratory motion and movement of the whiskers called whisking, actually regulates the activity of the sensory responses in the primary sensory cortices. In other words, sensations at the neuronal level appear substantially modulated by body movements, even though the corresponding neuronal circuits and the underlying mechanisms are not fully understood. To address this knowledge gap, a research team from Japan investigated the primary somatosensory barrel cortex (S1) -- a region of the mouse brain that handles tactile input from the whiskers. Their latest study, published in The Journal of Neuroscience on December 1, 2023, was conducted by Professor Takayuki Yamashita from Fujita Health University (FHU) and Dr. Masahiro Kawatani, affiliated with FHU and Nagoya University, along with their team. The S1 region receives input through the axons from several other areas, including the secondary somatosensory cortex (S2), the primary motor cortex (M1), and the sensory thalamus (TLM). To investigate how these regions modulate activity in S1, the researchers turned to optogenetics (a technique for controlling activities of specific neuronal populations by light) involving eOPN3, which is a recently discovered light-sensitive protein enabling effective inhibition of specific neural pathways in response to light. Using viruses as a vector, they introduced the gene coding for this protein into the M1, S2, and TLM regions in mice. Then, they measured neural activity in S1 in awake mice performing spontaneous whisking. During this process, they selectively inhibited different signal inputs going to S1 using light as an ON/OFF switch and observed the effect at S1. Interestingly, only signal inputs from S2 and TLM to S1, not from M1 to S1, modulated neuronal activity in S1 during spontaneous whisking. Specifically, the pathway from S2 to S1 seems to convey information about the motion state of the whiskers. Additionally, the TLM-to-S1 pathway appeared to relay information related to the phase of spontaneous whisking, which follows a repetitive and rhythmic pattern. These results challenge the established view that neuronal activity in sensory cortices is modulated primarily by motor cortices during movement, as Prof. Yamashita remarks: "Our findings provoke a reconsideration of the role of motor-sensory projections in sensorimotor integration and bring to light a new function for S2-to-S1 projections." A better understanding of how distinct brain regions modulate activities among each other in response to movement could lead to progress in myriad applied fields. These research insights have far-reaching implications, potentially revolutionizing fields like artificial intelligence (AI), prosthetics, and brain-computer interfaces. "Understanding these neural mechanisms could greatly enhance the development of AI systems that mimic human sensory-motor integration and aid in creating more intuitive prosthetics and interfaces for those with disabilities," Prof. Yamashita adds. In summary, this study sheds light on the intricate workings of the brain. It also paves the way for researching the connection between body motion and sensory perception. As we continue to explore brain-related enigmas, studies like this offer vital clues in our quest to understand the most complex organ in the human body.