Chugai Pharmaceutical Co., Ltd. (4519) Earnings Call Transcript & Summary

Good afternoon. I am President Okuda. Thank you very much for joining us today. First, I would like to give you an overview of Chugai's efforts to develop the therapeutic drugs for COVID-19. This slide shows the major milestones in the development in Japan to date. First, we started to work in-house product, Actemra. Roche started the global study, COVACTA, in March 2020. Around the same time, in parallel, we started the Phase III study J-COVACTA in Japan for similar patients in May 2020. Then we acquired the rights to develop and market Ronapreve in Japan, and antibody cocktail therapy in December, and also acquired the rights for AT-527, an oral antiviral agent under the strategic alliance with Roche in February this year. Then in May, we reached an agreement with the Japanese government to secure the supply of Ronapreve for 2021. We submitted an application for special approval on June 29th, and received the approval on July 19th, in an exceptionally short review period of 3 weeks. We were able to deliver Ronapreve to patients in Japan in a very short period of about 6 months, after acquiring the development and marketing rights in Japan. Now let me give you an overview of the 3 drugs Chugai is working on for COVID-19. First, Ronapreve, shown on the left, is an antibody cocktail therapy originated by Regeneron in the U.S. and in-licensed by Roche. It recognizes the spike protein of the etiologic virus, SARS-CoV-2, and inhibits its entry inventory into host cells, thereby suppressing viral replication. This is an injectable, where 2 kinds of antibodies are infused intravenous at the same time, and so it is called antibody cocktail therapy. The product is manufactured by Roche and Regeneron. It obtained emergency use authorization in the U.S. and special approval in Japan, as I mentioned earlier. Actemra, in the middle, is an antibody drug originated by Chugai, and has already been approved for several indications, including rheumatoid arthritis in many countries in the world. It is the first product co-developed globally under the strategic alliance with Roche. By inhibiting IL-6, a cytokine involved in immune regulation and inflammation. It is expected to suppress excessive immune and inflammatory responses associated with COVID-19. Several clinical trials and investigator-initiated clinical researches have been conducted in Japan and overseas. This is also an intravenous injectable drug. It has been authorized for emergency in the U.S. The third drug, AT-527, on the right, is a viral RNA polymerase inhibitor discovered by Atea Pharmaceuticals in the U.S. It is a small molecule initially intended for hepatitis C. But Atea is conducting a Phase II study, as it can be effective for COVID-19. Roche in-licensed it, and is responsible for manufacturing for global supply. Phase III, MORNINGSKY study, shown on the right, for patients with mild to moderate patients is currently underway. Next, I will explain the positioning of 3 drugs in the overall treatment of COVID-19. The figure on the bottom half was adapted from the approaches to pharmacotherapies for COVID-19, issued by the Japanese Association for Infectious Diseases at the end of July. After infection, as you know, COVID-19 progresses from asymptomatic to symptomatic, and from mild to severe disease as the virus proliferates. Therapies with likely efficacy are defined by the status and the severity of the disease. In asymptomatic to mild disease, where viral proliferation progresses, antiviral drugs are expected to be effective. In other words, AT-527 can be used here. When symptoms progress a little to mild moderate one, where oxygen administration is not required, antibody therapy is expected to be effective and Ronapreve falls into this category. Anti-inflammatory treatment is expected to be effective in moderate and later stages, where inflammation occurs, and Actemra is expected to be effective here. In this way, the drugs that Chugai is developing, AT-527, Ronapreve and Actemra will cover a wide range of patients with mild, moderate, and severe infections, and will contribute to the overall treatment of COVID-19. Here, I will introduce the development and are status of the 3 drugs in Japan and overseas. This is a little busy slide and difficult to read, and so I will keep it simple. The upper half of the slide shows the overseas status and the lower shows the status in Japan. First, as for Ronapreve, the originator Regeneron started several clinical trials in 2020. Based on the interim analysis of 1 of them, REGN-COV 2067, a study for high-risk COVID-19 patients who were not hospitalized. Regeneron received emergency use authorization from the FDA last November. Based on the results of the clinical trials conducted in parallel, emergency use authorizations for subcutaneous injection, and prophylactic administration to close contacts were obtained in the U.S. in June and July this year. Although we did not participate in the global study from Japan, a Phase I study in healthy subjects were conducted in Japan March this year. Together with overseas data and application for approval was submitted in June. Special approval was granted in July, as I mentioned earlier. As for Actemra, many overseas studies are shown. Several global comparative studies, including COVACTA study last year, and REMDACTA study in combination with Remdesivir were conducted under Roche's leadership. In addition, many physician-led studies were conducted, including the large-scale RECOVERY study in the U.K. The results of integrated analysis of multiple trials have demonstrated the efficacy of Actemra in reducing the risk of deaths, shortening the time to discharge, and reducing the need for ventilators in hospitalized patients with severe COVID-19. Based on these findings, the FDA granted the emergency use authorization in June this year. And the WHO announced in July that it would recommend Actemra in its treatment guidelines. Although there is no official regulatory approval in any country at this time. Actemra is being prescribed for severe COVID-19 patients in the real-world clinical practice. As for AT-527, Atea is conducting the Phase II study that I mentioned earlier in patients with moderate COVID-19, requiring hospitalization who have risk factors for severe disease. In its interim analysis, patients treated with AT-527 had a mean 80% greater reduction in viral load on day 2 compared to placebo group. No new safety findings were observed at the time of interim analysis. In addition, global Phase III study, MORNINGSKY study, was start in April this year, and Chugai has been participating in this study. The results of this study are expected to be available in the second half of this year, and we are aiming for submission in 2022. Finally, I will briefly discuss our future activities. First, about the Ronapreve. In response to the increasing demand for therapeutics worldwide due to the spread of delta variant, we secured the sufficient quantity in response to the government request, and promote proper distribution and proper use in coordination with the government, and other relevant parties. We expect the drug will have reducing the rate of patients progressing to severe disease, and avoiding pressure on the health care system. We will consider expanding the indication for prophylactic administration to close contacts, and applying for additional dosage, and administration for subcutaneous injection. For Actemra, we will promote data analysis and integrated analysis, and continue to discuss with the regulatory authorities about possibility of submission. We expect this will improve prognosis of patients with severe COVID-19. As for AT-527, results of the ongoing global Phase III study will be available in the second half of this year. We will promote development in collaboration with Roche and Atea, aiming for filing in 2022. Since this is an orally administered drug, we believe progression to severe disease can be prevented by providing early treatment to patients with mild diseases. This has been a brief explanation about the 3 drugs that we have been working on.

I am Iida, Ronapreve Lifecycle Leader. Ronapreve is the brand name, and its generic name is casirivimab/imdevimab. As shown in the photo on the right bottom, casirivimab and imdevimab are supplied in separate vials and they are mixed for use. Thus, it is called antibody cocktail therapy. It is indicated for SARS-CoV-2 infection and it is to be administered to patients who have risk factors for severe SARS-CoV-2 infection, and who do not require oxygen intervention. This is the history of development. In February last year, Regeneron began antibody acquisition. 2 months later, 2 therapeutic antibodies were selected. Another 2 months later, global Phase I/II/III study started. Only after 5 months later, emergency use authorization was granted in the U.S. based upon the results of Phase I/II study. In Japan, the Phase I study started in March this year. Regulatory application was filed in Japan at the June. And only 3 weeks later, on July 19th, special for emergency was granted in Japan. Let me briefly explain the mechanism of action of Ronapreve. The figure on the left shows the binding mechanism of SARS-CoV-2, and SARS-CoV-2 virus, and a cell in our body are shown. When the spike protein expressed on SARS-CoV-2 binds to a protein called ACE2 expressed on our cell, the cell is infected and then the virus proliferates. This is a known mechanism. Ronapreve binds to the spike protein and prevents the virus from entering the cell, thus suppressing the proliferation of the virus. For cocktail therapy, 2 different antibodies are used. Each antibody by itself can suppress the interaction between the spike protein and ACE2. But the significance of using 2 different antibodies for cocktail therapy is that it can be effective for various variants of the virus. Mutations often occur in the binding domain of the spike protein. If the binding activity on 1 of the antibodies declines due to a mutation, the activity of the other antibody still remains. And we know that the overall activity is maintained. I will show you activities against the variants in the next slide. The slide shows the activities against alpha variant, currently prevalent delta variant and other variants. Percent decrease in activity in the individual experiments is shown. It is known that the activity does not decrease when administered as a cocktail. Next, I would like to discuss about the Ronapreve's potential contributions to treatment in terms of its target population. Its target population is, as I explained at the beginning, patients with risk factors for progression to severe disease who do not require oxygen therapy. I will explain the risk factors for severe disease first. Risk factors for severe disease in COV-2067 study, Phase I/II/III study evaluating the efficacy are: age of over 50, obesity, cardiovascular disease, chronic lung diseases, diabetes, chronic kidney disease, chronic liver disease and immunosuppressed status. According to an announcement from MHLW, in addition to the inclusion criteria of COV-2067, treatment guideline version 5.1 at the time of the approval and dosing criteria by EUA in the U.S. are to be referenced for use in appropriate patients. Incidentally, latest version of the treatment guideline is 5.2. Patients who do not require oxygen therapy is explained in the table on the right. From the top, severity is mild, moderate 1, moderate 2 and severe. Oxygen therapy is required for patients of moderate 2 and later stages. Since the drug is for patients who do not require oxygen therapy, it is administered in patients in mild and moderate 1 stages. There has not been any therapy for patients with mild disease, and the Ronapreve is the first drug approved for mild disease. Next, I'm going to show you the study design of COV-2067 study. This protocol was modified during the Phase III period. Before the amendment, there were 2,400 milligram group and 8,000 milligram group. But it was known from the Phase I/II study results, that the efficacy was not very different between 2,400 milligram group and 8,000 milligram group. Thus, the protocol was amended to have lower dose of 1,200 milligram group and 2,400 milligram group. Also, requirement to having at least 1 risk factor for severe disease was added at the time of that amendment. I'm going to discuss the efficacy and safety, and the data is mainly from 1,200 dose, which is the approved dose. First is the statistical analysis plan. Sorry for the busy slide. Let me briefly discuss the plan. As for the efficacy, 736 patients who received the active drug and 748 patients who received a placebo, were analyzed. As for the safety data, 827 patients who received 1,200 milligram and 1,843 patients who received a placebo were included. For statistical analysis, multiplicity was taken into account in the analysis, not only for the primary endpoint, but also for secondary endpoint, which is written in detail in the bottom. Next is the efficacy data. The primary endpoint is ratio of Sars-CoV-2 infection-related hospitalization or all-cause death by day 29. The vertical axis of the graph on the left show a proportion of patients with events that is hospitalization and death. And horizontal axis show days passed since the administration. As a number of events increase, the lines will move upwards. In the gray placebo bar, 3.2% of the patients had the events. But in the blue 1,200-milligram drug arm, it was 1%, which means hospitalization and death risks were reduced by 70%. On the right, it shows secondary endpoint, that is time to resolution of infections. It took 14 days in the placebo arm, but was 10 days for Ronapreve 1,200 milligram arm, shortening the duration of the symptoms by 4 days. Next is safety. The adverse events data with Ronapreve 1,200 milligram arm data on the left and the placebo arm on the right. As for adverse events, it was 7% for the drug arm and 10% for the placebo arm. We believe that it was higher in the placebo arm related to deterioration of symptoms related to COVID-19. Bottom half show adverse events of special interest. Notably, grade 2 or above of infusion reactions through day 4, and hypersensitivity reactions through day 29, and COVID-19-related adverse events leading to medical attention through day 29. It was 2.1% for the drug arm and 2.8% on for the placebo arm. Infusion reaction and hypersensitivity are of most concern, but this is the results that achieved. Next is indication, dosage and administration. As I mentioned at the beginning, it is indicated for SARS-CoV-2 infection for patients who have risk factors for severe infection and who do not require oxygen intervention. Precaution of, they have been reports of symptoms worsening in patients requiring high-flow oxygen therapy or ventilator management has been added, due to the fact that in a different study namely COV-2066 study for in patients this was seen, although the causality with the drug is unclear. We also added that Ronapreve cannot necessarily be expected to be effective for SARS-CoV-2 variants in which the neutralizing activity of Ronapreve is low. Therefore, consider the appropriateness of administering Ronapreve based on the latest on the prevalence variants, as the stated efficacy may not be expected. As mentioned earlier, there are no variants identified currently that causes lower activity. But as the future is unclear, we have added this precaution. As for dosage and administration, single intravenous infusion of 600 milligrams each of casirivimab and imdevimab, total of 1,200 milligrams to be administered concomitantly. As for precautions concerning dosage and administration, it is stated that it is to be administered promptly after symptoms develop in patients. COV-2067 study was conducted with patients within 7 days of onset of symptoms. Therefore, no efficacy data is collected for patients post 8 days from the onset. This is a reason for this precaution. There was an announcement by Ministry of Health Labor and Welfare post approval. Ronapreve is to be administered to patients who have risk factors for severe SARS-CoV-2 infection and who do not require oxygen intervention. But in this announcement, it is stated that it used to be administered to patients who are hospitalized. However, the landscape is quickly changing. And as of August 13th, administration to patients in short hospitalization and patients in designated government care accommodations have started. And just yesterday, announcement was made that it can be administered in outpatient clinics as well. We believe a number of patients, who will be administer to Ronapreve will continue to grow. As for the approval conditions, it is stated that a pharmaceutical product risk management plan should be formally and implemented appropriately. I will explain the risk management plan in detail in the following slide. Another condition is to obtain written consent before administration from patient or their representative. This is a risk management plan for Ronapreve. Important identified risks are anaphylaxis and other serious hypersensitivities and infusion reaction. We will conduct early post-marketing phase vigilance as well as special drug use surveillance to collect any information related to adverse reactions. This pandemic can be defined as a national crisis, and with Ronapreve, we hope to be able to contribute to health care as much as we can. Thank you for your attention.

Thank you for the introduction. My name is Tateda from Toho University School of Medicine. There is no end in sight of the COVID-19 pandemic, with difficult situations continuing. Currently, under the fifth wave, we're seeing approximately 20,000 new cases here in Japan daily, with some areas in Japan requiring to introduce disaster medical care. But there are a number of bright spots as well. 1 of them is vaccines. Messenger RNA vaccine was developed for the first time in the world and reports showing high efficacy is seen. Here in Japan, approximately 40% of the population have completed their second doses. And we need to expedite the vaccination process so that all those who want to be vaccinated, may do so as soon as possible. The other bright spot is a therapeutic drug against COVID-19, which is the theme of this meeting today, antibody cocktail therapy, Ronapreve, which was approved by the regulatory authority, and its efficacy continuing to be confirmed. Expectation is high, especially among the clinicians. And I would like to explain mechanism of action of Ronapreve, and how this drug should be used. Now on this novel coronavirus disease. Common cold caused by 4 types of coronaviruses have been known. However, new coronavirus started to appear, starting with severe acute respiratory syndrome coronavirus, SARS in 2002, and Middle East respiratory syndrome coronavirus, MERS in 2012. And after such premonition, the novel coronavirus became a huge problem, spreading around the world from China at the end of 2019 to 2020. It is known that COVID-19 spreads to humans from infected animals, such as bats, reptiles, camels, dogs and cats. As you can on the left, it has a crown-like structure on the virus surface, thus the name coronavirus. More than 200 million people around the world have been infected with COVID-19. And unfortunately, more than 4 million deaths have been reported so far. Even today, more than 600,000 new cases are confirmed daily with more than 8,000 deaths worldwide. Japan is in the midst of the fifth wave, with peak out not in sight. Amid the confusion we are in, we have seen 1.3 million cases with sadly 15,000 deaths been reported. The black line shows the trend of death, which lags the peak of the reported cases, with peak of fifth wave, not in sight. By how much a number of this is going to increase is of a great concern. This is a chest CT of the first COVID-19 patient we have treated in our institution at Toho University. On hindsight, we can say that this is a typical image of a COVID-19 patient, showing ground-glass opacities in bilateral subpleural areas adjacent to the chest walls. This is a distinctive image, anyone can now recognize. Why does this infection show such an image? Is it because of the distribution of ACE2 the receptor of this virus? Or is it the size of inhaled particles? Recently, it is said that it may be by inhaled the microdroplets of the saliva ejected by himself, may be resulting in this kind of new pneumonia that we see in studies. First, it was pneumonia. But with this infection, it first infects ACE2 receptor, which exists in vascular endothelial cells and causing injury, leading to multiple organ damage. Resulting in progression to severe disease or it is involved in [ enclosing sequelae ]. The thrombus or blood clot formation is said to play an important role in the mechanism or progression to severe disease. Top left, the lung surface of the disease mosaic-like formation. Bottom left shows pulmonary embolism. Top right, thrombosis of the prosthetic vein. And bottom right, deep venous thrombosis is seen. It has become clear that thrombus formation has a significant role in progression to severe state more than first believed. This is also a surprising in a sense. It was thought that this infection spreads by droplets and contact, just like influenza. But it has become more apparent that aerosols during conversation plays an important role, transmitting the disease to those nearby. And as you all know, wearing masks, nonwoven masks, is effective in preventing aerosols infection. Infection you see in the salivary gland existing in high concentrations and the aerosols produced when speaking is inhaled. And this is how the infection is transmitted. This is a fact. Just using saliva, PCR test and antigen tests are now available. And we have seen big advancements in diagnostics, as you all know. This infection is often compared to influenza. Influenza virus has an incubation period of between 1 to 3 days and is transmitted from 1 person to 2, 2 to 4, 4 to 8, 8 to 16 and so on. It's spreading out [ in planes ] often dealing quickly to temporary closing of schools. On the other hand, with COVID-19, 1 person may transmit the infection to 5 people, but 4 out of the 5 people will not cause further transmission. That 1 person may be an asymptomatic carrier. And in a 3C condition, the virus is spread closed in a cluster. Therefore, the important characteristic of COVID-19 infection is that an asymptomatic carrier has a risk of spreading infection, making it difficult to tackle. The difficulties of the diagnosis is shown on this slide. With COVID-19, before the onset, that is appearance of symptoms, the live viruses are exhaled and they disappear in about a week. It is now known that with PCR tests conducted, positive results will continue to show for weeks. In other words, majority of the PCR positives we see are noninfectious positive. How to distinguish between PCR positives and negatives? One way is to check with a specific antibody or neutralizing antibodies produced. It is now thought that this will be an important factor in diagnosing COVID-19 going forward. The fact that COVID-19 spreads from asymptomatic people, then how can we prevent it? It is important to suspect COVID-19 from nasopharyngeal infection, when it is not even clear if the person has COVID or not. But when people start to show slightest of symptoms of a cold, so appropriate testing can be performed. Slightest of cold like symptoms like malaise, body aches, sore throat, slight runny rose, feverishness or chills. Currently, from these symptoms, it is not possible to distinguish between COVID and common cold. So it is important to take tests as early as possible to eliminate the possibility of COVID and if found positive, immediately to be placed into quarantine. The Japanese government with a target of 1 million vaccination daily. This recommending being vaccinated very strongly. It was deemed an impossible task. But with the cooperation of Japanese health care professionals and the general public, it is now proven that 1 million a day is possible. Because of difficulties with procurement of vaccines, the number has dwindled somewhat. But as supply of vaccines recover, we will see the number exceeding 1 million once again. For all ages, people who had 2 doses account for 40% and 1 dose 50%. And for over 65s, 2 doses 85% and 1 dose close to exceeding 90%. We are accomplishing high vaccination rates, as you know. The vaccines are proving to be highly effective, but their effective affecting their effectiveness. Effectiveness of differences attributable to vaccine type. And in Japan, messenger RNA and vector-based vaccines are being used. Prevention of not only onset, but progression, or infection is shown. But there is a vaccine hesitancy. It is a fact that there are people who do not want vaccination or cannot get vaccinated. I'm sure you have heard of the so-called breakthrough infections among vaccinated people, which is now an issue. Duration and waning of vaccine effectiveness related to antibodies need to be monitored closely. And the emergence of variants of concern. The delta variant has spread in Japan and around the world and is a cause for concern. This is a busy slide showing development status of major vaccines. From the top, Pfizer and Moderna developed the mRNA vaccines. And AstraZeneca developed virus vector vaccines. And these 3 vaccines are administered to people here in Japan. By administering vaccines, IgA, IgG and IgM in not only serum but also IgA in saliva is induced, neutralizing virus in saliva gland and saliva, and the possibility that the messenger RNA vaccine suppressing infection itself is being indicated. Messenger RNA being developed has the potential to be a game-changer in the vaccines development. This slide shows new positive cases by age groups in Tokyo metropolis. As vaccination rates go up, the number of new positives among the elderly population is going down. The dark green shows the 50s and anything above it are 60s and over, and they are decreasing rapidly. And now more than 90% of all positive cases are 50s and below. And people in their 20s and 30s now make up more than 50% of new cases. This is how the status of the infection is changing, which is important to note. This shows a number of hospitalized patients in Tokyo metropolis. The number was 3,800 as of August 16th. But as of today, the number has exceeded 4,000, and the surge is continuing with wave 5. Difficult conditions continue in those who should be hospitalized, not being able to be accommodated, and need to stand by at home as you all know. This page shows the number of hospitalized patients by age group. There are so many patients in their 50s, 40s, 30s and 20s, who had to be hospitalized according to this report. As for patients symptoms. There were over 270 patients with severe symptoms in Tokyo recently. Severe cases mean they require mechanical ventilators, or ECMO. They could become fatal any time. Those in their 50s are shown in purple, areas in purple and below are patients under 50s and younger, namely those in the 50s, 40s and 30s are hospitalized with severe symptoms, as you can see here. Furthermore, there's an issue of the vaccination rate, as a factor which can determine the efficacy of vaccines. Israel is set to be an advanced country in terms of vaccination. But unfortunately, it was reported that the vaccination rate was hitting the ceiling of around 60%. A similar phenomenon is also occurring in the United States, where the vaccination rate reached the ceiling, leveling off at around 50% to 60%. How to increase this vaccination rate is a very important theme. Each country is trying to come up with ideas like creating incentives to increase vaccination. There is the issue of vaccine hesitancy. How can we increase the vaccination rate among young people in particular. Education and awareness campaigns are very important. Symptoms can become severe even in young people. After effects are becomes big issues. Vaccination is necessary from the perspective of herd immunity to protect not only yourselves but also your family members and your loved ones. We also need countermeasures against fake vaccination-related information and false rumors. Not only the central government, local governments and academia, but also members of the media who are joining today, should cooperate to communicate the correct information and increase the vaccination rate. I think such initiatives are very important. We also need to create incentives to increase vaccination. When vaccines become available to most of the people, and we want to further promote vaccination. In what way can we create incentives to promote vaccination? For example, by issuing vaccine passports or certificates of vaccination. On the other hand, there are people who cannot be vaccinated or those who take the option not to be vaccinated. We should be considerate of these people and to take necessary countermeasures, so that this will not lead to discrimination or bias. In addition, there is the issue of variants of concern as was mentioned earlier. Infection is mediated by the virus spike protein in the body. Mutations there, lead to variants of concern, changing the interactivity and virulence, according to the report. For example, we have the alpha, the beta and gamma variant. Now the delta variant is becoming a big issue, and it's spreading all across Japan and also around the world as you know very well. Regarding the spread of delta variant in Japan, the ratio was about 34% as of the 5th of July, but exceeded to 60% by mid-July, and increased to about 90% by early August. It is reported that by now, most of the positive cases are due to the delta variant. Fortunately, the original efficacy of vaccines has been retained for sure, against the alpha, gamma and beta variants, although the efficacy is a little lower against the beta. There are some reports that vaccine efficacy is slightly reduced against the delta variant, but we can say there is efficacy for sure, which is an important fact. Under these circumstances, another worrisome phenomena is being reported. This is the so-called breakthrough infection. Those who were vaccinated and those who are not in the United States, who are infected in association with large events. More than 400 infections occurred in association with large events in July, and they were reported in August. More than half of them were vaccinated people. That was reported with a huge impact. Looking at the details at that time, 74% of those affected were vaccinated. Most of the infections were due to the delta variant. Having said so, about 80% of those infected post vaccination were asymptomatic. Ct values did not differ between the vaccinated and unvaccinated people, as you can see here. Those who were vaccinated may be infected. But many of them can be asymptomatic. Still, viral load can be as high. In other words, the symptoms can be mild, and they can become a driving force to spread the infection. Such new risks are also emerging. Regarding viral mutations and cost of evolution, a lot of new factors are becoming clear. With regards to this virus, mutations occur once every 2 weeks. Mutations occur in random locations. There is a risk of change in infectivity when the mutation occurs in the receptor binding domain of the spike protein, but infectivity and virulence do not necessarily coincide. In the long term, evolution generally proceeds toward greater transmissivity and lower virulence. But for COVID-19, it's difficult to predict how long it will take to reach such conditions. Next, with regards to treatment, we now see many new directions. As a drug to inhibit gene replication after viral infection, remdesivir was approved. Baricitinib cancer breast hyperinflammatory reactions by virus, the so-called cytokine storm conditions. Duxometasone and immunosuppressive drugs have been approved as well. And this time, Ronapreve, the antibody cocktail casirivimab and imdevimab has been approved to suppress injections through antibodies binds into the spike protein where the virus binds to cells. This page shows one of the ski masks posted on the website of the Japanese Association for Infectious Diseases about the approaches to pharmacotherapies of COVID-19. In this infectious disease, in the initial stage, viral proliferatoin is a main component. In the latter half, due to trigger immune response, disease formation due to cytokine storm becomes important. Different drugs are used in each of the different disease stages. From the extreme stage with strong cytokine storm towards terminal case, dexamethasone and the [ Baricitinib ] will be important. Remdesivir will be important to suppress the virus. In the initial stage when the disease is mild, Ronapreve can be used to suppress the virus. It was approved at this time as a therapy, which can be used from the initial stage, which is very important. We have more drug options to address infection from mild to moderate and severe cases, which is a big step forward. In COVID-19 pharmacotherapy. In principle, how to use antivirals, anticytokine storm agents, anticoagulants, and antivirus antibodies differently. And administer them effectively is important right now. This is a simplified image of Ronapreve monoclonal antibodies. For example, as shown on the left, Infection-induced antibodies, which is shown in red, yellow, green, et cetera, binds to viruses. In the case of infections, antibodies that bind to various locations are produced. On the other hand, monoclonal antibodies binds to S-protein in specific sites. Such antibodies are synthesized artificially, by doing administering and binding them to viruses, infections can be prevented. This can be an image of monoclonal antibodies. About Ronapreve's efficacy, various studies and clinical data have been reported. This is a model of prophylaxis in rhesus macaques. The antibody cocktail was administered before viral infection to see changes in the viral load. Looking at the amount of inoculated virus in the nasopharyngeal area, compared to the control group. The reduction was faster with Ronapreve administration. And interestingly, inoculated virus would proliferate in the lung and in the nasopharyngeal area. This antibody cocktail inhibited the value of proliferation very strongly. That was also reported in BAL, bronchoalveolar lavage. This is a model of prophylaxis and treatment in hamsters, to study the therapy before and after viral infection. Infections may reduce the body weight, but prophylaxis and treatment prevented weight loss. It was confirmed that the spread of pneumonia decreased. Here is in vitro data, about how much the antibody cocktail can utilize variants. Against the alpha variant, over the 3, including each of the antibodies and the combination had a very strong and effective neutralizing activity at a similar level. Against the beta variant, the neutralizing activity of casirivimab was a little lower. Also against the gamma variant, casirivimab's neutralizing activity was a little lower. But by using it in combination in the cocktail therapy, you can see recovery in its activity. As for the delta variant, good neutralizing activity was maintained according to the report. This shows where these antibodies bind to in the spike protein. Casirivimab is shown in blue and imdevimab in red. We're looking at the antibodies binding sites. By binding to different sites, independently, strong neutralizing activity can be shown also against variants. This indicates a possibility that such efficacy can be expected. This page shows the results. If you culture the virus in vitro or in the cell, resistant viruses could develop, resulting in the efficacy of the antibodies. Casirivimab alone within 2 passages could lead to resistant viruses. Also with imdevimab, resistant viruses emerge within 2 passages. But in the antibody cocktail, in combination, there is no such emergence up to 7 passages. It's demonstrated that it will be more difficult for resistant viruses to develop. Furthermore, experimentally, in a triple antibody cocktail, it will be more difficult for resistant viruses to emerge. This was a study to see how much efficacy to reduce the viral load in human. According to the results, as was expected, there was strong efficacy to reduce the viral load in the serum antibody negative group. Also strong efficacy to reduce the viral load was seen in those with high viral load as reported here. This page shows safety evaluation for Ronapreve. Sorry for this busy side, but this is a monoclonal antibody treatment. The actemra and anti-TNF alpha inhibitors. Here, the monoclonal antibody technology has been applied to viral infections. We don't see strong adverse reactions in particular. This is important. About Ronapreve's efficacy and expectations. As for its efficacy and safety reported to date, reduction of hospitalization, serious symptoms and death by more than 70%. Shortened time to symptom improvement by about 4 days. Reduction in the viral load with strong suppressive effect, particularly in high virus group. Regarding safety profile, no serious concerns has been reported, which is important. On the other hand, there are issues we need to consider for the future. Enlisted expansion of indications for outpatient administration, but this is going to be cleared. You are now on the way to be able to administer Ronapreve to outpatients and those who need to be watched or self isolating at home. Confirmation of further efficacy in combination with other treatments. You must consider the possibility of triple combination, et cetera, which I mentioned earlier, for the future. This is an overview of new COVID-19 treatments under development. The upper half of the page shows antibody-related products, like Eli Lilly, GlaxoSmithKlein and AstraZeneca. The bottom half shows small molecule compounds, including all treatments by MSD, and AT-527 by Chugai, as well as drugs by Pfizer and Shionogi. These all small molecule treatments are now under development. We're hoping that these treatments will be delivered to the clinical settings as soon as possible. How to make the list of the risk and post-COVID-19 age. Unfortunately, the fifth wave has developed as a huge 1. How can you control this? And bring this to an end is important. How can we increase the vaccination rate in Japan? Probably in Japan, I think we can exceed 70% and 80%, which is considered difficult elsewhere. That's my expectations. Clusters keep recurring primarily among unvaccinated population. 20% to 30% of the people cannot or will not be vaccinated. There is a possibility of clusters to develop among them. But it is expected that the risk of cluster chains and mega clusters will be declining. Then it's important to immediately revitalize society and economy with vaccines passports and negative test certificates. As specific therapies, antibody medicine must be further advanced. In addition, if oral treatments become available, SARS-CoV-2 can be made to the fifth common cold coronavirus. We should envision such a future. I think COVID-19, in a sense, was a pandemic we should have anticipated before. As was mentioned before, we had SARS in 2002, MERS in 2012 and COVID-19, emerging from bat, civet, dromedary camel, or reptiles. As we see these past examples, we must think that there can be a pandemic by new pathogen in the future, for sure. We need to continue to take countermeasures. That's an important lesson for us. This is my last page. COVID-19, became pandemic infections. I recognize once again the importance of risk management for that. How to prepare for control functions in emergencies? Is an issue. We must ensure surge capacity, including the issues of testing system, health centers and hospital beds. We need to develop and strategically place regional leaders. Also, I feel the importance of continued investments into new technologies, therapies and vaccine development. Last but not the least, when it comes to infections, there can be discrimination and bias. Sadly, even now it's still happening in reality. When we can overcome this infection. We should be able to establish a society invulnerable to infections, in my view. That's all from me. Thank you very much.

This is Wakao from JPMorgan. Thank you for your explanation. I have 2 questions. First question is about your thoughts on resistant strains to Ronapreve, and also your thoughts on resistant viruses to small molecule drugs. As for resistant strains to Ronapreve, since resistant strains do not appear before 7 passages, can we assume that the probability of the emergence of such resistant strain is very low? In addition, what are your thoughts about the risks of emergence of resistant strains to inhibitors of protases or RNA polymerases, which are the target of small molecule drugs? Since mutations occur randomly, should we consider risks of resistance? Or since RNA polymerases are important proteins for viral proliferations, if such mutations occur, the virus are often not produced. Do you think such risk of resistance is low for small molecules being developed by Chugai and others? This is a question for Dr. Tateda.

Thank you for your question. As you pointed out, according to the data I showed you earlier, resistant virus was observed after 7 passages in cell subculture. But this data is in vitro data. The pathogenicity of the virus in vivo is a totally different matter. I think what the data shows is that such resistant virus could possibly emerge as a very rare phenomenon. Of course, we need to be carefully watching what happens in real world. But I think it is safe to say that it is quite rare for a virus to mutate and become resistant to 2 antibodies at the same time. Another question was about resistant virus for RNA polymerase inhibitors. Naturally, living organisms mutate and evolve. So it is natural that resistant virus will emerge. But as you pointed out, the virus with such a mutation may be very weak or may not be able to survive. So you need to always think about mutation as a possibility. But I don't think it is necessary to think that such mutated virus would quickly spread around the world and become a new problem.

My second question is for Chugai. You mentioned that sufficient supply of Ronapreve has been secured for Japan. Specifically, how much quantity has been secured? Or is a plan to be secured? When will subcutaneous injection and prophylactic administration be available in Japan? Please explain the development time line for additional indications in Japan.

Thank you for your question, Mr. Wakao. This is Okuda. You asked 2 questions. 1 is about the Ronapreve supply system and the other is about the expansion of indication, subcutaneous injection and prophylactic administration for close contacts. As for the first question, we will establish supply system with close coordination with the Japanese government. And I think it is important that we secure the necessary amount of Ronapreve. In the agreement with the government that we announced in May, we agreed about the supply for 2021. We will secure the necessary amount in close communication with the government based on the current situation of infection. As for the second question of expansion of indication for subcutaneous injection, and prophylactic administration. We have diligently prepared materials, and discussing with the government that when we can file applications in the future.

In terms of the supply amount. The current situation of infection is quite different from the situation in May, when you agreed with the government. Given the current situation, may I assume that the amount requested by the government has now increased compared with the amount in May?

I am not allowed to give you the specific amount to maintain the confidentiality of contracts with the government. But as I mentioned earlier, we will secure necessary amount based on the changes of situation.

I understand. Thank you.

This is Hashiguchi from Daiwa Securities. My first question is to Dr. Tateda. When you explained Page 67, I think you said, the development of specific oral medicine is important for making SARS-CoV-2, the fifth common called coronavirus. Could you elaborate on the importance of the oral medicine a little more? And when such overall medicine becomes available and SARS-CoV-2 becomes the fifth common called coronavirus. What will be the positioning of vaccines in your opinion?

Thank you for your question. Earlier, I said that SARS-CoV-2 would become the fifth common cold coronavirus. At that time, diagnostics may be widely available. When you suspect that you have a cold, you may go to a hospital, then you can immediately have an antigen test using your own saliva. Then SARS-CoV-2 infection can be diagnosed. The doctor tells you to take for this drug 3 days. You will recover without having severe symptoms. SARS-CoV-2 infection may become such a disease. That is my image. Among the overall drugs being developed now, if some are successfully developed, that kind of scenario may be possible, although I don't know when it is.

At that time, will vaccines still be necessary? Vaccines may not be necessary anymore.

I cannot give you a definite answer. We will need to keep a close eye for a year or 2.

Next question is for Chugai. In the supply of Ronapreve to the Japanese market. I understand that 1 of the current hurdle is the difficulty of production. I think Chugai is not producing it now, and is importing the whole amount. What do you think of producing the drug in Japan in order to improve the limitation of the supply? Is it at all allowed for Chugai to manufacture it in Japan for the Japanese market by the contracts with Roche and Regeneron?

Thank you for your question, Mr. Hashiguchi. With regard to the production and supply of Ronapreve, Roche and Regeneron are manufacturing it currently. With global demand rising, how do you secure supply is an important point. As you pointed out, considering the capacity, it is important to secure the supply for the Japanese market, by correctly understanding the necessary amount for the Japanese market, and share the information Roche and Regeneron. I would like to refrain from talking about the contents of the contract. But let's consider with that it's realistic that Chugai produce Ronapreve in Japan. Since it is an antibody drug, if you were to produce it, you need to have enough capacity for tanks and technology transfer and other things will be necessary, which takes time. If you understand this, you will understand that possibility.

I am [indiscernible] from -- I have questions Dr. Tateda and Chugai. First, I would like to note Dr. Tateda's experience of the use of Ronapreve. How many cases in your hospital received the Ronapreve? And what were the clinical courses of the patients? Also is there anything you need to be careful about when you use the drug in outpatient clinics or at home?

Thank you for your question. This morning, we had an infection control meeting at our hospital. It was reported that the 12 patients received the drug so far, that the patients' conditions are good with no major side effects. Initially, this antibody cocktail therapy had to be administered for hospitalized patients to be cautious. But now that safety has been confirmed, it was announced yesterday that it is acceptable to administer the drug to patients in outpatient clinics as long as the patients can be monitored properly. Thus, many doctors felt the drug is quite effective. Although it is too early to show it as scientific data. Many doctors told the drug had good efficacy. Importantly, the drug should be administered to patients with risk factors, including those with over 50 years old, at an early stage in outpatient clinics, to prevent the worsening of the disease. It will be important to use the drug in such a manner.

Because Ronapreve is indicated to be administer to patients within 7 days from onset of symptoms. Well, the cases in which you had to forgo because of it was more than 7 days from the onset? In other words, with an administration now possible in outpatient clinics. Do you think the number of patients who will be able to receive this will increase?

Fortunately, in our hospital, we had kept stringently to within 7 days. And selected cases in a very careful manner, as this drug requires careful administration. But as you pointed out, the important point is that efficacy for patients within 7 days of onset of symptoms have been confirmed. Therefore, efficacy after 8 days is not available. The characteristics of this drug is to suppress progression of the infection from mild state and reduce hospitalization risks. These factors need to be understood properly. And it is important that it is to be administer at an early stage after onset to patients, who do not require oxygen intervention.

My next question is to Chugai. As for Actemra, mentioned earlier, Genetix has announced that there may be supply shortages that may continue for a few weeks or months. Is there such a risk here in Japan? Is they have plans to boost manufacturing or increasing capital investment at Utsunomiya plant.

Thank you for the question. As for the global supply situation, with a surge in delta variant, the demand has increased and the global is not keeping up. And as you know, in a few months, the situation will be quite difficult. But Roche and Chugai, we're discussing possible measures. We cannot talk about specific plans, such as boosting production here. But we can say that we have already started taking actions on a number of measures, exploring ways to reduce the impact as much as possible.

In other words, for Japan, you are moving towards avoiding risks? Is that the correct interpretation?

Yes. As for Japan, we believe will not be impacted directly by the global supply shortage. However, the number of new COVID cases are surge in here in Japan, requiring us to monitor very closely the demand of IV Actemra so that we can take measures appropriately.

I have 2 questions to Chugai. First, about the usage situation of Ronapreve. It is used widely in Japan, as it is now available in outpatient setting. But after the granting of the EUA in the U.S. last year, do you probably to the fact that it takes quite a long time for IV infusion. I don't know in a sense that a huge amount has maintained and its usage compared to Japan. What is the situation in the United States and other countries where Ronapreve is approved?

Thank you very much for your question. So comparing the user situation in Japan and overseas. For overseas, for example, in the United States with EUA, it can only be administer to patients in an outpatient setting. Therefore, patients will have 20 to 30 minutes for infusion, 1 hour will grow [ submission ] before they can go home, which is an obstacle. However, I hear that a number of administration is increasing recently. I do not have concrete numbers I can share with you today, but my understanding is that the number is increasing gradually. And here in Japan, it was limited to inpatients as an IV infusion. But that is not a stumbling block here. Therefore, we understand that the amount used in Japan is higher compared to overseas post-approval.

Thank you very much. My question is regarding to Chugai is regarding AT-527. Multiple companies are now working on development of oral antiviral drugs and are entering later clinical trial stages. After the primary endpoint of these studies are achieved, how will such drugs be used? In Japan, we have universal health care. So for example, anti-flu drugs are used readily, but not in the United States or in Europe. Do you think for COVID-19 these drugs will be used by all mild symptom patients overseas. Could you share your outlook, please?