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

Welcome, everyone. I am Katsuhiro Hara, ENSPRYNG Lifecycle Leader at Chugai Pharmaceutical Company Limited. I will give you the product overview of ENSPRYNG subcutaneous injection 120-milligram syringe. Please turn to Slide 2. Therapeutic classification is pH-dependent binding humanized anti-interleukin-6 receptor, IL-6R, monoclonal antibody. The name of the product is ENSPRYNG subcutaneous injection 120-milligram syringe. A generic name is satralizumab, a genetic recombination. The packaging is, as shown on the slide, with 1 milliliter syringe placed in the box. The syringe is a preferred one as the liquid drug is in the syringe in advance and can be taken out and immediately be injected subcutaneously. Moreover, it is equipped with a system to prevent needle sticks called needle safety device, where after injection, the needle retracts into the barrel to ensure safety. Please turn to Slide 3. This slide shows the involvement of IL-6 in the pathogenesis of neuromyelitis spectrum disorders, or NMOSD. As Dr. Fujihara will explain in more detail, IL-6 is known to play a key role in the disease process of NMOSD by extending the survival of plasmablast that produce anti-aquaporin-4, or AQP 4, antibodies. Let me explain about the diagram in the middle. The anti-AQP4 antibodies are cytotoxic to astrocytes, which help nerve cells survive and function, thereby contributing to the pathogenesis of NMOSD. ENSPRYNG is thought to bind specifically to IL-6 receptors and inhibit signal transmission of IL-6, which leads to the inhibition of the pathology of NMOSD. Please turn to Slide 4. Next, I will discuss characteristics and mechanism of action of ENSPRYNG. It is the product Chugai's proprietary recycling antibody technology has been applied to for the first time. As you can see on the left diagram, usually, an antibody, after binding to an antigen, will be taken up into the cell, degraded and eliminated. On the other hand, as you can see on the right, Chugai's proprietary recycling antibody is engineered to dissociate from the antigen in the pH-dependent manner, allowing the antibody taken up into the cell to let go of the antigen under the environment of pH-6 inside of cell and to get out of the cell and bind to an antigen again. This is what we call recycling technology. As a result, the antibody has an extended half life. Moving on to Slide 5. Let me now go over the history of the development of ENSPRYNG. In 2006, the drug discovery research started. And since then, it took us a total of 14 years until it was approved and launched this year. During this period, we obtained fast track orphan drug and breakthrough therapy designations in the U.S. and orphan drug designation in Europe. As for clinical studies, a Japanese Phase I study was started in 2010 and a global Phase III study was started in 2014. Consequently, the approval was granted in June this year in Canada and Japan. And in July, in Switzerland, and in August in the U.S. In Japan, we obtained approval on June 29 this year and got the drug listed on the National Health Insurance reimbursement price list and launched it in Japan on August 26. Please turn to Slide 6. I would like to discuss ENSPRYNG's contributions to NMOSD treatment next. ENSPRYNG is a subcutaneous injection administered every 4 weeks or every 2 weeks up to the fourth week of treatment for the convenience of patients and health care professionals. For patients, benefits of subcutaneous injection every 4 weeks are the following 3 points: one, for patients who have difficulty visiting the hospital due to physical disability, et cetera, it is expected to reduce the burden of hospital visits; two, the simple injection technique reduces the burden on the patient; three, more convenient for working patients. For health care professionals, the benefits are the following 2 points: one, shorter consultation times; two, less crowded outpatient chemotherapy offices. Moving on to Slide 7. Here, you can see ENSPRYNG indication, dosage and administration. The indication is prevention of relapses of neuromyelitis optical spectrum disorders, NMOSD, including neuromyelitis optica, NMO. Precautions concerning the indication is to administer ENSPRYNG to patients with NMOSD, including NMO. Reference should be made to the guidelines for the management of multiple sclerosis and neuromyelitis optica 2017 by Japanese Society of Neurology. The data showing efficacy for anti-AQP4 antibody negative patients are limited. ENSPRYNG should be administered to anti-AQP4 antibody positive patients. As for dosage and administration, the usual dosage for adults and children is a single dose of 120-milligram satralizumab, genetical recombination administered by subcutaneous injection at weeks 0, 2 and 4 and then once every 4 weeks thereafter. Slide 8 shows illustration of ENSPRYNG's dosing schedule. Usually, a single subcutaneous injection of 120-milligram satralizumab is administered by subcutaneous injection at weeks 0, 2 and 4, and then once every 4 weeks thereafter. On Slide 9, you can see conditions for approval: one, formulate and properly implement a risk management plan; two, given the very limited sample sizes in clinical trials in Japan, conduct post-marketing all-patient drug use surveillance until data on a certain number of patients has been collected to determine the background information of the patients using the product; and two, in the near term, collect data on the safety and efficacy of the product, implementing necessary measures to ensure the appropriate use of the product. Moving on to the Slide 10, which is my last one. This shows overview of ENSPRYNG risk management plan. It is exactly as described here, but I would like to draw your attention to the parts in red boxes. As for the safety specification, we will continue to pay close attention to important identified risks, i.e., infections, neutropenia, leukopenia, agranulocytosis and thrombocytopenia. As part of additional risk minimization activities, we will provide information through early post-marketing phase vigilance and information on appropriate use before delivery. We will also create and disseminate literature for health care professionals the appropriate use guide; and for patients, information for patients prescribed ENSPRYNG. That is all for the product overview of ENSPRYNG subcutaneous injection 120-milligram syringe. Thank you for your attention.

Thank you. I am Kazuo Fujihara, Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine. I will talk about the current status of the treatment for neuromyelitis optica spectrum disorders, NMOSD, and expectations for this new drug, ENSPRYNG. You can find the slide number on the right top corner of each slide. If you can turn 1 page to Slide 12, where you can see my disclosure of conflicts of interest. Turning to Slide 13. You can see etymological facts about neuromyelitis optica spectrum disorders, NMOSD. As will be mentioned later, there is an antibody called anti-aquaporin-4 antibody that comes into play. This is one of the autoimmune diseases, which is a disease of the central nervous system with autoantibody mistakenly attacking its own cells and tissues. The total number of patients across Japan is about 4,300, though the statistics is a bit outdated. In the new epidemiological study, which is under analysis currently, it is estimated to be more than 5,000. As many as 90% of anti-aquaporin-4 antibody positive patients are female, which means that this is an overwhelmingly female-dominant disease. The age of the onset is around 40 years old. Though slightly younger and middle-aged people are most susceptible, the age groups of patients are broad, ranging from under 10 to about 90. Slide 14 shows facts about neuromyelitis optica spectrum disorders, NMOSD. In the diagram, the central nervous system, including brain, optic nerve, which extends from the brain to eyeballs and the spinal cord that extends from the brain to the back. What happens with NMOSD is the inflammation of those parts. If inflammation is observed in the nerve, it's called neuritis. If in the brain, encephalitis. And if in the spinal cord, myelitis. Symptoms of inflammation develop relatively abruptly. In the case of optic neuritis, as described on the right top, seeing becomes difficult, visual field defects occur or eyes hurt when you try to move them, if there is inflammation in the optic nerves. In the case of the brain, in the medulla oblongata, which is located slightly above the spinal cord, there's a nausea and respiratory center of the brain. If there is a lesion there, you experience incessant hiccups or nausea and vomiting. On the left bottom, you can see symptoms of myelitis. In the spinal cord, motor and sensory nerves run through it, and therefore, symptoms include numbness in the arms and legs, loss of strength, weaker sensation or sensation of intense pain and other abnormal senses. Slide 15 shows the evolution of the disease concept. Multiple sclerosis, or abbreviated as MS, is one of the representative diseases with inflammation in the central nervous system, such as the brain and the spinal cord. There was a time when NMOSD was considered a subtype of multiple sclerosis. However, since the discovery of the anti-aquaporin-4, or AQP4 antibody, and autoantibodies specific to this disease, it was learned that this is a disease different from multiple sclerosis. There is a brief history shown on this slide. In 1894, a little more than 100 years ago, as shown in the photo on the right, a French doctor, Dr. Devic, reported one case of this disease. Since then, various reports of cases followed. And in 1990s, MRI made it possible to see the lesions inside the central nervous system in more detail, which led to the understanding that it was different from MS in terms of the distribution of the lesions, among others. Then in 2004 and 2005, Dr. Lennon of Mayo Clinic and our University, Tohoku University, identified an NMO autoantibody, which was called NMO-IgG back then and later named anti-aquaporin-4 antibody. Aquaporins are like tunnels or pores through which water molecules go out of or come back into the cell. There are many kinds of aquaporins, but aquaporin-4 is in the central nervous system, especially found on the surface of the astrocyte in large numbers. These are pores through which water comes in and goes out of the cell. And in 2015, the international consensus diagnostic criteria for NMO spectrum disorder was published. And the overarching term, NMOSD, or neuromyelitis optica spectrum disorders, was proposed. NMO stands for neuromyelitis optica, but why was the term spectrum disorder attached? The disease is not just about neuritis and myelitis. But as I said before, some patients develop lesions in the brain. Therefore, given the neuromyelitis optica alone cannot represent the whole picture of this disease, it was decided that the overarching term NMOSD, neuromyelitis optica spectrum disorders, should be used for this disease. Moving on to Slide 16. Here, you can see Mayo Clinic and Tohoku University were the first report in The Lancet in 2004 that an autoantibody called NMO-IgG, which is characteristic of NMO, was detected in the blood of the patients. As you can see in the images on the right, where there are parts stained in green, when the sizes of the brain of a mouse are soaked in the serum of an NMO patient, an antibody in the serum found to have been bound to the tissues of the brain, which was stained in green. They are located in the perivascular sites and the inner surface of the brain. If you take a look at the graph on the left, you can see, it was confirmed that the antibody detected was specific to NMO in patients at both Mayo Clinic and Tohoku University. So that was a paper published in The Lancet in 2004. Slide 17. How are NMO and MS related? NMO used to be considered a subtype of MS once, but now it has been found that NMO is different from MS. Now you can see the comparison of those 2 on this slide. The main differences are highlighted in bold letters, and they are the ones that I will discuss. The male-to-female ratio is, as I said, 1:9 for NMO. While for MS, there are more female patients, but the ratio is 1:3. The age of onset for NMO is 30s to 40s, while for MS, it is a bit younger at 20s and 30s. The onset of NMO could come for people around 90, which is an old age onset case, while it is rare to see the onset of MS at the age of over 50. In terms of ratio differences, for NMO, there is a slight tendency to be more prevalent in Asia, where we live, while MS is more common in Caucasians and in high latitude regions. For instance, it is more common in Hokkaido than in Kyushu in Japan. In terms of relapse, frequency and severity, if you leave NMO cases unattended, it could relapse every year and become severer, making patients go blind or unable to walk, requiring a wheelchair. Compared to such severe cases of NMO, MS cases generally tend to be mild. NMO patients also could develop various other autoimmune diseases as complications, such as Sjögren syndrome, which makes the eyes and mouth dry, systemic lupus erythematosus, or SLE, or Hashimoto disease, a thyroid autoimmune disease. Moving over to the right table. A major difference that characterizes NMO is that lesions in the spinal cord extend across 3 or more vertebral segments, making them quite long. While in MS, lesions extend for 2 or fewer vertebral segments, making them relatively short. Now the anti-aquaporin-4 antibody is an antibody specific to this disease. And therefore, in NMO, this antibody is positive, while in MS, it is negative. On the other hand, spinal fluid, OB, or oligoclonal IgG bands, is positive in about 80% of the cases of MS, which is important in its diagnosis. But NMO, for some reason, OB is negative. Neuropathological findings are totally different between the 2. NMO is about cytotoxicity on the astrocyte, which expresses aquaporin-4. In MS, what happens is demyelination where medullary sheath is damaged. In an analogy of an electric cable, medullary sheath is plastic wrapped around the cable. And if it gets damaged by inflammation, the cable become exposed and its transmission suffers. That is kind of what is happening in MS. Regarding the prophylactic treatment, oral steroids have been used in Japan. Importantly, some drugs approved for MS often exacerbate NMO, so it is important to differentiate these 2 diseases from the beginning. Slide 18 shows the symptoms of optic neuritis. Symptoms include rapid decrease of visual acuity and visual field defects, meaning blurry vision and difficulty seeing, which worsens rapidly within several hours to several days. Symptoms may include inability to differentiate colors, things appearing bright and pain at the back of the eyes because of inflammation. In the illustration below, optic nerves come out from the eyeballs, they go through optic chiasm, where right and left optic nerves cross and then go down to the back. And they are now called optic tracts. Depending on the location of the lesions, different visual field anomalies may happen. Examples are shown on the right. Far left, central scotoma means you cannot see the center. You may not see the outer parts of both sides. Homonymous hemianopsia means you may not see the half. With altitudinal hemianopsia, you may not see the upper half. There are various patterns of visual feed anomalies depending on the lesion. Slide 19 shows the symptoms of myelitis, including paralysis and weakness as well as numbness and pain. The diagram shows various patterns of paralyzed areas in pink. Far left is hemiplegia, showing the left limbs are paralyzed. This is often seen when there is a lesion such as cerebral infarction on the right brain. Next to it is paraplegia, when there is a lesion in the spinal cord. In this case, around the chest. Next to it is quadriplegia, when the lesion is in the cervical cord. When the lesion is only a part of the cervical cord, monoplegia, on the far right, could be seen. As shown in the bottom right illustration, in addition to the sensory and motor dysfunctions, excretory disorder may be seen such as difficulty urinating or defecating, frequent episodes, sudden urge to urinate, no relief after urinating or incontinence. As shown on the bottom left, patients complain that tingling or lightning-like pains are quite bothering. Painful tonic convulsions mean when you stand up or start moving, your limbs cramp and you cannot move. It's painful, but it will go away soon. But it happens repeatedly, and it is a big problem. Slide 20 shows the lesions in the brain. Most common one is the inflammation on the medulla oblongata, where there is the center for breathing and nausea. Hiccups may persist or you have nausea. Sleepiness may occur when the lesions are in the hypothalamus, shown on the right bottom. When there is a lesion here, you have problems being awake and feel sleepy all the time. When the inflammation is in the cerebrum, depending on the location and the extent, your thinking may be unclear or your decision-making ability may be compromised. Or as I explained earlier, you may suffer from the hemiplegia where limbs on the other side may be paralyzed. So depending on the site of the brain, symptoms are totally different. Slide 21 explains fatigue and malaise, which bother many NMO patients. When you walk a little, you're tired, and you need to take some rest. You feel heavy and get tired very easily. This is another big problem. Slide 22 shows the relapses and course of this disease. If untreated, patients suffer a relapse every year. And every time they have relapse, their disabilities become more serious. As shown in the red, frequency of relapse is more than once a year. One episode of optic neuritis may lead to blindness, or one episode of myelitis may make the patient wheelchair-bound. As for the sign of relapses, it is said that brain syndromes may precede myelitis. In relapses, sequelae are more common in patients resistant to acute-phase therapy. In the past, when a patient is pregnant, immunosuppressing treatment was discontinued, considering the risks for the fetuses. Then it was found that the patients have 4 or 5x higher risk of relapses for 3 to 6 months after the delivery. Thus, some kind of immunosuppressing treatment is now continued during pregnancy to reduce the risk of relapses. In the bottom right graph, red bars show acute exacerbations, which happens occasionally and light blue areas in between are remissions. Every time the patient has a relapse, there's more disabilities. So it is important to prevent relapses to stop the progression of the disease. Let me show you some cases in Slide 23. Case 1 is a 36-year old woman. She lost the vision in both eyes suddenly. She cannot sense the light. It is serious optic neuritis. And when the lesion is at the crossing of the optic nerves, one lesion causes the blindness of both eyes. Three months later, she had the paralysis of both lower limbs, sensory disturbance below abdomen, and had difficulty urinating and defecating. The lesion extends the whole cross-section of the spinal cord called transverse myelitis. She did not improve afterwards. So very severe optic neuritis and myelitis occurred in succession. Case 2 is a 64 years old woman. When she was 60, she lost sight in her left eye due to optic neuritis. Although she received treatment with immunosuppressants, such as azathioprine and corticosteroid, she had 7 relapses. So she was blind in her left eye and bound to wheelchair. She had intense pain and numbness from the chest down. You will understand that the disease can have very serious courses. Slide 24 shows the blood testing. As repeatedly mentioned, it is important to test anti-aquaporin-4 antibody, or anti-AQP4 antibody, for this disease. Another test is cerebral spinal fluid testing. When anti-aquaporin-4 antibody, or anti-AQP4 antibody, are detected in the blood, it means the patient has NMOSD. So it is a very important test for diagnosis. As shown on the right, lumbar puncture is another important test for this disease. Cerebrospinal fluid is taken from the spinal cord at the lumbar area to detect the increase of cells or proteins. Slide 25 shows the MRI images for this disease. There are 4 of them. Far left is the corpus callosum lesions in NMOSD. There are many white lesions in the fish hook-shaped area, which is the corpus callosum, which connects right and left brains. This image is a lateral view of the brain, cut lengthwise in the middle. Second image is a little larger, and you see an eye ball. Around the ventricles or holes in the brain, you see white lesions like brushstrokes. It is characteristics of MS and called Dawson's fingers, named after Dr. Dawson, who described this finger-like lesion. It is a characteristic of MS. The 2 images on the right are spinal cord lesions, showing the differences between NMOSD and MS. In the case of NMOSD, the red arrow shows the white shadow extending 3, 4 or 5 vertebra. It is a long lesion. On the other hand, in the case of MS on the far right, the lesions are much shorter. MRI scans are very important for differential diagnosis between NMOSD and MS. Slide 26 shows the evaluation tool for disability called EDSS, or Expanded Disability Status Scale, mainly evaluating the ability to walk. Zero means normal. And the higher the number, severer the disability. And 10 is death due to the disease. Scores show the status from being able to run, needing a cane, needing a walker, to needing a wheelchair. It is a very reliable evaluation scale for MS, not created for NMOSD. But it is often used for NMOSD, although there are not many evidences. Slide 27 shows the international consensus diagnostic criteria for NMOSD published in 2015. It is diagnostic criteria of NMOSD for adults. Mainly, there are 2 main categories shown in red. First is aquaporin-4 antibody positive NMOSD. The other is NMOSD without aquaporin-4 antibody or unknown status. In the case of aquaporin-4 antibody positive, criteria require at least one clinical symptom of NMOSD. You may think that the neuromyelitis optica means the patient needs to have both optic neuritis and myelitis to be so diagnosed, but when many patients with aquaporin-4 antibody were studied, it was found that some patients have both optic neuritis and myelitis, some repeatedly have optic neuritis only, and others repeatedly have myelitis only. Some patients have lesions in the brain such as medulla oblongata and have hiccups. These are all the same disease with different types of manifestations. Therefore, one clinical symptom is enough. Then aquaporin-4 antibody is positive and alternative disease can be eliminated. Then aquaporin-4 antibody positive NMOSD is diagnosed. On the other hand, aquaporin-4 antibody negative, NMOSD, may include various diseases. The diagnostic criteria are more stringent, although I'm not going to explain this in detail. Today's topic, ENSPRYNG, is mainly used for aquaporin-4 antibody positive, NMOSD. Slide 28 shows the treatment of NMOSD. It is composed of 3 categories: acute stage treatment, prevention of relapses and symptomatic therapy for sequela. For acute exacerbations or early stage of relapses, main therapy is steroid pulse therapy, that is a high-dose steroid is infused. If it doesn't work, plasma purification or immunoglobulin infusion is used. On the other hand, steroids and various immunosuppressants have been used for prevention of relapses. And now satralizumab, ENSPRYNG, and other monoclonal antibodies have become available, meaning molecular targeting therapies are now available. As for symptomatic therapy for sequela, various therapies are used for paralysis, dysuria, painful tonic convulsions and conservation of motor functions. Slide 29 shows unmet needs in NMOSD treatment. Drugs were used off-label because there were no drug indicated for NMOSD. Suppressing relapses is important for prevention of severe disabilities, but a high-dose oral steroid was often used to prevent relapses in Japan. Although it may be effective, some patients are refractory and long-term use of steroid may give rise to various side effects, which are difficult to manage. For example, various infections, osteoporosis leading to pathologic fractures, high glucose levels leading to diabetes and moon face. Side effects of steroids are very problematic. From Page 30 onward, I'd like to talk about the correlation between IL-6 and pathophysiology of NMOSD. This slide was shown at the beginning of the presentation to explain pathophysiology with anti-AQP4 antibody and astrocyte cytotoxicity. In NMOSD, AQP4 is expressed on the surface of ASTRO sites. AQP4 is a tunnel or a hole through which water molecules go in and out of a cell. And this becomes a target of immunological attack and ASTRO sites are damaged, which leads to demyelination and neuroaxonal cytotoxicity. So NMOSD is regarded as an autoimmune astrocytopathy. A schematic diagram is shown on the slide. The pink circle on the left is a blood vessel of brain or spinal cord. In it, alveolar lymphocytes and plasmablast indicated by an oval pink cell is shown at the top part. And anti-AQP4 antibodies are produced, which are shown as pink Y-shaped objects. They pass beyond the wall of the cell, the astrocyte in reddish brown is around the blood vessel. And yellow one on the surface of the blood vessel is AQP4. When the antibody passes beyond the wall of the blood vessel, it binds to AQP4 as a result of the binding complement, which is a fluid element of immunity, is activated to make holes in cells to damage astrocytes sites. Then axon, nerves and myelin around astrocytes are damaged secondarily. This is the basic pathophysiology of NMOSD. On the next page, IL-6 is added in red to the previous slide to explain how IL-6 is involved in this mechanism, and IL-6 is involved in many places. IL-6 effect lymphocytes and plasmablast and admittedly to promote reduction of anti-AQP4 antibodies. The antibodies pass beyond the wall of the blood vessel and reach AQP4 in yellow on the surface of astrocytes. IL-6 disrupts the pink wall of the blood vessel or blood-brain barrier to help antibodies bind to AQP4. Astrocytes, which is shown in the center, secretes IL-6 by itself. And at the lower right, it is indicated IL-6 is involved secondarily in damaging neurons and myelin. As such, IL-6 plays an important role in multiple places in this pathophysiology. Page 33 is about high blood IL-6 levels with NMO patients. And the chart shows blood IL-6 levels of control, all subjects without NMO. And next to it is NMO patients in remission. And the one on the right is NMO patients at the time of relapse. As you can tell, blood IL-6 levels are significantly high with NMO patients with relapse. Page 34 is about importance of IL-6 in NMO. The graphs show another study result to indicate patients with NMO had higher levels of IL-6 in the serum and CSF than patients with other diseases. The left graph is for blood IL-6 levels and the right one is for CSF, and both indicate many NMO patients had high IL-6 levels. Page 35 indicates the correlation of CSF IL-6 with clinical and test parameters in NMO. The graph upper left says GFAP, which is protein of astrocytes, and detection of GFAP in CSF indicates astrocytes are damaged. The graph at the upper right shows the correlation with CSF cells or with the level of inflammation. And the one at lower left shows the correlation with anti-AQP4 antibody. EDSS indicated at lower right is about severity, and IL-6 is correlated with severity. As such, IL-6 is closely correlated with clinical and test parameters, and this means IL-6 is deeply involved in the pathophysiology of NMO. Next page is about CSF IL-6 and NMO outcomes. The bar chart on the left compares NMO patients with low IL-6 and the ones with high IL-6 to see how much EDSS score improvements were achieved. If severity is improved from 6 to 3, 3 points improvement. And from 6 to 5 is just 1 point improvement. According to the graph, patients with high IL-6 have less improvement than patients with low IL-6. The EDSS scores did not change significantly, and this means no improvement in severity. The graph on the right indicates the rate of relapse-free survival for NMO with high IL-6 and NMO with low IL-6. Over time, NMO with high IL-6 relapses occurred one after another, and the rate of relapse-free survival substantially dropped. On the other hand, NMO with low IL-6, the number of relapse-free patients was higher. This indicates NMO with high IL-6 is more susceptible to relapse and more difficult to control. Next, I'd like to talk about clinical data announced last year from global Phase III, double-blind, randomized, parallel group comparative study. This is a combination study conducted by adding ENSPRYNG to baseline treatment such as corticosteroid or immunosuppressant. It is called as SAkuraSky. This study was multicenter, placebo-controlled, randomized, double-blind, parallel group study. And study patients were randomized to 2 groups at 1:1. All of them had been using corticosteroid or immunosuppressant before this study. And ENSPRYNG or placebo were additionally administered to them for the double-blind study to compare the occurrence of relapse. Primary endpoint was time to first relapse and secondary endpoint covered pain, fatigue and others. Page 39 explains study synopsis during double-blind period. The study patients were randomized to ENSPRYNG or placebo at a 1:1 ratio. And both groups continued baseline treatments with corticosteroid or immunosuppressant. And if patients experienced the relapse in this period, then they could start receiving ENSPRYNG. And the decision to continue their baseline treatment or not was made depending on their conditions. As such, the significance of this study was in comparing relapses between the 2 groups in a double-blind manner. This page is about patient characteristics. Age is indicated on the left, and the mean age was around 40 years old. And over 90% of patients were female. This study was a global study and about 1/4 of the patients were Japanese, and about half of them were Caucasian. The second item on the right is about anti-AQP antibody and about 66% to 67% or 2/3 of patients were positive, and the remaining patients were negative. As for baseline treatment, they were using corticosteroid or immunosuppressant like azathioprine. This slide shows time to first relapse. The graph indicates the proportion of relapse-free patients. The gray line is placebo group, and it is lower than ENSPRYNG group indicated by a red line. This means more patients experienced relapse. This comparison is made for the overall study population. And the risk of relapse decreased with the ENSPRYNG group by 62% compared to the placebo group. If it is limited to patients with anti-AQP4 antibody positive subgroup, time to first relapse indicated more significant difference between the 2 groups, as shown by the graph. In this case, the ENSPRYNG group decreased the risk of relapse by 79% compared to the placebo group. Page 43 is about subgroup analysis for Japanese and non-Japanese subgroups. For overall Japanese population, 11 patients were randomized to ENSPRYNG and 10 were placebo. And for anti-AQP4 antibody positive subgroup on the right, ENSPRYNG was 10 and placebo was 9. Below that, PDR or protocol-defined relapses are described. And none of the Japanese patients in the ENSPRYNG group experienced relapses, but in the placebo group, 3 patients out of 10 or 9 experienced relapses. This is about safety evaluation and the ENSPRYNG group adverse drug reactions were not significantly higher than the placebo group. As described below the table, the most common adverse drug reactions in the ENSPRYNG group were decreased white blood cells, injection-related reaction and decreased lymphocytes. As for the serious adverse drug reaction described below, pneumonia was reported in 1 patient in the ENSPRYNG group. No deaths were reported in this study. SAkuraStar is a global monotherapy study conducted mainly in North America. This used ENSPRYNG or placebo without concomitant drugs like immunosuppressant. A study synopsis was similar to the study explained earlier, but in this study, 95 patients were randomized at 2:1, 2 for the ENSPRYNG group and 1 for the placebo group to compare time to first relapse between the groups. This is about how the drug was administered to the patients. As I explained, patients were randomized to either ENSPRYNG or placebo at 2:1 with 63 for ENSPRYNG and 32 for placebo. Patients who experienced the relapse, then they were administered with ENSPRYNG. This is patient characteristics. Regarding age, they were in early 40s, and 80% to 90% were female. As for race or ethnicity, about 60% were Caucasian and Asians were 10% to 20%. The second item on the right, anti-AQP4 antibody, again, 60% to 70% were positive and about 30% were negative. This is the result of the study. This graph shows time to first relapse by the proportion of relapse-free patients. The ENSPRYNG group reduced the risk of relapse by 55% compared to the placebo group. This is the analysis for anti-AQP4 antibody positive subgroup. The difference between the 2 groups is larger than that of the overall study population. The ENSPRYNG group reduced the risk of relapse by 74% compared to the placebo group. Some of you may have already noticed, but compared to SAkuraSky, a combination study with baseline treatment by immunosuppressant, the reduction of relapse risk is slightly smaller. This is probably because that the baseline treatment was effective to some extent and higher efficacy was indicated when it was combined with ENSPRYNG. This is about safety. As described below the table, the most common adverse reactions in the ENSPRYNG group were injection-related reaction and diarrhea. The serious adverse drug reactions were pneumonia and pulmonary sepsis. No deaths were reported in this study as well. Indication, dosage and administration. Indication is prevention of relapses of neuromyelitis optica spectrum disorders, including neuromyelitis optica. ENSPRYNG is administered to patients who are positive for anti-AQP4 antibodies as there is limited data on the efficacy in patients who are negative for anti-AQP4 antibodies. As for dosage and administration, in SAkuraSky, there were about 8 patients who are younger than adults, and the efficacy were equivalent to adults. Therefore, dosage and administration include children and a single dose of 120-milligram satralizumab administered by subcutaneous injection once every 2 weeks for the first 3 doses and then once every 4 weeks thereafter. Next page describes expectation for ENSPRYNG. The remarkable relapse-preventing effect and good safety profile of ENSPRYNG were observed in anti-AQP4 antibody positive patients that were evaluated in 2 global Phase III clinical studies. Subcutaneous injection every 4 weeks is convenient for patients. And as I just mentioned, based on the data of a limited number of adolescent users, ENSPRYNG can be used in children for wider indication. In summary, as for progress, the concept of anti-AQP4 antibody disease has been established, and its pathophysiology has been elucidated to identify a quite important role of IL-6. And ENSPRYNG has become available as a molecular targeted therapy to inhibit IL-6 signaling. Although this has a significance, there are some issues. As diagnosis-related considerations, we should note that some cases are difficult to be diagnosed. I repeatedly said, spinal cord lesions of NMO is long with 3 or more vertebral segments. But in some cases, lesions are shorter than that. And the precision of currently used anti-AQP4 antibody test is another issue. Any task could generate false positive or false negative results. So it is necessary not to be bound by the test results, and all the clinical information should be examined totally. Next issue is to establish measures of disease severity and biomarkers of disease activity. They would help physicians prepare better treatment plans by estimating when relapse could occur or if more relapses can be expected for a patient. That is a challenge for the future. The third issue is determining the characteristics of patients who relapse while on the molecular targeted drug and reducing concomitant drugs. If concomitant drugs can be reduced, adverse drug reactions can be reduced as well. So this is another important issue. And lastly, efficacy of the treatment for anti-AQP4 antibody negative patients could not be clearly observed in these studies, but they include cases with anti-MOG antibody positive disease, which is an antibody to myelin protein, even though I did not explain today. Therefore, it is a substantial issue for the future about how we should treat this anti-AQP4 antibody negative NMOSD. That is all from me. Thank you for your attention.

I am Hashiguchi from Daiwa Securities. There are several questions I want to ask Dr. Fujihara. First of all, I'm interested to know how you are going to choose which of the 3 drugs to use. Satralizumab, eculizumab approved earlier than satralizumab, and inebilizumab, which is expected to be approved next year. With regard to efficacy, if I compare Kaplan-Meier curves of the 3 drugs, though I do know it is not a correct way to simply compare those curves from different studies, the satralizumab arm seems to have slightly more cases of relapse right after the initiation of the administration than the other 2, which makes me wonder if there are possibly some nonresponders. So could you tell us your view on the efficacy?

Thank you for your question. It is true that we want to prevent a relapse that would happen before the effect of the drug administered kicks in. Therefore, the way to start on satralizumab is probably to use it in combination with other drugs, to some extent, initially, to ensure there won't be any relapse until the drug starts to work for the disease. You mentioned nonresponders, but the characteristics of those patients who did have relapse should be analyzed further for satralizumab. On the other hand, Soliris, approved in November last year, is a monoclonal antibody targeted against a complement. As you know, it has reduced the risk of relapse by 94%, proving to be a highly effective drug. What we do know from another indication, PNH, a hematological disease, is that 3.5% of the Japanese people or 1 out of every 30 have a genetic mutation in the complement C5 making it difficult for eculizumab to bind to the complement. In those cases, the expected effect of eculizumab of inhibiting the cleavage of C5 into C5a and C5b cannot be relied on. Those are exactly what we call nonresponders. What we need to do is to identify those patients early on and choose the most appropriate treatment. Now as to the question of how I am going to use those 3 drugs, since there are no clinical trials done yet to look at head-to-head comparisons, I cannot casually comment on that. Moreover, it is not just efficacy and mechanism of action that matters, but the fact that eculizumab requires an infusion every 2 weeks, while satralizumab needs subcutaneous injection every 4 weeks. And the one expected to become available next year which depletes B cells will need infusion every 6 months. Does the patient have a job or children to raise or wish to become pregnant, those considerations as well as the method of administration could make difference.

What about safety? Satralizumab could mask underlying infectious diseases. And therefore, patients need to be checked before starting on the drug whether they have been infected with tuberculosis and others. While patients on eculizumab need to be vaccinated for meningitis and inebilizumab requires a drug used in combination to control infusion reactions. So each of the drugs requires attention of some sort. Do you, as a physician, feel any difference in the degree of attention required among the 3 drugs?

As for eculizumab, since it inhibits a complement, it does increase the risk of getting infected with meningococcus. So every one of the patients on eculizumab needs to be vaccinated. But meningitis B is not covered by the vaccine used currently in Japan. Moreover, simply vaccinating patients may not necessarily ensure they will develop antibodies. Therefore, although there have never been any case of infection in NMOSD, there's always that risk. And in other diseases, there are cases of deaths in a day or so after they got infected with meningococcus. Therefore, what many are considering as a possible solution is to ask every patient to carry an effective antibiotic with them. And if they have high fever, they need to take their medicine first and then to get in touch with their physicians so they can curb infection. I don't believe vaccination can control everything. With regard to satralizumab, if IL-6 is inhibited, even if the patient develops an infectious disease, they may not have high fiber or may not see CRP go up in a blood test, an infection marker we often use. Thus, it is hard to see whether the patient has an infectious disease, and we'll need to remain vigilant. But during the clinical studies, there are no cases where this became a serious issue. As for inebilizumab, you mentioned infusion reactions, but in its clinical studies, more infusion reactions were experienced actually by patients in the placebo arms. What makes neurologists extremely nervous about multiple sclerosis drugs recently is progressive multifocal leukoencephalopathy, or PML, where JC virus gets mutated and causes an illness in the brain and even death if it gets very serious. So with a treatment with a drug that depletes B cells, patients could develop a complication like PML, albeit infrequently. So we will all need to be mindful of those issues.

Very clear. Another follow-up question. In the package insert, it was mentioned that anti-satralizumab antibodies were observed in many patients. Am I correct to assume that this is because the drug is being recycled? And to what extent does this affect your choice of satralizumab? And there's another question I want to ask, if you know the answer. We're interested in not just NMOSD, but future possible additional indications. Do we not have to worry about the possibility that it was not an issue for NMOSD, but could become serious in other diseases. If someone from Chugai could add some comments, that will be appreciated. But as far as I understand, it is true that satralizumab is more likely to trigger generation of anti-satralizumab antibodies than conventional antibodies. At least in the analysis done so far, it is not the case that any evidence has been obtained to show that patients with anti-satralizumab antibodies start to respond less. Therefore, my understanding is that although antibodies that bind to the drug are generated, it has not affected the action of the drug so far. If someone from Chugai has some more comments to add, I would like to hand it over.

Thank you for the question. Hara from Chugai speaking. So far, as for anti-satralizumab antibodies, there has not been any major impact on the safety or efficacy of the drug in the Phase III clinical study, as Dr. Fujihara answered. With regard to future potential addition of indications, since the pathologies will differ from disease to disease, we'll need to give more thoughts to dosage, administration and safety, which you recognize as one of our future challenges.

Yamaguchi from Citigroup Global Markets, Japan. Thank you for your very easy-to-follow presentation today. My first question has to do with the positive and negative cases of anti-aquaporin-4 antibody. In both of the studies, the rate of negative cases was 1/3 approximately. But in the actual clinical practice, do we understand correctly that about 1/3 of the patients are negative as well and therefore, not eligible for this antibody treatment?

In case of adults, if tests are done in different geographic regions, the accuracy of antibody tests is not necessarily the same, but the patients that tested positive account for 60% at the lowest and 90% at the highest. Therefore, a value somewhere in between is not that far-stretched and, in fact, seems reasonable. However, when it comes to how to define the negative cases, as I said, it still remains open to discussions. As I showed with my last slide, some tested positive for anti-MOG antibody or other specific antibodies while others tested negative for both anti-aquaporin-4 and anti-MOG antibodies. Probably, patients in this category are heterogeneous in nature characterized by not a single disease, but a mixture of multiple diseases. Furthermore, some in this category could have anti-aquaporin-4 antibodies even though they are undetectable by the antibody test done at that point in time because there are some who tested negative at the time of initial onset of the disease, but tested positive at the time of relapse. Therefore, we still have much more to learn about the patients in this category.

I see. Then it is my understanding that for those patients, neither of the existing monoclonal antibody drugs are indicated yet and that you are now treating them with the combination of other drugs used to prevent relapse and curve progression such as corticosteroid, immunosuppressants, plasma purification and immunoglobulins, am I correct?

Well, that is the case so far. The clinical study for Soliris, anti-complement C5 was conducted only for anti-aquaporin-4 antibody positive patients. Thus, there is no data now about how effective the suppression of complement is for anti-aquaporin-4 negative NMOSD patients.

I see. Apart from satralizumab, how do you use various drugs for the treatment of NMOSD patients currently for prevention of relapses and slowing progression, oral steroid, immunosuppressants, eculizumab and others. What do you use mainly in terms of the number of patients?

Well, in Japan, traditionally, steroid is used very often. In addition, azathioprine, Imuran among immunosuppressants has often been used. On the other hand, recently, some patients developed another neurologic autoimmune disease, myasthenia gravis, together with NMOSD. Tacrolimus, Prograf is approved for myasthenia gravis, or MG, and it is thought that it can treat both MG and NMOSD. But it is not a very cheap drug and no clinic trial was conducted for NMOSD. So we always worry that it may not be reimbursed in national health insurance.

How much monoclonal antibodies do you use for the treatment now?

As for monoclonal antibodies, Soliris was approved in November last year, and about 50 cases received so far. One issue is that it needs to be infused every 2 weeks, and annual cost is about JPY 60 million. Advantage of satralizumab is that it is less expensive than that, and it is administered by subcutaneous injection. Self-injection may be possible in the future, and patients can have longer interval between visits. Now most of the patients in the U.S. have been using rituximab or Rituxan, and I think they are now experiencing the changes with satralizumab.

This is Sakai from Crédit Suisse. Thank you for your very informative lecture. I think you mentioned that the number of patients in Japan is about 5,000 or higher according to the latest epidemiology study. How many new patients are there annually? Are there cases where a patient was thought to have MS, but now it is correctly diagnosed as having NMOSD?

Yes. Thank you for your question. A new nationwide epidemiology study was conducted last year. Preliminary results were reported at a study meeting at the beginning of this year. The number of patients seemed to be more than 5,000 according to the report. I think the final data are being put together now. There is a tendency that the number of patients increases for other autoimmune diseases as well, maybe due to the improvement of diagnosis. I understand the number of NMOSD patients is more than 5,000. As for the number of new patients a year or so-called incidence, I do not know if the epidemiology study is able to show the incidence. The prevalence is known, and it is about 5,000. This nationwide epidemiology study is the first one in more than a decade. Ideally, the designated intractable disease system should register all the patients using the new diagnostic criteria. Then you will understand the prevalence and the incidence every year. But according to the current registration system, there is a cutoff by the severity of the disease or only patients with mild symptoms are registered. So the total number of patients cannot be obtained from the designated intractable disease system. This is a problem. And so epidemiology study is occasionally conducted. I think the designated intractable disease system should register all patients, then we can answer questions like the one you asked correctly. Thank you.

Basically, NMOSD patients will continue their therapy throughout their lives?

Well, it is a very important question. In the case of MS, whose differential diagnosis from NMOSD was a problem, a recent topic is aging of immune system. If the patient is over 55 years of age and MS is controlled for several years, tapering down of the treatment may be possible. It is a recent topic. On the other hand, some patients newly developed NMOSD in their 80s and 90s. There is another important consideration. If the patient relapses and no immunosuppressant is being used, the severity is overwhelmingly worse compared with the case where the patient is receiving some immunosuppressant such as steroid. There were cases where the therapy was discontinued and patients were not receiving any treatment when they relapsed and then became blind. So it is very risky now to say that you can discontinue the therapy if the disease is controlled for a certain period of time. Some patients may be fine, but if they relapse, I worry that more serious sequelae may result.

This is Muraoka from Morgan Stanley. Regarding the 3 drugs mentioned earlier, Soliris, ENSPRYNG and inebilizumab, how are they used differently? My understanding from your lecture is that Soliris is very effective, but it is expensive and needs to be infused every 2 weeks, so a little troublesome. Conversely, satralizumab, ENSPRYNG is for a monthly subcutaneous injection and self-administration will be possible in the future, and it is inexpensive. So it is quite easy to use. On the other hand, inebilizumab has the issue of side effects such as PML. It is administered every 6 months. From your point of view, I thought 6 months is a little too long not to see the patient with such a major potential side effect and you may be concerned. Is that since satralizumab is an easy-to-use drug and doctors may want to use it? Is my understanding correct?

Of course, that is one way to understand. As I mentioned earlier, if you know what is the mechanism of the effects for the patient, for example, complements are especially important for this patient or IL-6 is important for that patient or B-cell is important for this patient, if you know the mechanism, it is rational to select a treatment based on the mechanism. The dosing methods and intervals are totally different. Then you may also have to consider the personal situations of the patients, for example, extremely busy with work or have children or want to get pregnant. Consider these and then dosing methods or intervals will also need to be taken into consideration when deciding the therapy. Also, 94% reduction of risk of relapses by Soliris is very impressive. If you simply calculate the relapse rate of patients in Soliris arm, it is like once in 62 years. The average age of the onset of this disease is about 40. Simply put, if you start the Soliris, then next relapse may come when you are 102 years of age. When I say that patients may never experience relapse, some neurologists are quite impressed. So the efficacy is good, but potentially fatal meningococcal infections were observed for its previous indication. So you also need to be aware of that when you use it.

I understood. May I ask one last question. According to the study data of satralizumab, it seemed to be effective also on anti-AQP4 antibody negative patients to some extent. So I personally had expected the drug would be approved for the indication for those patients, but its indication was limited to the positive patients. Are you disappointed a little with this limitation? Or do you think it is reasonable based on the clinical study data?

The evaluation at the predefined time point showed reduction of the relapse risk by 32% or so compared to placebo, even for patients with anti-AQP4 antibody negative. But if you follow the Kaplan-Meier curves shown earlier for the satralizumab group and placebo group, they almost overlap each other. So it may not be obvious if you focus on a certain point, but in the study SAkuraSky, which Japanese participated as well, the group with negative antibody were only 28 in total, with 14 allocated to each group. It is hard to derive a conclusion from such a small number of samples, but according to the overlapping Kaplan-Meier curves, it will be difficult even for the experts to be certain about the efficacy. Also, as I said in the earlier answer, this negative group could include patients with different diseases. So it could not be effective for some patients but could be effective for others. As such, we should not consider the patients in the negative group are the same. At least anti-MOG antibody positive disease has been identified now, but it is still unknown how many patients in the negative group in the SAkuraSky study had the disease. Therefore, further investigation is required in the future. For your information, we have analyzed 27 cytokines in acute phase CSF of anti-AQP4 antibody positive NMOSD and anti-MOG antibody positive disease. And these 2 diseases are similar in terms of increased Th17-related cytokines, including IL-6. So I think satralizumab could have efficacy on it as well. But it is very difficult to mention something clearly about the negative patients without further research. That is my observation.

I am Arai from Merrill Lynch. I have a simple question. I'd like to ask about your prospect about how many of those 4,300 patients will be able to access to such new therapies with satralizumab, Soliris or inebilizumab. I understand Soliris is currently used by only about 50 patients due to its high price and other reasons, but by the launch of ENSPRYNG and inebilizumab, can I assume these new therapies will be applicable to all of these 4,300 patients or certain number of patients will continue to use current corticosteroid or tacrolimus, depending on their symptoms or age? I'd like to know if you have any idea about how many of them will be able to receive such therapies.

This is a very important issue. But honestly speaking, I do not have an instant answer to this question. I think the expensive treatment by Soliris is one of the reasons for people to hesitate to use it. But now a clinical study is conducted for Soliris to develop a drug formulation for once every 8 weeks administration. If complement treatment can be switched to such a drug burden, a frequent visit as once every 2 weeks can be alleviated a little. It is true that there are patients who can control the disease with existing corticosteroid or immunosuppressant, and they may not have to switch to the new therapies. But according to my daily clinical experience, I know, for example, there is a patient who controls the disease by tacrolimus, which is not so an inexpensive drug. So as new drugs are approved after official clinical studies, it might be questioned. Why those approved drugs are not used? And tacrolimus might not be able to be used with insurance coverage. So I think it would be possible that we will be encouraged to use those approved new therapies. Another point is the risk of relapse. It seems the risk level is not uniform throughout the duration of the disease. To be more specific, it is reported that patients often experience relapses in 1 or 1.5 years after relapse. And if that is the case, drugs said to be expensive can be administered during the period of 1 or 1.5 years after relapse to prevent next relapse. Then after that, it can be replaced with milder drugs. I think such treatment will be considered in the future. So it is not like using a same drug forever, rather, it can be used at the beginning as an induction to put out a fire, then move on to deescalation with milder drugs. I suppose discussion will be made in the future about changing treatment like this in different stages of the disease. Considering such a situation, I cannot answer with a specific percentage of patients right now.

I am [ Hashimoto ] from Nikkei BP. I have just one question. I guess pathophysiology of NMOSD became clear, and these 3 drugs have been developed almost at the same time. Do these 3 drugs satisfy the treatment requirement? Or do you think there will be more new drugs developed for different targets, for instance, an antibody to inhibit anti-AQP4 antibody itself? I appreciate if I could have any information about it, if you have any.

This is another important question. Regarding the antibody to inhibit anti-AQP4 antibody itself, an U.S. group developed a monoclonal antibody named aquaporumab. This binds to AQP4, but it is genetically modified in the part to activate complement as well as in the part to bind to a cell to damage astrocytes, so that harmless aquaporumab can bind to AQP4 and inhibit binding of pathogenic anti-AQP4 antibodies. Such an antibody was developed by a U.S. group. This is a very disease-specific antibody. However, to date, it has not become a subject of clinical studies. This is too specific to be used for other purposes and probably this is because pharma companies hesitate to work on this antibody. Also in the acute stage of this disease, neutrophil and eosinophil, such granulocytes of white blood cells infiltrate. Small-scale studies are conducted for drugs to reduce activation of such neutrophil and eosinophil. So I think new drug development will continue by focusing on different aspects of the pathophysiology of this disease. All existing drugs suppress the immune system to prevent relapses. But I suppose, neuroscientific efforts are necessary to promote recovery from neural damage. Satralizumab has also been expected for the following efficacy. When myelitis develops in this disease, severe pain and numbness remain after inflammation subsides. As Hippocrates said, removing pain is one of the fundamental purposes of medicine. Regardless of IL-6 signal involvement, developing treatment for such symptoms have not been conducted at all. Although satralizumab has been expected to have such efficacy, regrettably, it was not clearly indicated in the studies. However, I believe there is room for further consideration. So treatment development for various aspects of the disease will be continued in the future. Thank you.