Thank you very much for joining us today for Takeda's online disease seminar. Despite your very busy schedule, I'm the master of the ceremony today. My name is Iwamuro from IR. Thank you very much for this opportunity. Allow me to explain about the language setting for today's program. Please find the language button at the bottom of the Zoom window. If you wish to listen in Japanese, please select Japanese. If you wish to listen in English, please select the English language channel. I'd like to remind everyone that we'll be discussing forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those discussed today.
The factors that could cause our actual results to differ materially are discussed in our most recent Form 20-F and in our other SEC filings. Please also pay attention to the important notice indicated on the second page of the presentation material today. Today, for the presentation as well as the Q&A, we have from Japan Medical Office, Rare Disease Medical Expert, Gen Suzuki, Rare Disease Medical Franchise, Medical Office, Medical Unit Head, Sanghun Iwashiro, are joining us. We would like to ask Suzuki-san to give a presentation first. Please find the material in front of you, which should be disclosed on our website by now. Please download the file. I would like to hand over to Suzuki-san.
Thank you for the kind introduction, Iwamuro-san, and very nice to meet you all. My name is Suzuki, and I'm a medical expert at the Japan Medical Office. I work in rare diseases at Takeda, but I also see patients at the internal medicine clinic. My specialty originally was cardiology, and I was previously an associate professor in the Department of Cardiology at the State University of New York School of Medicine for about 20 years, involved in clinical and basic research. I really appreciate today's opportunity.
Today's presentation is about Gaucher disease, Fabry disease, and Hunter syndrome, but before that, I would like to introduce what lysosomal storage disease is. Next slide, please. First, I'd like to give you an overview of lysosomal storage diseases. It will be starting from page four of the slide deck. First, let me explain about the lysosome. Lysosome is a 0.1-0.2 µm organelle discovered by Belgian researcher Christian de Duve in 1955. It was thought to be an organelle mainly found in liver cells and leukocyte cells where intracellular degradation products were processed.
However, it is now thought to have other functions besides that, such as endocytosis, autophagy, and salvage, as well as cellular metabolism and homeostasis. An enlarged image of the cell organelles and lysosomes is shown at the bottom of the slide, as shown on the right-hand side image. Normally, in the lysosome, hydrolytic enzymes shown in green break down a substance called substrate presented by the small blue circle. In this figure, only one lysosome is magnified, but there are actually 50-1,000 lysosomes in each cell.
Next slide, please. Lysosomal storage diseases, LSDs, are caused by congenital deficiency of the hydrolytic enzyme indicated in green, leading to the intracellular accumulation of intermediate metabolites existing in the decomposition process of the substrates indicated by the blue circles in the previous figure that should be metabolized by lysosomes. This accumulation triggers intracellular abnormalities such as abnormal vesicular trafficking, shown in blue, impaired autophagy, abnormal intracellular signal transduction, abnormal electrolyte, and especially calcium balance, and abnormal energy regulation by mitochondria.
Thus, the accumulation of substrates and intermediate metabolites in the cell causes the cell to fail to function properly, and the symptoms appear in the various parts of the body. Now, can you guess when LSDs were discovered? Go to the next slide, please. This is slide seven. The slide shows the evolution of the discovery and treatment of LSDs. In fact, LSDs have been reported for a long time, with reports of patients with Gaucher disease, Fabry disease, Hunter syndrome already from the 1880s, more than 130 years ago.
Currently, the standard treatment for these diseases is mainly enzyme replacement therapy, ERT. However, it was not until the 1990s, about 30 years ago, that ERT and other treatments were actually initiated. LSDs are also characterized by their hereditary nature. The next slide will show you the inheritance patterns.
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Many of the inheritance patterns of lysosomal diseases, on the left, you'll find autosomal recessive inheritance pattern or X-linked inheritance pattern. For autosomal recessive type, when both parents are carriers of the mutation, then the child will have a 25% probability of the disease onset. In X-linked inheritance, when the mutation is on the X chromosome of the mother, then the mother and the daughters with two X chromosomes, X chromosomes, they are carriers, but the son with one X chromosome may develop the disease, but it cannot be generalized. Even with the same mutation, onset, disease type, and disease cause may be different.
You need to monitor carefully the disease course. For the details, I will explain later more in detail when I explain each disease. Next slide, please. This is a list of lysosomal storage diseases. There are 31 LSDs considered as designated intractable diseases, and Takeda's products contribute to the ones in red, Gaucher disease, Hunter syndrome, and Fabry disease. I will explain each disease today. In the next slide, I will explain intractable disease designation in Japan. In Japan, lysosomal storage disease is considered as intractable disease or specified pediatric chronic disease subject to the National Health Subsidy, as shown here.
Intractable disease means mechanism is not clear, therapy is not established, rare disease requiring long-term care. For specified pediatric chronic disease, it has a chronic disease progress, life-threatening for long-term, and these symptoms and therapies go for long-term, undermining QOL, and medical expenses burden remain high for a long time. Lysosome therapies are not always inexpensive, but because of the designation, the cost required for therapy can be subsidized as a part of the National Healthcare System.
What are specific therapies? I will explain very representative ones in the next slide. Slide 11. This summarizes lysosomal storage disease. As I have explained to you, this disease is caused by intermediate metabolite accumulation. The main purpose of the therapy is to correct enzyme activity to degrade substrates. The first choice is ERT or enzyme replacement therapy. Defect enzymes are directly administered to degrade substrate in the lysosome.
The second is HSCT, donor-derived hematopoietic stem cells are transplanted to produce enzymes. However, you need to continue immunosuppressive therapies, and we have nowadays ERT, so only limited patients receive this therapy. The third is substrate reduction therapy, and that is to control synthesis of substrates to control accumulation in the lysosome. The fourth is chaperone therapy. That is to stabilize degradable 3D structure of the enzyme to normalize enzyme activity. The fifth is gene therapy. The genes are corrected to have normal enzyme activities. I explained there are 31 LSDs, and for each indicated therapies are different slightly. I will explain later in each section.
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Here is the summary of the lysosomal storage diseases. Page 12, please. Here is the summary. Lysosomal storage diseases are inherited metabolic diseases caused by deficient lysosomal enzymes characterized by the accumulation of substrates, and Gaucher disease, Fabry disease, and Hunter syndrome are LSDs, and there are 31 types of lysosomal storage disease specified as intractable diseases. Lysosomal storage disease was confirmed about 130 years ago, and ERT started about 30 years ago. The purpose of the treatment is to normalize enzymatic activities to degrade substrates to improve pathology. There are several therapies available. In the next slides, I will explain each disease and therapies.
I would like to explain about Gaucher disease. Please see page 14 in your handout. Gaucher is caused by deficiency of reduced activity of glycolipid hydrolase, glucocerebrosidase. This enzyme is necessary for the breakdown and recycling of ceramide, which is a component of cell membrane. This disease was discovered by French physician Philippe Gaucher in 1882. The mode of inheritance, which will be explained on the next slide, is autosomal recessive, with the mutations in the glucocerebrosidase gene, GBA1, on the first long arm of the autosomal chromosome, causing the enzyme abnormality.
Prevalence of Gaucher disease is approximately 1 in 330,000 in Japan, with about 150 patients currently diagnosed in this country. The actual number of patients diagnosed is lower than the calculated number, which should be around 400 patients. Outside of Japan, on the other hand, the number is 1 in 800 in Ashkenazi Jews and 1 in 40,000-60,000 in non-Jewish Europeans. The picture on the right shows a four-year-old patient with type 1 Gaucher disease. As you can see, the patient has a markedly distended abdomen. This shows hepatomegaly, which is abdominal swelling of the liver, which is one of the characteristic symptoms of Gaucher disease.
Next slide, please. This slide provides an explanation of autosomal recessive inheritance. As explained in the previous overview, Gaucher disease is inherited in an autosomal recessive form, and when both parents have mutations in the glucocerebrosidase gene, there is a 25% chance that the child will show symptoms of Gaucher disease. As autosomal chromosomes are in pairs, a carrier with a genetic mutation in one arm only will not show the symptoms. In this diagram, the parents and the two children would be carriers. Next, I would like to introduce the mechanism of Gaucher disease.
Page 16, please. This is a description of the mechanism of Gaucher disease. As shown, it is caused by a genetic mutation of glucocerebrosidase GBA1 that results in reduced activity. As shown in the chart on the left, GB3, an intermediate metabolite produced during ceramide degradation, accumulates in cells such as monocytes and macrophages, which in turn cause liver and spleen enlargement, anemia, and thrombocytopenia. It also causes bone pain, pathological fractures of the bone marrow, and as shown in the chart on the right, when glucosyl sphingosine, lyso-Gb3, secreted by monocyte macrophages, accumulates in the brain, it causes central nervous system disorders.
Next slide, please. According to the mechanisms shown on the previous slide, the main clinical manifestations of Gaucher disease include enlargement of the liver and spleen and increased spleen function, and as shown in the bottom left of the picture, the thrombocytes and erythrocytes would be destroyed, leading to anemia and thrombocytopenia. It also causes reduced bone density, bone deformations, and bone pain. The central nervous system involvement, as shown in the top left, may result in delayed psychomotor development, horizontal eye movement disorder, convulsions, myoclonus, dysphagia, as well as epilepsy.
Therefore, Gaucher disease is a disease that causes enlargement of the liver and spleen, bone abnormalities, and a variety of neurological and hematological symptoms. On the next slide, I would like to explain the specifics of the bone symptoms. This is slide 18. As an example of clinical manifestations of this disease, I would like to explain the bone manifestations. The picture on the left is an MRI T1-weighted image showing the morphology of the femur bone. Thinning and deformation of the cortex of the femur has resulted in a triangular flask-like deformation on the end of the femoral bone, as shown in the red box.
In the middle, you can see thinning in the bone cortex. This is due to infiltration of mononuclear Gaucher cells with glucosylceramide deposits. Due to these bone symptoms, growth retardation and short stature are observed in childhood, as shown on the right. The clinical presentation of Gaucher disease is classified from left to right according to the presence or absence and severity of neurological symptoms: type 1, non-neurologic; type 2, acute neurogenic; and type 3, subacute neuro. Type 1 is characterized by the absence of neurological symptoms and can occur at a wide range of ages, from infancy to adulthood.
The main complaint is hepatomegaly and splenomegaly, as well as bone symptoms, but the severity varies. Type 2 develops in infancy and progresses rapidly with hepatosplenomegaly, developmental delay, and neurological disorders such as convulsions. Type 3 is from infancy to school age and is associated with neurological symptoms such as abnormal eye movement, ataxia, and convulsions, in addition to hepatosplenomegaly, but it's all mild, and the progression is said to be slower than type 2. In this section, we present data of the distribution of Gaucher disease types 1 to 3 in Japan and the rest of the world.
This is a comparison of the distribution of Gaucher disease types between Japan and the rest of the world, as shown in the pie chart on the right. According to a 2010 report by the Gaucher Registry, an overseas registration system for patients with Gaucher disease, 92% of registered patients were type 1, 1% were type 2, and 7% were type 3. In the survey of Japanese patients shown in the pie chart on the left, 41.8% were type 1, and more than half, 58.1%, were type 2 or 3 with neurological symptoms.
Although it's not shown here, it is known that the distribution of disease types differs between overseas and Japan because even in the same site mutation, the portion that the DNA sequence mutates differs by race. In the Japanese distribution on the left, you may notice that type 3 in pink is divided into two parts. I will explain at this point in more detail on the next slide. Next slide, please. Slide 21. This slide shows the changes in the types of Gaucher disease in Japanese patients. The pie chart on the right is the same as the one shown on the previous slide, but if you compare it with the distribution at the first visit on the left, you see that the distribution of types 1 and 3 has changed.
This indicates that during the follow-up period, there was a change from the disease type at diagnosis to other types. In a survey of 129 Japanese patients with Gaucher disease, 28 patients were diagnosed with type 3 at the time of first visit, but this number increased to 44 after follow-up, with 16 cases changing from type 1 to type 3. Thus, we know that there are cases in which neurological symptoms are not present at the time of diagnosis but develop during follow-up, resulting in the transition from type 1 to type 3. I will now talk about the diagnosis on the next slide, page 22.
This summarizes the diagnosis of Gaucher disease. In addition to the clinical manifestations as previously described, the diagnosis of Gaucher disease is confirmed by low levels, less than 10% of normal, of glucocerebrosidase activity in skin, fibroblasts, blood, and bone marrow. Measurement of lyso-Gb1 levels has also been reported to be useful in monitoring disease progression and response to treatment, and is currently being studied in Japan. Angiotensin-converting enzyme, acid alkaline phosphatase, chitotriosidase, and ferritin levels are also useful as auxiliary diagnostic tests.
Identification of Gaucher cells like, as you can see here on the right, large macrophages that accumulate and are stained blue in tissues, in liver and bone marrow tissue samples, or genetic testing to identify gene mutations in DNA can also be useful in disease classification. As you see, the diagnosis of Gaucher disease is based on clinical symptoms as well as decreasing glucocerebrosidase activity. Although the diagnostic procedure is relatively established, patients are not necessarily diagnosed with Gaucher disease as soon as symptoms develop. Please turn to page 23.
In fact, we know that patients with Gaucher disease are not being diagnosed in a timely manner. As noted in the upper portion of the slide in gray, the average delay in diagnosis in type 1 Gaucher disease was four years, and the number of physicians seen before definitive diagnosis was approximately three. The physicians who made the diagnosis were specialized in hematology, pediatrics, primary care, and internal medicine. The main symptoms were splenomegaly, thrombocytopenia, anemia, hepatomegaly, and osteoarticular pain. The delay in diagnosis was due to lack of disease awareness, misdiagnosis, and non-specific symptoms.
This suggests that early diagnosis and early treatment of Gaucher disease requires an increase in awareness of the disease. Please go to the next slide. Here, as one example to promote early diagnosis, I present an initiative taken in Japan. In Japan, neonatal mass screening for early diagnosis of inborn errors of metabolism is currently conducted in each local government for the diseases shown below right in the green square. Some local governments have begun to include lysosomal diseases like Gaucher, Fabry, and so on in neonate mass screening.
I mentioned earlier that it is an inherited disease and that diagnosis can be delayed even after the onset of symptoms. By performing such newborn mass screening, we can expect to identify LSDs at an early stage, thereby accelerating the timing of therapeutic intervention. I will now introduce the treatment options from the next slide. Page 25, please. As discussed in the previous overview, drug therapy for Gaucher disease includes ERT, substrate synthesis inhibition therapy, hematopoietic stem cell transplantation, and chaperone therapy. ERT is used as a first-line therapy, and its mechanism of action is to break down intracellular glucosylceramide by intravenous administration of the deficient glucocerebrosidase enzyme.
Replacement therapy includes a product, velaglucerase alfa, trade name Vpriv, shown in red. Another commonly used therapy is substrate reduction therapy, which suppresses the synthesis of substrates that accumulate in cells. Other therapies that are being investigated at the research and clinical trial level include gene therapy, nanoparticles, and in utero enzyme replacement therapy. I will now introduce the clinical results of our product, Vpriv, from the next slide to show how ERT, which is a main treatment method, can be expected to be effective. Next slide, please.
This shows the mechanism of action of enzyme replacement therapy. Velaglucerase alfa is a human cell line-derived product, and mannose ligand is added, which binds to mannose receptor on the surface of the macrophage shown in Y-shape symbol, and they are taken up by cells by endocytosis. Ultimately, this enzyme preparation is delivered to lysosomes for action as an enzyme. That way, glucosylceramide can be degraded. With this mechanism, lysosome in the macrophage is normalized. In the next slide, I will show you the clinical trial results.
This is a clinical study for adult and pediatric patients with a global phase III clinical study protocol. On the left, you find three core clinical studies. On the right, you find an extension study for each trial. The study has the arms for five-year treatment of Velaglucerase alfa and the arm that switched from imiglucerase to Velaglucerase alfa switch. In the next slide, I will show you the result. Page 29, please. First, I will show the data of the untreated Gaucher disease patient and healthy population. The blue bar is healthy population data. Green line shows untreated patients' data.
As the left chart shows, spleen and liver volume are greater than the healthy population. In the center, hemoglobin parameter is shown, showing the extent of anemia, and compared to the healthy population, untreated patient has a lower level. On the right, platelet counts are shown, and in the untreated group, compared to the healthy population, the levels are lower. These are the symptoms of Gaucher disease and how the change by velaglucerase alfa is shown in the next slide, slide 30. Velaglucerase alfa given for four years and the treatment goal achievement is shown.
On the right-hand side of each parameter title, you find target value and achievement is shown. For example, left top, hemoglobin parameter target for female was 11 g/dL, for men, 12 g/dL, and if you achieve that or over, then the goal is achieved. Similarly, platelet counts, liver, and spleen volume compared to the baseline at year one and year four after the treatment, the treatment goals are achieved. On the right bottom, BMD is shown, and Z-score is shown, which shows the deviation of the average BMD of the age-matched population. This also shows for four years, BMD was achieved and it was maintained.
This is a five-year result of velaglucerase alfa on BMD. On the left, untreated group treated, and on the right, the prior treatment was given and the treatment continued, and the vertical, the BMD change, and horizontally, number of months of treatment. Red line shows lumbar BMD, and blue line shows femoral BMD. On the left, you see that untreated velaglucerase alfa, and in that population, you can see BMD change, improvement. On the right, the patient received prior treatment of imiglucerase and switched to velaglucerase alfa, and after the switch, BMD was maintained. Next slide, please.
This slide shows the five-year follow-up result of the switch from imiglucerase to velaglucerase alfa for five years. Hemoglobin concentration, platelet count, spleen volume, and liver volume, those are observed, and the switch from imiglucerase to velaglucerase alfa and each parameter are maintained for a long term. Next, I will show you the safety profile. Slide 33, please. Safety profile for this study is shown. During the clinical trial, a more serious adverse event was hypersensitivity observed in 2.1% of the patient by dosing discontinuation or symptomatic treatment. The reaction was resolved. The most frequently observed was infusion-related reaction at 39.4%.
Most commonly, frequently reported AE includes headache, dizziness, abdominal pain, bone pain, and joint pain. Next slide, please. This is a slide summarizing Gaucher disease phase III, IV. In Gaucher disease, glucocerebrosidase activity is reduced, and this is autosomal recessive inheritance. When there are mutations on both parents, then the onset is observed in the child, and the prevalence in Japan is 1 in 330. Type 1, 2, and 3 are evenly distributed, but as I mentioned, as you follow up the patient, some patients switch from type 1 to type 3 with neurologic symptoms.
The worldwide prevalence in Ashkenazi Jewish is 1 in 800, non-Jewish 1 in 40,000-60,000, and more often type 1 and type 3. ERT is a standard therapy of Gaucher disease, and velaglucerase alfa can improve hepatosplenomegaly, anemia, thrombocytopenia, and bone health. That is all from myself. Next, Fabry disease will be explained by Iwashiro.
I'm Sanghun Iwashiro, Medical Unit, Head of Rare Disease Medical Franchise, Japan Medical Office, and I'm here to discuss Fabry disease. I'm responsible for rare metabolic diseases within the company. My main tasks are to identify unresolved medical problems based on communication with specialists and to design clinical studies as a way to solve them. As a clinician, I have experience in surgery, and I'm currently treating patients as well. Next slide, please.
This is slide 36. I would like to go through the overview of Fabry disease. Fabry disease was described by Dr. Anderson and Dr. Fabry, respectively, in 1898 due to an abnormality in the enzyme of alpha-galactosidase A, the substrate globotriaosylceramide GB3, resulting in damage to various organs and early death in some patients. The disease involves a mutation in the alpha-galactosidase A gene on the X chromosome and is inherited in the form of X-linked inheritance. How the disease is inherited from parent to child will be explained later.
X chromosome recessive inheritance usually affects only males, but women can also develop this disease. In the picture on the right, the male in the center wearing the blue shirt is Ramon, a patient diagnosed with Fabry disease, and he had been suffering from unexplained pain for many years. On one occasion, a nurse found signs that led to the diagnosis of this disease. Many people in the family died early, and Ramon's diagnosis revealed that Fabry disease was the cause. Genetic diseases can lead to a diagnosis not only for the patient themselves but also their family.
Next slide, please. Page 37. This slide summarizes the incidence and prevalence. In Japan, it is reported to be about 1 in 7,600-12,000. As you can see, the figures vary from region to region. This is partly due to differences in study design and populations between reports. It is also assumed that the actual frequency may be a little higher, as some cases of Fabry disease are asymptomatic or do not present with typical symptoms. Slide 38, please. The genetic form of Fabry disease is explained on this slide.
How the mutated gene is passed on from parent to child depends on which of the parents carries the mutated gene. On the left is a case where the father carries the mutated gene. Girls inherit the X chromosome from their father and therefore always carry the mutant gene. If a boy is born, the X chromosome is not inherited from the father and therefore cannot be passed on to the boy. On the right is a case where the mother carries a mutated gene on one of the X chromosomes. In this case, there is a 50% chance that the mutated gene will be passed on, whether the child is a boy or a girl. Fabry disease is an X-linked genetic disease that can be inherited from either of the parents. Next slide, please.
This slide shows how Fabry disease presents itself. As you can see, various parts of the body and organs are affected. The symptoms of the skin, digestive organs, bones, joints, some nerves, and the eye, which are highlighted in pink, are said to occur relatively early. Late-onset symptoms that may affect the patient's prognosis include heart failure due to left ventricular hypertrophy in the heart and also renal dysfunction in the kidneys. It is important to detect these symptoms at an early stage and to intervene early to prevent them from progressing, especially those that have an impact on prognosis. Slide 40, please.
This slide shows the age at which symptoms of Fabry disease occur in men and women. The data is from the Fabry Outcome Survey, a multicenter international observational study that we have sponsored since our days at Shire. The vertical axis shows the site of symptom onset, and the horizontal axis shows the mean age. The red bar shows the standard deviation, and the mean age of onset is shown by gray vertical line. The data show a wide range of affected sites in male patients, as well as the appearance of organ damage, including kidney, brain, and heart damage as they get older. In female patients, symptoms are more common between the ages of 20s and 40s, and the range of affected sites is as wide as that of men.
While there are differences in the timing of symptom onset, the disease is characterized by a similarly broad spectrum of disorders in both men and women. Slide 41, please. This illustration shows the clinical course of classical Fabry disease. Accumulation of the substrate GB3 begins in childhood. Initial symptoms include pain, GI symptoms, and the hypohidrosis, resulting in impairment of QOL. As time passes, the disease progresses to tissue and organ damage, and people in their 30s and 40s, it progresses to irreversible organ damage such as kidney and heart damage.
The previous slide showed the chronology of symptom onset, and as you can see, in this type of progressive disease, it is important to intervene early to limit the progression to a wide range of organ damages. I will now discuss the aspect of QOL in patients with Fabry disease. Please turn to page 42. This is a report examining the extent to which QOL is impaired in patients with this disease. SF-36 is a survey instrument that uses 36 questions to measure health status and QOL. The data presented here are a pooled analysis of the SF-36 subdomain scores and the comparison of scores with the reference population of people without Fabry disease.
As you can see, the scores of patients with this disease are lower in various indices, including physical function and in daily life and body pain, leading to a decrease in QOL. Often, patients with this disease suffer psychologically as well, with depression being one of the most common complications. As a patient's appearance does not differ much from that of a normal person, it is difficult for people around them to understand the pain and the limitations of physical functions, which can also be a factor leading to depression.
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Next slide, please. The current methods of Fabry disease diagnosis are shown here. In the upper part of the slide, it shows that the diagnosis method is different between men and women. When Fabry disease is suspected based on symptoms and family history, alpha-galactosidase A enzyme activity is examined in males, leading to a definitive diagnosis. In female patients, alpha-galactosidase A enzyme activity is often within the normal range, so a genetic test to analyze the GLA gene is used to confirm the diagnosis.
Next slide, please. I mentioned earlier the significance of early treatment intervention, and I'd like to discuss how long it takes from the onset to diagnosis. The graph on the left shows the number of years from symptom onset to diagnosis for adults and children, divided into two time periods, 2001 to 2006 and 2007 to 2013. In adults, it took a median of 14 years to reach diagnosis between 2001 and 2006, but this was reduced to 10.5 years between 2007 and 2013. In children, it took 5 years for the former period and 4 years for the latter.
Although the number of years it takes to reach a diagnosis has been shortening, perhaps due to increased disease awareness, it still takes more than 10 years for adults. Misdiagnoses that patients have suffered before diagnosis include rheumatology-related diseases and neuropsychiatric disorders. There are still challenges in making an accurate diagnosis at an early stage. Now, let me move on to the treatment. Slide 45, please. Currently, there are two types of treatment for Fabry disease:
ERT, enzyme replacement therapy, and chaperone therapy. ERT, as described by Suzuki in the Gaucher disease section, is a treatment that slows the progression of the disease by replacing missing enzymes. Patients with a confirmed diagnosis of Fabry disease are indicated for long-term use, and home administration is an option if it is well tolerated. In chaperone therapy, a chaperone compound binds to alpha-galactosidase A, an enzyme destabilized by genetic mutation, to stabilize its structure and promote its normal transport within the cell. This treatment improves enzyme activity.
In addition to these two standard therapies, research is also being conducted to investigate the therapeutic application of substrate reduction therapy, SRT, and gene therapy. We have an ERT, agalsidase alfa, or Replagal, product name, Replagal. I will present clinical results from the next slide. Page 46, please. Here are the data from the phase II/III clinical trial at the time of approval of Replagal, which investigated the effect on pain and on renal dysfunction associated with Fabry disease.
Twenty-six adult male Fabry disease patients with neuropathic pain were randomized to receive agalsidase alfa 0.2 milligrams per kilogram every other week or placebo for six months. As shown in the upper right graph, patients in the agalsidase alfa group showed a continuous decrease in the score of worst pain in the last week on the Brief Pain Inventory BPI questionnaire and showed a significant improvement over the placebo group. In an open-label extension study, the effect on renal dysfunction was also examined.
The lower right graph shows the estimated glomerular filtration rate by stage of chronic kidney disease at baseline. Agalsidase alfa contributes to the stabilization of estimated GFR, especially in patients with mild to moderate renal dysfunction in stages 1 and 2. This suggests that therapeutic intervention before the progression of renal dysfunction may help maintain renal function. The treatment was well tolerated in both studies.
Next slide, please. Slide 47. Here we are studying the effect of the substrate, a group of globotriaosylceramide GB3, on myocardial accumulation and left ventricular myocardial rate. Fifteen adult Fabry disease patients with left ventricular hypertrophy were randomly assigned to receive agalsidase alfa 0.2 milligrams per kilogram every other week or placebo for six months. As a result, the graph on the right shows the absolute change in myocardial GB3, which was reduced by 20% in the agalsidase alfa group. In the secondary efficacy endpoint, agalsidase alfa significantly reduced left ventricular myocardial mass versus placebo.
Open-label extension study has also confirmed consistent results, with agalsidase alfa significantly reducing LVM compared to baseline after 24 to 36 months of treatment. These trials also showed generally good tolerability, with no reports of serious adverse events associated with agalsidase alfa. Next, please turn to page 48. As I mentioned earlier, renal function and left ventricular hypertrophy are important factors in the prognosis of patients with Fabry disease. Here are the long-term data of agalsidase alfa with a 20-year follow-up of the Fabry Outcome Survey. The left shows the annual rate of change in eGFR.
Although no comparison with the untreated group is available to make a precise assessment, it is interpreted that agalsidase alfa treatment has slowed the decline in renal function. On the right is the annual rate of change in LVMI, left ventricular mass index. A measure of left ventricular hypertrophy, although there is no comparison with the untreated group, it is interpreted that agalsidase alfa treatment moderates the increase in LVMI. As I mentioned earlier, administration of agalsidase alfa contributes not only to pain but also to stabilization of renal function and prevention of progression of left ventricular hypertrophy.
I'd like to introduce safety. Slide 49, please. Agalsidase alfa safety profile. The most frequently reported AE adverse event in clinical trials was infusion-related reactions at 13.7%. They occurred most frequently during the first two to four months of treatment and decreased in frequency as the duration of treatment increased. Symptoms included chills, headache, fever, and nausea, which are common to those shown in the second point on the slide. Most adverse events were mild to moderate in severity.
A low-titer IgG antibody response to agalsidase alfa was observed in approximately 24% of male patients. This reaction occurred between 3 and 12 months post-treatment, and after 54 months of follow-up, 7% of patients had resolved IgG antibodies, indicating that immune tolerance had been established. Now, please turn to slide 50. Take-home messages of Fabry disease. Fabry disease is an X-linked genetic disease that can be inherited from either parent with a mutation in the GLA gene on the X chromosome. The transmission of the disease to the child depends on which of the parents carries the mutated gene. Fabry disease is characterized by a variety of symptoms in multiple organs, including heart and kidney, that can affect the patient's prognosis.
The onset timing of symptoms may differ between men and women. Adults often remain undiagnosed for nearly 10 years after the onset of symptoms. Since organ damage may progress during this time, you'd understand why it is so important to make an early and accurate diagnosis. Finally, about treatment. The standard treatment for Fabry disease is enzyme replacement therapy and chaperone therapy. Adenosidase alpha and ERT improve the pain, stabilize renal function, and contribute to the prevention of LV mass increase, an indicator of left ventricular hypertrophy. That's all about Fabry disease. Please go to the next slide.
Next, I will explain Hunter syndrome. I will continue to explain. Page 52, please. Hunter syndrome is also called as mucopolysaccharide II, but in today's presentation, I will continue to use Hunter syndrome. Hunter syndrome was reported in 1917 by Dr. Charles Hunter when he saw the brothers with this disease. It's a kind of lysosomal storage disease. Iduronate-2-sulfatase is the enzyme that is mutated, and the substrate, a glycosaminoglycan, is accumulated in the cell and starts to develop. Hunter syndrome, like Fabry disease, is X-linked recessive hereditary disease, 0.38-2.16 in every 100,000 live births. It's a record of prevalence. Next slide, please.
I will explain hereditary pattern of Hunter syndrome. Like Fabry disease, it is X-linked recessive inheritance disease. How the mutation is passed on to the child depends on which parent holds the mutated gene. On the left, when the mother has a mutation on one of the X chromosomes, in this case, the child, either a boy or a girl, will inherit this mutation with 50% of probability. On the right-hand side, when the father has a mutation, a girl receives X chromosome from the father; therefore, mutation is always passed on to the girl. In case of a boy, X chromosome is not passed on from the father; therefore, no inheritance to the boy.
Slide 54. Next slide, please. Next is symptoms of Hunter syndrome. Physical features that are typical are snoring or respiratory signs and hepatomegaly or splenomegaly in GI area and prominent forehead and thick dark eyebrows and some characteristic features in the face. Others include cardiac valvular disease, bone deformity, low stature, and musculoskeletal symptoms. In two-thirds of Hunter syndromes, there are CNS symptoms of mental and retardation in cognitive functions. Thus, there is a broad range of symptoms, and the patients with Hunter disease have to bear various burdens leading to lower QOL.
Especially patients with CNS signs, then the average lifespan is set to be 10-15 years on average, and it is not uncommon that there are some serious outcomes. Next slide, 55, please. Clinical features of Hunter syndrome are divided into two types: non-neuronopathic and neuronopathic. As summarized in the slide, one-third is non-neuronopathic, and neuronopathic is said to be about two-thirds. Also, the age diagnosis with neuronopathic type is 1.7-2.7 years old, and non-neuronopathic is 3.7-6.8 years old. The symptom onset is earlier in neuronopathic. Regarding signs and symptoms, in non-neuronopathic, mainly somatic symptoms are the main symptoms. In contrast, in neuronopathic
Hunter disease, then in addition to somatic symptoms, CNS symptoms also emerge. As for life expectancy, in non-neuronopathic patients, they quite often reach adulthood, but with complications of cardiac or respiratory diseases, they may pass away in their 20s and 30s. Neuronopathic patients, after the onset, rapid progression of somatic and neurological symptoms are observed, and by neurodegeneration or cardiorespiratory complications, they tend to be deceased in the teenage years. Next page, please. I explained clinical symptoms of Hunter syndrome. This slide explains non-neuronopathic disease progression. From left to right is the flow as the age advances.
A few months after the birth, normally respiratory signs are presented, then in the childhood, delay in bone formation shows the symptoms of musculoskeletal and developmental delay, and CV events also may emerge. As the patient ages, there could be secondary cognitive impact. As I mentioned before, non-neuronopathic patients quite often reach to the childhood or adulthood. However, the most common cause for death is respiratory, about 65%, and cardiac disease is 16%. Complications of respiratory and CV diseases are important risks. Next slide, please. Page 57, please. This shows the disease burden of a neuronopathic patient with a poor prognosis.
On the left, you'll find cognitive function disorder and developmental delays and other neurologic symptoms that can undermine day-to-day life and QOL of the patient. It can also be burdened not only for patients, but for caregivers also. On the right, you find behavioral problems from about two years after birth: hyperactivity, aggressiveness, biting, impulsiveness, sleep disorder, and social dysfunction are some of the symptoms which can give very serious impact on family life. Patients with neuronopathic Hunter disease, in addition to somatic symptoms, CNS symptoms come along; therefore, disease burden is higher.
Page 58, please. As I have explained in the previous slide, in the Hunter syndrome, there are various symptoms throughout the body, so monitoring of the whole body is recommended, and that means various healthcare professionals need to provide support. It is hard to predict which body part will be affected and when it gets serious, so doctors of various specialty areas, but also many healthcare professionals in a multidisciplinary manner need to provide support. To support patients with Hunter syndrome, many healthcare professionals should be aware of the disease symptoms, and they should be aware of methods and guidelines for evaluation and monitoring. Those should be available. Next, I'll explain diagnosis of Hunter syndrome. Page 59, please.
[Foreign language]
This is an overview of the tests that are usually performed with a suspected case of Hunter syndrome. If there are initial clinical signs, tests are carried out in the order of urinalysis, blood tests, and genetic testing. We will not go into technical details but give you an idea of the testing process. If the urine test shows the presence of substrate glycosaminoglycans and Hunter syndrome is suspected, a blood test is performed. If the blood test shows a low enzyme activity of iduronate-2-sulfatase and multiple sulfatase deficiency can be excluded, we proceed to genetic testing.
If possible, the presence of mutation in the iduronate-2-sulfatase gene is confirmed, and a definitive diagnosis is given. If no mutation is identified or genetic analysis is not possible, a second enzyme activity assay is performed to confirm the diagnosis, looking at white blood cells. Again, it is important to understand that when Hunter syndrome is suspected clinically, a definitive diagnosis is reached through a process of urinalysis, blood tests, and gene testing. Slide 60, please. In the previous slide, we talked about the diagnosis process for Hunter syndrome.
As with Gaucher disease and Fabry disease, early diagnosis and early therapeutic intervention are important factors in improving prognosis. Patients with Hunter syndrome have no obvious symptoms at birth, and many of the early manifestations are very similar to common childhood diseases. This makes early diagnosis very difficult. As it is a genetic disorder, a family history may allow suspicion of Hunter syndrome at the onset of symptoms. However, without family history, diagnosis may be delayed. Many patients experience a delay in diagnosis for approximately two to four and a half years.
There are available treatments such as Takeda's Elaprase, and new treatments are also expected in this area, and therefore, early diagnosis and therapeutic intervention is important. Newborn screening programs may also contribute to early diagnosis. I would like to talk about the treatment, starting with the next slide, slide 61. This slide summarizes the treatment of Hunter syndrome. ERT, enzyme replacement therapy, has long been the standard of care for physical symptoms in the treatment of non-neuronopathic Hunter syndrome. Takeda's idursulfase, product name Elaprase, is an enzyme replacement therapy. ERT may improve physical symptoms, reduce urinary glycosaminoglycan levels, and decrease liver and spleen volume.
Hematopoietic stem cell transplantation may also be used as a treatment for non-neuronopathic Hunter syndrome. This treatment involves the transplantation of donor-derived blood stem cells that provide a source of normally functioning enzymes, but the number of actual cases is limited, and there could also be risk of complications and even death. ERT and HSCT are used to treat non-neuronopathic Hunter syndrome, but supportive care is needed to care for the overall symptoms, including neurological symptoms.
In Japan, Pabinafusp alfa, which is also expected to have an effect on neurological symptoms, and JCR Pharma's Pabinafusp alfa were launched last year and are expected to contribute to patients with neuropathic Hunter syndrome. Starting with the next slide, I would like to talk about the clinical results of Elaprase. This is a clinical trial of Elaprase, phase two-three, and I will use the generic name idursulfase. In this study, patients were stratified according to the baseline profile and were randomized into three groups: a weekly intravenous infusion of etasulfate 0.5 milligram, a biweekly infusion of the same dose, alternating with placebo, and placebo.
They were looked at for 53 weeks. Primary efficacy endpoint was to compare the change in the composite score of respiratory and motor function from baseline, and this is a comparison between once-weekly etasulfate group and the placebo group. Next is page 63. This is a primary efficacy endpoint result on composite scores. The first one is physical performance shown on the left-hand side, which is the six-minute walk test. Six-minute walk test is a walking test in which participants walk as fast and as far as possible within six minutes. The weekly etasulfate group showed a significant improvement in the six-minute walk test score compared to the placebo group.
The right-hand graph assesses respiratory function by looking at the change in the amount of forceful rapid exhalation volume. The once-weekly etasulfate group improved significantly on this measure compared with the placebo group. Next slide, please. This slide shows the safety of etasulfate in this study. 59.6% of patients had one or more adverse events where causal relationship to the treatment could not be denied. Serious adverse events occurred in 28.7% of patients, including six cases of carpal tunnel syndrome, two cases of bacteremia, chronic otitis media, sleep apnea, abdominal strangulated hernia, and obstructive airway disorder.
Over two cases of obstructive airway, one patient had a life-threatening adverse event. 53.2% of patients had at least one dose-related reaction. The most frequent symptoms were headache in 16%, urticaria in 11.7%, and fever in 8.5%. The graph at the bottom of the slide shows the proportion of patients who experienced dose-related reactions over time. The proportion of patients who developed dose-related reactions decreased with continued treatment. Please turn to slide 65. The impact of Elaprase on life expectancy is shown on this slide.
This data comes from the Hunter Outcome Survey, a multicenter international observational study that we have sponsored since the time of Shire. The study included 895 male patients enrolled in the observational study until 2016, who were divided into two groups: those who had at least once been treated with intravenous Elaprase and those who had not. Patients treated with Elaprase had a median survival of 33 years based on Kaplan-Meier estimates, compared with the untreated group with a median survival of 21.2 years. In other words, there was a difference of 11.8 years. This is an increase in survival.
The graph at the bottom of the slide shows Cox regression modeling of survival from birth. The risk of death in the group of patients treated with intravenous Elaprase was reported to be 54% lower than the untreated group. Treatment with Elaprase mainly improves the physical symptoms but may also contribute to improved life expectancy, as you can see from this information. Next slide, please. This is a summary of Hunter syndrome. Hunter syndrome is caused by an abnormality in the iduronate-2-sulfatase enzyme, which results in the accumulation of the substrate glycosaminoglycans and mucopolysaccharide in the cells.
It is an X-linked genetic disease, and it is inherited differently depending on which of the parents carries the mutated gene. We also mentioned that it mainly occurs in men. Clinically, the disease is characterized by the development of multi-organ disorders and symptoms. In particular, neuropathic Hunter syndrome presents with central nervous system symptoms and has a poor prognosis, with many patients dying in their teens. We have already mentioned that early diagnosis of Hunter syndrome is difficult because the early signs and symptoms are very similar to those of other common pediatric conditions.
It is important to further raise awareness of the condition among healthcare professionals in order to raise awareness of the condition so that signs and symptoms can be recognized at an early stage. Finally, we discuss the treatment options. Enzyme replacement therapy is a standard of care for non-neuropathic Hunter syndrome, and our Elaprase has been shown to improve physical symptoms and life expectancy. I will now summarize today's discussion on the next slide, slide 67. This is a summary of information on lysosomal storage diseases presented by myself and Suzuki.
Although the enzymes involved vary from disease to disease, it is a genetic disorder caused by the accumulation of substrate that should be degraded due to deficiency or reduced activity of lysosome enzymes, causing dysfunction and symptoms in various parts of the body. The incidence varies from disease to disease, but the cumulative incidence of all lysosomal storage diseases is reported to be one in 7,000 live births. Gaucher disease, Fabry disease, and Hunter syndrome, which we have introduced to you today, are also reported to have an incidence of one in thousands to hundreds of thousands, making them extremely rare diseases.
Clinical manifestations include hepatosplenomegaly, pulmonary and cardiac abnormalities, and musculoskeletal abnormalities, including developmental effects. The importance of early diagnosis and therapeutic intervention was also discussed, as approximately two-thirds of patients with lysosomal storage disease present with neurological symptoms, some of which can be a significant prognostic impact. It is also important to understand that ERT is a common treatment for the three diseases introduced today and that it contributes to the improvement of patients' symptoms and life expectancy. This concludes today's presentation. Thank you very much for listening to us.
[Foreign language]
Thank you very much. Now I'd like to move on to the Q&A session. We have two presenters and also other panelists in this Q&A session. We have Sachiko Yoshimoto, Japan Medical Office, and Kazuhiko Enya, and Emiko Komura from Japan Development Center. Please click the Zoom's hand-raising button, and we'd like to call your name one by one. If you want to ask a question, please press the button of the hand-raising feature of the Zoom. Now, the first question is Morgan Stanley, Muraoka-san. Please unmute yourself.
Hello. Can you hear me? Muraoka, Morgan Stanley, yes, we can hear you. Please go ahead. Thank you very much. Regarding Hunter syndrome, I actually re-learned that neuropathic manifestations are so severe, and I'd like to talk about the biosimilar and Hunter syndrome. In Hunter syndrome, in order to improve neuropathic manifestation, I believe that it is truly important.
In Japan, now we have Pabinafusp alfa, that is your partner's product. I think that penetration is so quick. Maybe in six months or so, that would be 50/50 in market share. Given the severity of neuropathic manifestation of Hunter syndrome, it might be difficult for you to comment, but is it as you expected, or the penetration with Pabinafusp alfa is much higher than your original expectation? If there is any gap from your original expectation, what's the difference?
Enya, would you like to answer your question? Muraoka-san, thank you for your question. First, regarding Pabinafusp alfa in Japan, JCR has been marketing, so for the details, I cannot comment on that. However, as we presented, in Hunter syndrome, there is a need, a very high need for neuropathic symptoms. So far, various companies made efforts in research and development to cross the blood-brain barriers. From the market, from the patients, and also from the physicians, there are high levels of needs expressed. Therefore, I think that the current penetration rate is as I expected personally. However, for the details, please ask JCR because it is not our own product. Thank you very much for your answer.
You have the right, ex-America, ex-U.S., i f you can successfully launch TAK141 in the countries you have rights for, do you think the market penetration will be as fast as or even faster than what we currently see in Japan? Thank you for your question. I'd like to also answer to that question. As you know, currently, global phase III has started, and we have to wait and see the results of phase III study. Without seeing the results, we cannot make a specific comment. However, concerning the needs of neuropathic symptoms, that is quite high, not just in Japan but also overseas. Therefore, from physicians and patients, I think it is highly expected.
Understood. Thank you very much. Another question about biosimilar. I'd like to ask you a question. Beepleaf, Elaprase, and Replagal. I think mostly their substance patents are almost expiring or already expired. Worldwide, I don't see or hear much information about new biosimilars. How should I understand the status? My rough understanding is that protein production yield is quite low, very inefficient. That's what I heard in the past. That's why it is difficult to produce. Is it the right understanding, or are there any other reasons, like relationship with the patients is quite important? Therefore, it is quite a challenge for any biosimilar to come in. Could you explain?
Komura from development, thank you for your question, Muraoka-san. How hard it is for biosimilars to come into market? It is our imagination, but as Muraoka-san said, one point is that it requires special manufacturing, and genetic recombination technology is needed. Therefore, some special knowledge and capabilities are needed. Because it is a rare disease, market size is not so big. Together with difficult manufacturing, I think it is probably difficult to make the business viable. As you said, patients and the healthcare professionals, in these disease areas, we need a strong tie and linkage.
Therefore, if it is a new company to come into this space, it might be difficult for them to step in. Currently, there are three products available in the market, and with those, we'd like to continue to contribute to the patients. Thank you very much. I believe annual sales of your products are about JPY 50 billion-JPY 70 billion, and competitor products exceed JPY 100 billion. Can we understand that it is difficult for biosimilars to enter the market due to the reasons you just explained, even after a patent expiry and even with a market size? Yes, that's what we consider. Understood. Thank you very much. I could learn a lot. Thank you very much.
村岡さん、ありがとうございました。
Thank you very much, Muraoka-san. Next question, please. Next question from Daiwa Securities, Mr. Hashiguchi. Please unmute yourself and address your question. Hashiguchi from Daiwa Securities, thank you very much. My first question is about the difference in treatment between Japan and overseas. You may have mentioned in your presentation today, but I understood that you mainly talked about treatment concepts in Japan. If there are differences in treatment concepts or data between Japan and Western countries, can you please introduce them? In my understanding, for example, for HSCT in Japan, performance is good but not so good overseas, and that may impact selection of therapies. I heard this is a basic question, but can you give your answer to this?
Hashiguchi-san, thank you. This is Suzuki speaking. Let me explain that. Hashiguchi-san, as you mentioned, the approach of therapy in Japan versus overseas, like Gaucher disease, I explained that, so let me take that example. Disease type in Japan versus Europe and U.S. is a bit different. In overseas, the majority is type 1, which mainly shows organ damage, whereas in Japan, neuropathic patients weigh almost two-thirds. In overseas, those treatments, such as enzyme replacement therapy that target organs, can address organ damages.
In Japan's case, on the other hand, enzyme replacement therapy can address organ damages, but neurological complications remain unresolved. When you look at overseas situation, ERT is the main therapy, and many patients benefit from that. That is the main therapy. In terms of research, chaperone therapy or SRT therapies and other therapies are becoming available. Some oral possibilities are explored, and gene therapies are also considered. Maybe that kind of fundamental therapy at the research level is drawing attention. Comparing Japan versus the U.S., the U.S. has a much larger budget for research development, and that is moving ahead, in my impression.
Therapies, main is ERT, but in Japan, there are other needs going up in demand. HSCT, that is for Gaucher disease, if I may take that example. Therapy by HSCT, as I explained before, bone marrow is attacked, and you try to introduce fresh bone marrow, and then immunosuppression continues to be used for the rest of the life almost. That is the type of therapy. In the meanwhile, graft versus host disease and other rejection issues may arise. HSCT may be effective, we are aware of that, but some doctors hesitate to use that approach.
When you look at Gaucher disease, ERT, when that becomes available, and much of the therapy can be achieved to a certain extent, so there is not so much desperate need for HSCT among some patients. As of now, in Japan and US together, overseas together, about 50 cases of HSCT. In the past 10 years, there has been no new HSCT therapies. In other lysosomal storage disease, different, but HSCT is one of the options we are aware of, but it is not actively introduced as of now. I hope this answered your question. Yoshimoto from Japan Medical Office, if I may add some comment.
The approach to therapy in Japan versus overseas, rather than there is a big difference, it is all genetic diseases. Therefore, depending on disease type, options for therapy will differ, and also access to medicine differs country by country. That is another significant factor, I think, in Japan, as lysosomal storage diseases are designated as intractable diseases, and medicine to access is easier for the patients, but that's not true in other countries.
Therefore, treatment options may be impacted by that. As Suzuki explained, HSCT regarding efficacy in LSD is significant, but that burden associated with the therapy is strong. If there are no other options of therapy, then this could have been a very strong one, but now we have ERT and other therapies available to cover or address some needs. Therefore, it's not considered very actively as for HSCT. I think that's the realistic situation.
Thank you very much. Another question. For gene therapy in LSD, merits and demerits, can you explain merits and demerits? Gene therapies advance in other diseases, and in other diseases, there are some pros and cons, and how much actively gene therapy should be introduced. There are various opinions, but for LSDs, especially in case of ERT, there is a burden for administration. It takes time for IV infusion, but with genes, less frequency of medication, that is a big benefit, I suppose. Gene therapy in LSD, what are pros and cons, please?
Mr. Hashiguchi, thank you for your question. I will answer to this question. As for gene therapy, including LSDs for congenital metabolic diseases, it would be the core of the pipeline in future. With that idea, we have R&D activities ongoing. As for merits and demerits, Fabry disease is one example to use for explanation. The patient in Fabry disease and organ damages, it can be addressed by ERT to a certain extent.
However, to stop organ damage completely is not yet achieved. One of the reasons for that is enzymes do not penetrate into the deep part of the body or in a stable manner to express in the tissue, and we can't continue to do that. There is a limit to what we can with ERT. We start seeing that. In that sense, gene therapy may be addressed in the deeper part of the body, and active enzyme expression may be possible. That is the modality that gene therapy can achieve. For the uncontrolled patient, this can be a promising therapy in future.
On the other hand, demerit or disadvantage is because gene therapy is still at the research level, and safety risk is one important aspect. ERT has a long history. Compared to that, safety profile sufficiently has not been demonstrated with gene therapy, and that is one of the demerits, I think. That's all. Thank you very much. That's all.
橋口さん、ありがとうございました。
Thank you very much, Mr. Hashiguchi. We would like to accept the next question. Credit Suisse. It's either Harutosa or Sakai-san, please unmute yourself and ask your question. Is this Sakai with Credit Suisse? Thank you very much for your presentation today. It was very informative. I'm sorry, my question is very basic. Four or five different treatments, including gene therapy for LSDs. ERT, chaperone is in R&D.
Anyway, the idea is that the necessary enzyme has to be delivered to the specific organ or tissue where there is a need. I think there are different steps of improving this. Gene brain cargo, this is delivery into the brain. Takeda now has a partnership here. Other than that, outside of that, are there any technological advancements or drug development that Takeda is considering? Can you please talk about your plan?
Mr. Sakai, thank you very much for your question, and I would like to answer your question from my side. Gene brain cargo, gene therapy combination. Needed enzyme should be expressed or delivered to the target organ, and in that sense, we expect it to play a very important role. Similarly, we are now doing joint development with a peptide dream, transferring receptor-binding peptide. With large or small molecules, we will not really deliver the enzyme to certain organs, but we should be able to do that with this new vehicle, so we have expectation for that.
With regard to gene therapy, what you have mentioned is a big discussion point. For example, when we use adenovirus vector, depending on the type, the likelihood of expression or transfer to different organs differs. We want to take advantage of this, and also using engineering technology, hopefully we can change and somehow deliver to the target organ. This is something that is being researched. Adenovirus AV for gene therapy. You intend to use adenovirus AV, is that correct?
Yes, AV is considered as one of the options for gene therapy. It's just one of the many options, is that correct? That's correct. Another question. I'm really sorry that my questions are so basic, but are you all from Shire originally, those of you who are here today? Now you have become part of Takeda. If you look at their corporate advertising, you see that Takeda is really focusing on treatment of rare diseases. This is a social message. The integration has been completed, and in terms of R&D and management resource allocation, do you see a big difference?
This is Komura from development. I have been working for Takeda from the beginning, and now I have started working with people from former Shire, including Global. Ex-Shire, ex-Takeda, all the employees are working together. As you can see, we have this R&D portfolio. I used to be a pediatrician, and the Takeda portfolio did not really contribute to that segment in the past so much, but now we are with Shire, we're able to do that, which means that we now have a path to contribute to all the patients throughout the world.
Any other comments? Yes, I would like to add some comment from my side. I am in charge of rare disease, and I've been working for Takeda for more than 20 years, but actually, many of the employees in rare disease come from former Shire. LSD and rare disease, we all have very strong passion for this. We see patients struggling in front of our eyes, and there is a very strong passion to R&D. Takeda already had a passion, but there is a synergistic effect, and we're able to exchange new ideas, something that we have never really thought of.
We believe, we're proud that we are creating something much better than what we used to. We are influencing each other and creating something better. That's the environment that we're working in right now. From Japan Medical Office perspective, I would like to share some comments. After the integration of Takeda and Shire, actually, I joined as a mid-career person after working in R&D in another company. The R&D medical franchise where I work deals with R&D products, for example, rare hemorrhagic disease and also rare immunology disease products, in addition to LSD, and many of them come from former Shire.
In R&D, there are many unresolved or unmet medical needs, and therefore, through dialogue with doctors outside, we are looking at and pursuing meeting the unmet medical needs. Some people used to work in R&D, sorry, rare disease in Shire, and some people joined from Takeda to the rare disease team. Like myself, some people had experience with another company. Our team structure is very diversified, and we all want to contribute to the rare disease patient, and we share the same passion as we work on a day-to-day basis. Thank you very much.
どうもありがとうございました。
Sakai-san, thank you very much. We'd like to move on to the next question. Next question is NISSEI Asset Management, Yatsunami-san, please. NISSEI Asset Yatsunami, can you hear me? Yes, we can. Thank you for today's very informative seminar. I'd like to ask you a question about overall lysosomal storage diseases. How to discover patients and how to shorten the time taken from the symptom onset or disease development to diagnosis?
For each disease, you discussed how long it takes in terms of number of years, and it was quite informative, but probably one way is to raise awareness about the disease. For instance, your competitor, Sanofi, has some collaboration with the government, and with a specific target, they try to shorten the time period to reach the diagnosis or making use of some expertise. Do you have any specific approaches or initiatives that you plan to take?
Yatsunami-san, thank you for your question. This is Suzuki. We gave you an overview, and disease awareness needs to be raised, and by so doing, we'll be able to achieve earlier discovery, earlier diagnosis, and earlier start of treatment. In order to raise awareness about the disease, yes, we have been involved in those educational activities, and major events is in every two years. On the final day of February, we have a rare disease day, and with patients with rare diseases, we implement this event as an epoch-making event, although we also have ongoing programs or events held all the year.
The journey to discover and get a diagnosis, how we should consider and we'll be able to improve from the patient viewpoint, physicians, or ours, or caregivers, we collect opinions, inputs, and finding new challenges, we try to solve those challenges and taking a step forward. It is not our collaboration, but each local government also implements the newborn mass screening for those inborn inheritance diseases, and LSDs are included. When a newborn baby is born and also in its infancy, those screenings are held, but it is not nationwide efforts, it is conducted by local governments.
In the disease areas, we have some treatment providing from our side. Some local governments are taking those initiatives, and it takes time, but I think we'll be able to see the effect of those efforts.
Also in Tokyo and Kanagawa, there are some optional testings or examinations available in some facilities, which will also promote earlier diagnosis. We would like to also make a contribution helping out those efforts. Thank you for your support. Thank you very much.
Thank you very much, Yatsunami-san. Seems there are no more questions. It is a bit early from the planned schedule, but we would like to close. Thank you very much for your participation. With this, we would like to close today's webinar. Thank you very much for your attention.