Aiming at Developing Original New Drugs to Global Standards

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1 Aiming at Developing Original New Drugs to Global Standards R&D Ono Pharmaceutical s Foundation and Core Commitment Develop original and first-in-class drugs that do not exist anywhere and that no one has dealt with before. This is the unchangeable philosophy inherited by all Ono researchers. As a manufacturer engaged in drug discovery, Ono will continue to set as its research and development principle, Challenge diseases that have yet to be conquered and contribute to the society by developing drugs that truly benefit patients. We also will set (1) placing priority on our strategic areas, (2) committing ourselves to a compound-oriented research, (3) dealing with the world s leading-edge technologies, and (4) pursuing quality and speed of research as the management policy of our R&D activities, and aim at development of global new drugs. Gaining a world lead through accumulating top-quality technology and know-how in the four priority areas, prostaglandins (PGs), enzyme inhibitors, neuroscience, and intracellular signaling Pharmaceutical manufacturers working on the development of new drugs invest a great amount of time and money into drug discovery research. It takes a long period of time, possibly between 10 and 18 years, and an enormous amount of R&D expenditure from the time a useful compound is discovered until it is approved as a new drug. Yet, there is no guarantee that a new candidate drug can be developed to approval, no matter how much time or money is spent. The probability of success is about one out of every 10 thousand compounds discovered. Ono is continuing this high-risk challenge of developing unique new drugs. In order to develop Ono s original and innovative new drugs, we have narrowed down our priority areas to prostaglandins, enzyme inhibitors, neuroscience, and intracellular signaling, and are proceeding with drug discovery research. Prostaglandins An area with large potential in the treatment of increasing lifestyle-related diseases. Prostaglandins (PGs) are substances produced at the cell membrane that cause biological defensive responses against various stimuli. It has been elucidated that a number of diseases are associated with the impairment of the balance in the production of various PGs. After successfully establishing the world s first manufacturing process for the complete 4 ANNUAL REPORT 2006 Ono Pharmaceutical Co., Ltd.

2 Aiming at Developing Original New Drugs to Global Standards chemical synthesis of PGs Ono has gone on to develop a number of PG drugs in the cardiovascular area such as Prostandin and Opalmon. With their many still untapped aspects, PG agents have a large hidden potential as a therapy for lifestyle-related diseases and modern intractable diseases. Ono continues to pursue second- and thirdgeneration PG based research for improved efficacy and safety. This research is progressing steadily and is expected to further accelerate in the future on bioactive lipids such as PGs by utilizing genome information. Enzyme inhibitors Focus on enzymes that cause intractable diseases. Expanding research areas. Disseminated intravascular coagulation (DIC), chronic pancreatitis, diabetic peripheral neuropathy, etc. are diseases that are said to be particularly intractable even with modern medicine. Ono has focused its attention on endogenous enzymes that cause such diseases, and has carried out R&D on drugs that inhibit and/or regulate abnormal enzyme activity. Thus far, we have created FOY, a therapeutic agent for DIC that is highly appraised at clinical sites; Foipan, the world s first therapeutic agent for chronic pancreatitis; Kinedak, indicated for the treatment of diabetic peripheral neuropathy; Cataclot, used for the treatment of cerebral thrombosis during acute phase and cerebral vasospasms following surgical operation of subarachnoid hemorrhage; Elaspol, the world s first drug for treating acute lung injury associated with systemic inflammatory response syndrome, and others. We are further searching for new targets existing within the body and expanding research in those areas. Research in the areas of neuroscience and intracellular signaling is also progressing rapidly. While exploiting the most of the know-how and technology cultivated in the areas of PG and enzyme inhibitors, in our quest to develop original and innovative drugs, we have broadened our scope of research to include such rapidly advancing areas as neuroscience and intracellular signaling. A world-class compoundoriented research organization For the development of original and innovative drugs, unlike pharmaceutical companies that narrow down research areas by therapeutic class, Ono focuses its attention on physiological substances that are believed to play an important role in biological processes and illnesses and has committed to compound-oriented research, in which search is focused on new chemical entities that have effects on such substances, and then investigation is carried out to identify diseases in which the entities show therapeutic efficacy. The Minase Research Institute in Osaka ANNUAL REPORT 2006 Ono Pharmaceutical Co., Ltd. 5

3 scientists and their ability to think along new paths. Ono sets out clear research targets to enhance such motivation and creative thinking of its researchers. Our research organization is based on project teams whose members have cutting-edge expertise in different areas. The Tsukuba Research Institute in Ibaraki Preparation of DNA Microarrays Compounds that are discovered and developed without being limited to specific disease areas could have efficacy in a broad range of diseases. From a single compound, Ono has been able to create a number of world-recognized products one after another. A research structure that breeds motivation and fresh ideas The development of original new drugs is driven by the motivation of individual Refining the most advanced techniques and data to develop new drugs Research to develop new drugs is the lifeline of any pharmaceutical manufacturer. Ono has a distinguished record of creating many first-in-class drugs, and our ongoing basic and applied research programs serve the goal of continued development of original new drugs. Tsukuba The Tsukuba Research Institute consists of Exploratory Research Laboratory and Pharmacokinetic Research Laboratory. The former utilizes the latest genome techniques to identify compounds with therapeutic potential and investigates the precise links between various compounds and illnesses, and the latter conducts pharmacokinetic research for new compounds discovered by Ono. Minase Medical Chemistry Research Laboratory is engaged in the discovery of new compounds by utilizing advanced computing techniques to design compounds and an array of high-speed synthesizing and screening devices to efficiently synthesize compounds. Discovery Research Laboratories I, II, and 6 ANNUAL REPORT 2006 Ono Pharmaceutical Co., Ltd.

4 Aiming at Developing Original New Drugs to Global Standards III are devoted to evaluating the pharmacodynamic efficacy of synthesized compounds, focusing on the critical research areas of prostaglandins, enzyme inhibitors, neuroscience, and intracellular signaling. The work is designed to identify original and innovative new drugs. Fukui Studies using state-of-the-art equipment at the Fukui Safety Research Laboratory cover the potential general toxicity, carcinogenicity, reproductive toxicity, and genotoxicity of compounds under evaluation for pharmaceutical use. The Fukui Chemical Process Research Laboratory conducts research to enable large-scale synthesis of drug substances for mass production, actively developing synthesizing techniques required for mass production and reducing costs. Highly anticipated genomebased drug discovery towards next-generation drug discovery The entire sequence of the human genome has been decoded. If, as a next step, the 3-D Molecular Modeling The Fukui Research Institute in Fukui functions and the control of genes are identified, the entire biochemical information could then theoretically be predicted, which should clarify the causes and treatment of diseases. In addition, it is expected that the mechanisms of drug action and causes of adverse drug reactions would also be revealed. It is said that individual differences, such as those who are more likely to develop a disease or more likely to develop adverse drug reactions, would be identifiable based on even slight differences in genes. Ono has been conducting joint research efforts with universities and research institutions overseas to actively utilize genome technology and information as a means for drug discovery for some time. Through these efforts, we have obtained many genes with novel sequences, and the Copyright 2006 Medarex, Inc. All rights reserved. Used with permission. ANNUAL REPORT 2006 Ono Pharmaceutical Co., Ltd. 7

5 functional analysis of these new genes and their protein products is progressing smoothly. Among those for which functions have been already clarified, there are several enzymes and receptors related to areas we are strong in, and these proteins all closely relate to drugs. We wish to maximize these gene assets for the next-generation drug discovery, for example, as building blocks for antibody drugs. New Drugs in Development In our ongoing effort to create products that will promote the health of more people worldwide, Ono has many new drug formulations under development, including the following major drugs: Staybla Tablets (ONO-8025 / KRP-197) Staybla, an antagonist selectively binding to muscarinic receptors, is for the treatment of overactive bladder (pollakiuria and urinary incontinence). The drug remarkably reduces burdens on patient daily life, such as frequent urination, urinary incontinence, and urgency of urination. The drug is characterized by having the high efficacy, and by having less adverse effect, such as dry mouth, caused by existing drugs with similar modes of action. Japan: NDA filed / Overactive bladder (pollakiuria and urinary incontinence) (co-development with Kyorin Pharmaceutical Co., Ltd.) Recalbon Tablets (ONO-5920 / YM529) Recalbon (formerly known as Onobis ), a drug for the treatment of osteoporosis, is one of the most potent bisphosphonates, rapidly preventing bone resorption at low doses and increasing in bone mineral density. The drug is characterized by having the high efficacy, and by having less adverse reaction on the digestive tract. Japan: NDA filed / Osteoporosis (codevelopment with Astellas Pharma Inc.) ONO-5435 / MK-0431 ONO-5435, a dipeptidyl-peptidase (DPP) IV inhibitor, is a new class of drug for type II diabetes and is expected to be useful for control of postprandial hyperglycemia with low risks of hypoglycemia and/or weight gain in type II diabetes patients. 8 ANNUAL REPORT 2006 Ono Pharmaceutical Co., Ltd.

6 Aiming at Developing Original New Drugs to Global Standards Japan: Phase III / Type II diabetes (codevelopment with Banyu Pharmaceutical Co., Ltd.) Overseas: NDA filed / Type II diabetes (Merck & Co., Inc.) Arocyte for Injection (ONO-2506) Arocyte (formerly known as Proglia ) is a drug to prevent expansion of cerebral infarction by improving function of astrocyte, a kind of glial cells in the brain. In the late Phase II study in Japan, safety and efficacy of Arocyte in patients with acute ischemic stroke has been confirmed. Since the drug does not act on the blood coagulation system, the drug is expected to have no risk of haemorrahge and to be highly effective. Japan: Phase II/III / Acute ischemic stroke North America: Phase II / Acute ischemic stroke (Merck & Co., Inc.) Emend Capsule (ONO-7436 / MK-0869) Emend is the first neurokinin (NK) 1 antagonist in the world. The drug is effective not only for acute phase of chemotherapy-induced nausea and vomiting, but also for delayed phase (24 hours or later after start of chemotherapy) of nausea and vomiting caused by chemotherapy for which there was no effective drug. The drug is also approved for prevention of post-operative nausea and vomiting in the US. Japan: Phase II completed / Chemotherapy-induced nausea and vomiting Overseas: Marketed (Merck & Co., Inc.) ONO-2540 / ENA713D (transdermal patch) ONO-2540 or rivastigmine patch is a drug for the treatment of Alzheimer s disease with an inhibitory action on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The Exelon capsule, an oral formulation of rivastigmine, is widely used in more than 70 countries outside Japan. The drug inhibits not only AChE which is known as an enzyme deeply involved in Alzheimer s disease, but also BuChE which reportedly increases as the disease progresses. Therefore, the drug is expected to have an effect in patients who do not respond to existing drugs. The rivastigmine patch is the first transdermal system developed for the disease and is expected to provide greater convenience, e.g. caregivers can easily confirm the administration of the drug. Japan: Phase II / Alzheimer s disease (codevelopment with Novartis Pharma K.K.) Europe & US: Phase II/III completed / Alzheimer s disease (Novartis) Cereact Capsules (ONO-2506PO) Abnormal activation of astrocyte has been blamed for neurodegenerative diseases such as Alzheimer s/ Parkinson s diseases and amyotrophic lateral sclerosis (ALS), one of the intractable diseases. Cereact has a new mechanism of action to prevent the occurrence and progression of various neurodegenerative diseases, by improving astrocyte function. Japan: Phase II / Parkinson s disease Europe: Phase II / ALS North America: Phase II / Alzheimer s disease ONO-5129 (tablet) ONO-5129, a dual agonist of PPARα and PPARγ, intracellular nuclear receptors, has both the hypoglycemic effect exerted by PPARγ action and the hypolipidemic effect exerted by PPARα action. The drug is being developed primarily for the treatment of type II diabetes. Existing PPARγ agonists increase insulin sensitivity, leading to accumulation of visceral lipid and weight increase, in addition to lowered blood glucose level. However, the dual agonists of PPARα and PPARγ do not contribute to triglyceride accumulation because of their hypolipidemic effect. Therefore, it is expected that ONO-5129 will be developed as an anti-type II diabetic drug ANNUAL REPORT 2006 Ono Pharmaceutical Co., Ltd. 9

7 with the advantages in low risks of fatty liver and weight increase. Japan: Phase II / Type II diabetes US: Phase II / Type II diabetes ONO-2333Ms (tablet) ONO-2333Ms, a corticotropin-releasing factor (CRF) receptor antagonist, is developed primarily for the treatment of depression and/or anxiety disorder. The drug is characterized by exhibiting more potent activity and more rapid onset of action, compared with existing drugs. In addition, based on the mechanism of drug action, ONO- 2333Ms is expected to exhibit a fewer adverse reactions, such as dry mouth, gastrointestinal disorders, sexual dysfunction, and others than those with existing drugs. Japan: Phase I / Depression and anxiety disorder US: Phase I / Depression and anxiety disorder ONO-2231 (injection) ONO-2231, a poly ADP-ribose polymerase (PARP) inhibitor, is being developed for acute ischemic stroke. Since a poly ADPribose polymerase is an enzyme involved in cellular death, the drug is expected to be an effective drug for diseases such as acute ischemic stroke. Europe: Phase I / Acute ischemic stroke negative regulatory system to suppress the activated lymphocytes. It has been reported that tumor cells utilize this system to escape from the host immune responses. It is anticipated that blockade of the negative regulatory signal mediated by PD-1 will promote the host s immune response, in which tumor cells are recognized as foreign and eliminated. US: Phase I / Cancer Onoact for Injection Japan: NDA filed / Postoperative tachyarrhythmias (additional indication) Phase II / Improvement of multislice CT coronary imaging ability (additional indication) Onon Dry Syrup Japan: Phase II/III / Allergic rhinitis (pediatric) (additional indication) Onon Capsules Japan: Phase II / Chronic sinusitis (additional indication) Opalmon Tablets Japan: Phase II / Cervical Spondylosis (additional indication) (co-development with Dainippon Sumitomo Pharma Co., Ltd.) ONO-5334 (tablet) ONO-5334, a cathepsin K inhibitor, is being developed for osteoporosis with a novel mechanism of action. Unlike bisphosphonates, the drug only inhibits bone resorption without having impact on bone formation. Europe: Phase I / Osteoporosis ONO-4538 / MDX-1106 (injection) ONO-4538, a fully human anti-pd-1 antibody, is expected to be a potential treatment for cancer. PD-1 is one of the receptors expressed on activated lymphocytes, and is involved in the 10 ANNUAL REPORT 2006 Ono Pharmaceutical Co., Ltd.

8 Aiming at Developing Original New Drugs to Global Standards Status of Development Pipeline (as of August 4, 2006) Developments in Japan NDA filed: New chemical entities: Staybla Tablets (ONO-8025 / KRP-197) (co-development with Kyorin Pharmaceutical Co., Ltd.) Overactive bladder (pollakiuria and urinary incontinence) [M3 muscarinic receptor blocker] Recalbon Tablets (ONO-5920 / YM529) (co-development with Astellas Pharma Inc.)* 1 Osteoporosis [bone resorption inhibitor (bisphosphonate)] Additional indications: Onoact for Injection Postoperative tachyarrhythmias [short-acting β1 blocker] Ongoing clinical studies: New chemical entities: ONO-5435 / MK-0431 (co-development with Banyu Pharmaceutical Co., Ltd.)* 2 Type II diabetes (Phase III) [DPP-IV inhibitor] Arocyte for Injection (ONO-2506) Acute ischemic stroke (Phase II/III) [neuroprotective effect (astrocyte modulator)] Emend Capsules (ONO-7436 / MK-0869) (in-licensed from Merck & Co., Inc.)* 3 Chemotherapy-induced nausea and vomiting (Phase II completed) [NK1 antagonist] ONO-2540 / ENA713D (transdermal patch) (co-development with Novartis Pharma K.K.) Alzheimer s disease (Phase II) [dual inhibitor of AChE and BuChE] Cereact Capsules (ONO-2506PO) Parkinson s disease (Phase II) [neuroprotective effect (astrocyte modulator)] ONO-5129 (tablet)* 4 Type II diabetes (Phase II) [dual agonist of PPARα and PPARγ] ONO-2333Ms (tablet) Depression and anxiety disorder (Phase I) [CRF receptor antagonist] Additional indications: Onon Dry Syrup Allergic rhinitis (pediatric) (Phase II/III) [LTC4 and LTD4 antagonist] Onon Capsules Chronic sinusitis (Phase II) [LTC4 and LTD4 antagonist] Opalmon Tablets (co-development with Dainippon Sumitomo Pharma Co., Ltd.) Cervical Spondylosis (Phase II) [increase of blood flow in nerve tissue] Onoact for Injection Improvement of multislice CT coronary imaging ability (Phase II) [short-acting β1 blocker] Developments abroad Ongoing clinical studies: Arocyte for Injection (ONO-2506) (out-licensed to Merck & Co., Inc.)* 5 Acute ischemic stroke (Phase II) [neuroprotective effect (astrocyte modulator)] Cereact Capsules (ONO-2506PO) Amyotrophic lateral sclerosis (ALS) (Phase II) Alzheimer s disease (Phase II) [neuroprotective effect (astrocyte modulator)] ONO-5129 (tablet) Type II diabetes (Phase II) [dual agonist of PPARα and PPARγ] ONO-2333Ms (tablet) Depression and anxiety disorder (Phase I) [CRF receptor antagonist] ONO-2231 (injection) Acute ischemic stroke (Phase I) [PARP inhibitor] ONO-5334 (tablet) Osteoporosis (Phase I) [cathepsin K inhibitor] ONO-4538 / MDX-1106 (injection) (co-development with Medarex, Inc.)* 6 Cancer (Phase I) [fully human anti-pd-1 antibody] *: Changes from the First Quarter Flash Report for the fiscal year ending March 2007 (announced on May 15, 2006) *1: Ono and Astellas submitted an application for approval of Recalbon Tablets, (formerly known as Onobis ) a drug for osteoporosis, jointly developed by the two companies, to the MHLW in July *2: Banyu Pharmaceutical Co., Ltd. completed Phase II studies of ONO / MK0431 a medication for type II diabetes, licensed from Merck & Co., Inc. for joint development by Ono and Banyu for Phase III studies and afterwards, and Ono and Banyu have commenced Phase III studies in Japan. *3: Ono completed Phase II studies of Emend Capsules, an antiemetic for chemotherapy-induced nausea and vomiting, licensed from Merck & Co., Inc. for exclusive development by Ono in Japan, and the results demonstrated that the Emend Capsules had the expected efficacy. Ono will make a decision on the development strategy in consultation with the Pharmaceuticals and Medical Devices Agency (PMDA) in order to obtain approval for this drug as soon as possible. Meanwhile, an additional indication of prevention of post-operative nausea and vomiting was approved for Emend in the US in July *4: Ono completed Phase I studies of ONO-5129, a drug for type II diabetes, and commenced Phase II studies in Japan in May *5: Merck & Co., Inc., our out-licensing partner for Arocyte for Injection (formerly known as Proglia ), is planning a new Phase II study of the drug for acute ischemic stroke and will soon commence the study in North America. *6: The US FDA approved an IND for ONO-4538 / MDX-1106, a fully human anti-pd-1 antibody, jointly discovered by collaborative research between Ono and Medarex, Inc. Medarex will commence Phase I studies in patients with cancer in the US. ANNUAL REPORT 2006 Ono Pharmaceutical Co., Ltd. 11