The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only.

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1 The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only. Please note that the results reported in any single trial may not reflect the overall potential risks or benefits of a product which are based on an evaluation of an entire research program. Before prescribing any Takeda products, healthcare professionals should consult prescribing information for the product approved in their country.

2 2. SYNOPSIS Title of Study: A long-term administration study of AF37702 in chronic renal failure patients on hemodialysis and on ESA treatment Name of Sponsor: Takeda Pharmaceutical Co., Ltd. Study Drug: AF37702 Trade Name: Not yet determined Investigator(s) and Study Site(s): 46 study sites Publication: None Study Period: Date first subject signed consent: December 26, 2008 Date last subject had last visit: April 26, 2011 Development Phase: Phase 2 Objectives: To evaluate the safety and efficacy of AF37702 [conversion factor (CF): 0.066] administered intravenously once every 4 weeks for 52 weeks in place of the previous ESA in chronic renal failure patients on hemodialysis and on ESA treatment in an open-label manner Study Design: This study was a multicenter, open-label study for the evaluation of the safety and efficacy of long-term administration of AF37702 [conversion factor (CF): 0.066] in chronic renal failure patients on hemodialysis and on erythropoiesis stimulating agent (ESA) [recombinant human erythropoietin (rhuepo) (epoetin alfa or beta) or darbepoetin alfa] treatment. Among chronic renal failure patients on maintenance therapy with ESA (rhuepo at least once weekly or darbepoetin alfa once a week or 2 weeks) for 8 weeks before the start of study drug administration who had been receiving hemodialysis for at least 6 months prior to signing informed consent, those who had a mean hemoglobin (Hgb) value of 10.0 g/dl or more and 12.0 g/dl or less at 3 measurements during the Screening Phase were included in the study. The planned number of subjects in the study was 300 subjects who started to receive the study drug, and the study was conducted in 46 medical institutions in Japan. The study duration was a total of 56 weeks consisting of the Screening Phase (4 weeks) and the Treatment Phase (52 weeks). During the study period, the specified tests/examinations and observations were performed. Subjects who gave consent to participate in the study and were considered eligible for the study based on the tests/examinations and observations performed during the Screening Phase were enrolled in the study through a specified fax form sent to the registration center and started to receive the study drug in place of the previous ESA at the dose calculated using a conversion factor of The study drug was administered intravenously once every 4 weeks on up to 13 occasions. From the second dose onwards, the dose was adjusted based on each subject s body weight (dry weight) and Hgb values. rhuepo was replaced with the study drug at an interval of at least 2 days from the final dose of rhuepo. Darbepoetin alfa was replaced with the study drug at an interval of at least 7 days (14 days if it was administered once every 2 weeks) from the final dose of darbepoetin alfa.

3 After the first dose, study site visits were scheduled every week until Week 52 (4 weeks after the 13th dose). On the specified test/examination day, laboratory tests, electrocardiography (ECG), and observation of subjective/objective symptoms were performed. Number of Subjects: Planned: Number of subjects who were to receive the study drug: 300 subjects Analyzed: Full Analysis Set (FAS): 307 subjects Inclusion Criteria: 1) Those aged 20 years or more at the time of informed consent 2) Males or females 3) Those who had been receiving hemodialysis for at least 6 months (180 days) prior to signing informed consent and were clinically stable 4) Those who had been receiving maintenance therapy with ESA [rhuepo (epoetin alfa or beta) (at least once weekly) or darbepoetin alfa (once a week or 2 weeks)] for 8 weeks (56 days) before the start of study drug administration 5) Those who had a mean Hgb value of 10.0 g/dl or more and 12.0 g/dl or less at 3 measurements during the Screening Phase (blood sampling was to be performed prior to the 1st dialysis session of each week) 6) Those with a serum ferritin level of 100 ng/ml or more or a transferrin saturation of 20% or less during the Screening Phase 7) Those who were capable of giving consent to participate in the study and understanding the informed consent form and other explanatory documents, and provided written consent

4 Exclusion Criteria: 1) Those who were known to be intolerant to any ESAs 2) Those who were known to be intolerant to iron preparations 3) Those who received red blood cell (RBC) or whole blood transfusion within 12 weeks (84 days) before the start of study drug administration 4) Those who had hemoglobinopathy (e.g., sickle cell disease, thalassemia) 5) Those who had a current or past history of any hemolytic disease 6) Those who had poorly controlled inflammatory disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) 7) Those who had suffered from moderate to severe infection within 2 weeks (14 days) before the start of study drug administration 8) Those who had evident coagulation disorder found clinically or in the test/examination during the Screening Phase (APTT and INR prior to dialysis session) 9) Those who had no vascular access for maintenance hemodialysis 10) Those who had poorly controlled secondary hyperparathyroidism 11) Those who had poorly controlled hypertension 12) Those who had a history of epileptic seizure within 6 months (180 days) before the start of study drug administration 13) Those who had a current or past history of chronic heart failure (class III or IV according to NYHA classification) 14) Those who had a current or past history of malignant tumor within the past 5 years before the start of study drug administration 15) Those who had a plan to undergo a surgery with significant blood loss during the study period 16) Those who were pregnant, lactating, or potentially pregnant, or those of child-bearing potential using no contraceptive measure 17) Those who had a current or past history of drug abuse or dependence 18) Those who had a current or past history of allergy to peptide preparations, PEG, or other protein preparations 19) Those who had previous exposure to any study drug (including those used in postmarketing clinical studies) within 12 weeks (84 days) before the start of study drug administration 20) Those who had previous exposure to AF ) Those who were likely to drop out or be withdrawn prematurely from the study (e.g., those who had the following diseases or conditions within 1 year before the start of study drug administration: myocardial infarction, severe or unstable coronary disease, cerebral stroke, severe or unstable respiratory diseases including reactive airways disease, autoimmune disorder, neuropsychiatric disorder, neurological disorder, viral liver disease such as active hepatitis B or C, active HIV disease, past history of serious allergy to multiple drugs, and other clinically serious diseases or conditions that, in the opinion of the investigator or subinvestigator, would jeopardize the subject s safety or complicate the evaluation or follow-up) 22) Those who, in the opinion of the investigator or subinvestigator, were ineligible to participate in this study

5 Test Product, Dose and Mode of Administration, Lot Number: Dosage form and content AF37702 Injection (10 mg/1 ml): A colorless, clear to light yellow injection solution containing 10 mg of AF37702 per vial Dosing regimen AF37702 was administered intravenously once every 4 weeks. Dose (1) Switching from rhuepo to AF37702 The dose of AF37702 was calculated based on a ratio of mg/kg/4 weeks relative to 100 units/kg/week for rhuepo. (2) Switching from darbepoetin alfa to AF37702 The dose of AF37702 was calculated based on a ratio of mg/kg/4 weeks relative to 0.5 or weekly dose if administered once every 2 weeks) for darbepoetin alfa. Batch/Lot number Period of Evaluation: Study Drug Batch/Lot Number Expiration Date AF37702 (Injection) Z July 2010 Z October 2010 Z December 2010 Z April 2011 Z February 2013 Screening Phase (4 weeks) + Treatment Phase (52 weeks) (if there was no dose interruption after the start of study drug administration) Main Endpoints: (1) Safety Primary endpoints: Adverse events (AEs), laboratory test results, ECG, and vital signs (2) Efficacy Secondary endpoints: Time profile of proportion (%) of subjects whose changes from baseline in Hgb values were maintained within ± 1.0 g/dl Time profile of proportion (%) of subjects whose Hgb values were maintained within a range of 10.0 to 12.0 g/dl Time profile of proportion (%) of subjects whose Hgb values were maintained within a range of 9.5 to 12.5 g/dl Time profile of Hgb values Time profile of changes from baseline in Hgb values Proportion (%) of subjects with no dose adjustment Proportion (%) of subjects who received RBC transfusion after the start of study drug administration

6 Other endpoints: Pharmacodynamic parameters [reticulocyte count (absolute count), red blood cell (RBC) count, hematocrit, serum ferritin concentration, transferrin saturation, transferrin receptor protein] Proportion (%) of subjects whose Hgb values were maintained within a range of 10.0 to 12.0 g/dl during Weeks 16 to 24 and during Weeks 25 to 52 Changes from baseline in mean Hgb values during Weeks 16 to 24 and during Weeks 25 to 52 Mean Hgb values during Weeks 16 to 24 and during Weeks 25 to 52 Changes in Hgb values from the previous week (each visit visit in the previous week) Differences between maximum and minimum Hgb values at 4-week intervals (maximum minimum) Time profiles of the dose of the study drug Mean dose of the study drug administered during Weeks 16 to 24 and during Weeks 25 to 52 (3) Pharmacokinetics Plasma concentration of unchanged AF37702 Statistical Methods: The following were performed on the FAS: Treatment emergent AEs (TEAEs) were defined as events occurring or concurrent medical conditions worsening after the start of study drug administration. The frequencies of the following TEAEs were tabulated by System Organ Class (SOC) and Preferred Term (PT). All TEAEs TEAEs by causal relationship to the study drug TEAEs by intensity Drug-related TEAEs Drug-related TEAEs by intensity TEAEs by time of onset TEAEs leading to study drug discontinuation Serious TEAE SUMMARY-CONCLUSIONS: Subject Disposition A total of 418 subjects provided consent, and 307 subjects received the study drug. For the remaining 111 subjects who did not received the study drug, the reasons for withdrawal from the study were failure to meet the entrance criteria in 102 subjects, pretreatment events/aes in 6 subjects, and voluntary withdrawal in 3 subjects. Of the 307 subjects who received the study drug, 232 subjects completed the study and 75 subjects were withdrawn from the study. The reasons for withdrawal from the study were

7 pretreatment events/aes in 41 subjects, major protocol deviation (Exclusion criterion 14: Those who had a current or past history of malignant tumor within the past 5 years before the start of study drug administration) in 1 subject, voluntary withdrawal in 6 subjects, lack of efficacy in 7 subjects, and other reasons in 20 subjects. Other reasons were as follows: any excluded concomitant medication was used during the Treatment Phase (10 subjects); no ESA was necessary (3 subjects); the starting dose was inappropriate (2 subjects); the possibility of pregnancy could not be ruled out based on the acceptable range (1 subject); the subject s safety could not be ensured due to overseas travel during the study period (1 subject); all subjects completed 48 weeks of study treatment (1 subject); the subject s safety was considered (1 subject); and the anti-af37702 antibody was detected (1 subject). In addition, 13 subjects with an Hgb value of more than 12.0 g/dl at the completion or discontinuation of the study were followed up, and all of these subjects were confirmed to have an Hgb value of 12.0 g/dl or less during the follow-up. Safety Conclusions The incidence of AEs was 96.4% (296/307 subjects, 1913 events). AEs with an incidence of 5% or higher were nasopharyngitis (51.5%, 158/307 subjects), fall (19.2%, 59/307 subjects), diarrhoea (13.4%, 41/307 subjects), back pain (11.4%, 35/307 subjects), shunt stenosis (11.4%, 35/307 subjects), upper respiratory tract inflammation (10.1%, 31/307 subjects), arthralgia (9.1%, 28/307 subjects), contusion (8.8%, 27/307 subjects), hypertension (8.5%, 26/307 subjects), shunt occlusion (7.2%, 22/307 subjects), puncture site reaction (6.5%, 20/307 subjects), pharyngitis (5.9%, 18/307 subjects), pain in extremity (5.9%, 18/307 subjects), and procedural hypotension (5.5%, 17/307 subjects). No obvious trend was observed for the incidence of AEs or incidences of individual AEs by time of onset. The incidence of drug-related AEs was 13.4% (41/307 subjects, 49 events). The only drugrelated AEs with an incidence of 5% or higher was hypertension (6.5%, 20/307 subjects). Most of these AEs did not lead to study drug discontinuation and resolved during the study period. Hypertension did not resolve in 4 subjects (4 events); however, it became stable with treatment and was thus considered not necessary to follow up at the end of the study in all subjects. In addition, AEs led to study drug discontinuation in 4 subjects (4 events), but all of these AEs resolved after study drug discontinuation. Most AEs were mild or moderate in intensity. Severe drug-related AEs were loss of consciousness (0.3%, 1/307 subjects), tonic convulsion (0.3%, 1/307 subjects), acute myocardial infarction (0.3%, 1/307 subjects), and aortic calcification (0.3%, 1/307 subjects); however, all of these AEs may have been related to the underlying condition of each subject. Two deaths were reported during the study period. Fatal AEs were acute myocardial infarction and pulmonary oedema in 1 subject (2 events), and disseminated intravascular coagulation in 1 subject (1 event). Except for acute myocardial infarction, all of these AEs were not related to the study drug. Acute myocardial infarction may have been related to the underlying condition of the subject such as concurrent medical conditions since no excessive increase in Hgb was noted at the time of onset. The incidence of serious AEs (SAEs) including deaths was 25.4% (78/307 subjects, 103

8 events). In addition to 1 death, drug-related SAEs were reported in 6 subjects (7 events): loss of consciousness and tonic convulsion in 1 subject (2 events), and cerebral infarction, lacunar infarction, aortic calcification, shunt occlusion, and shunt blood flow excessive in 1 subject each (1 event). All of these AEs may have been related to the underlying condition of each subject such as concurrent medical conditions since no excessive increase in Hgb was noted at the time of onset and some were observed before the start of the study. The incidence of AEs leading to study drug discontinuation was 13.0% (40/307 subjects, 43 events). Of these AEs, drug-related AEs were hypertension in 4 subjects (4 events), loss of consciousness and tonic convulsion in 1 subject (2 events), and dizziness, cerebral infarction, lacunar infarction, acute myocardial infarction, atrial flutter, aortic calcification, large intestinal ulcer, and shunt occlusion in 1 subject each (1 event). Of these AEs, cerebral infarction, loss of consciousness, tonic convulsion, lacunar infarction, acute myocardial infarction, aortic calcification, and shunt occlusion were drug-related SAEs mentioned above. Hypertension in 4 subjects (4 events) and dizziness, atrial flutter, and large intestinal ulcer in 1 subject each were mild or moderate in intensity, and all of these AEs except for atrial flutter in 1 subject resolved after study drug discontinuation. Atrial flutter had not resolved when the subject died of congestive cardiac failure, which occurred after the end of the study. No clinically significant changes were observed in laboratory tests or vital signs. In ECG, 5 subjects had abnormal and clinically significant 12-lead ECG findings at some visits; however, relevant AEs were not related to the study drug, except for atrial fibrillation and atrial flutter in 1 subject each. For blood transfusion, 4 subjects received RBC transfusion after the start of study drug administration. All of these subjects received transfusion due to a decrease in Hgb associated with hemorrhage or blood loss. The anti-af37702 antibody was detected in 8 subjects; however, no relevant AEs including clinical symptoms and laboratory test results were observed in any of these subjects except for 1 subject withdrawn from the study due to lack of efficacy. No cross-reaction between the antibody and EPO was observed in the 8 subjects. In conclusion, 52-week treatment with AF37702 in chronic renal failure patients on hemodialysis and on ESA treatment was associated with no clinically significant notable events, indicating that there was no significant safety concern with the treatment. Efficacy Conclusions Among the secondary endpoints, the proportion (%) of subjects whose changes from baseline in Hgb values were maintained within ± 1.0 g/dl ranged from 71.7% to 89.5% throughout the study period. The proportion (%) of subjects whose Hgb values were maintained within a range of 10.0 to 12.0 g/dl and within a range of 9.5 to 12.5 g/dl ranged from 64.6% to 86.3% and from 85.4% to 96.3% throughout the study period, respectively. Hgb values (mean ± SD) ranged from ± to ± g/dl during Week 0 (start of study drug administration) to 24 and ranged from ± to ± g/dl during Week 25 to 52, showing that mean Hgb values were maintained within a range of 10.0 to 12.0 g/dl throughout the study period. Changes (mean ± SD) from baseline

9 in Hgb values ranged from ± to 0.52 ± g/dl during Week 0 to 24 and ranged from ± to 0.36 ± g/dl during Week 25 to 52, showing that mean changes from baseline in Hgb values were maintained within ± 1.0 g/dl throughout the study period. Among the other endpoints, the proportion (%) of subjects who had a mean Hgb value of 10.0 to 12.0 g/dl during Week 16 to 24 and during Week 25 to 52 was 79.8% (217/272 subjects) and 91.9% (237/258 subjects), respectively. Mean Hgb values (mean ± SD) during Week 16 to 24 and during Week 25 to 52 were ± g/dl and ± g/dl, respectively, showing that mean Hgb values were within a range of 10.0 to 12.0 g/dl in both periods. The proportion (%) of subjects whose changes from baseline in mean Hgb values were within ± 1.0g/dL during Week 16 to 24 and during Week 25 to 52 was 88.2% (240/272 subjects) and 93.8% (242/258 subjects), respectively. Changes (mean ± SD) from baseline in mean Hgb values were ± g/dl during Week 16 to 24 and ± g/dl during Week 25 to 52, showing that changes from baseline in mean Hgb values were within ± 1.0 g/dl in both periods. The proportion (%) (mean ± SD) of subjects whose Hgb values were maintained within a range of 10.0 to 12.0 g/dl during Week 16 to 24 and during Week 25 to 52 was 76.3 ± 29.14% and 79.0 ± 19.66%, respectively. Differences (mean ± SD) between maximum and minimum Hgb values at 4-week intervals were 0.77 ± to 0.85 ± g/dl during Week 0 to 24 and 0.80 ± to 0.83 ± g/dl during Week 25 to 52, showing that mean differences between maximum and minimum Hgb values at 4-week intervals were 1.0 g/dl or less in all periods. Changes (mean ± SD) in Hgb values from the previous week were ± to 0.42 ± g/dl during Week 0 to 24 and ± to 0.25 ± g/dl during Week 25 to 52, showing that mean changes in Hgb values from the previous week were within ± 0.5 g/dl throughout the study period. The proportion (%) of subjects whose changes in Hgb values from the previous week were increases exceeding 0.5 g/dl was 2.5% to 37.3% during Week 0 to 24 and 2.8% to 24.8% during Week 25 to 52, and the proportion (%) of subjects whose changes in Hgb values from the previous week were decreases exceeding more than 0.5 g/dl was 2.9% to 28.1% during Week 0 to 24 and 6.3% to 27.5% during Week 25 to 52. The dose of AF37702 per unit body weight and the dose of AF37702 administered actually during Week 16 to 24 and during Week 25 to 52 were increased from those at the start of study drug administration (Week 0). In conclusion, Hgb values were consistently maintained within the target range for 52 weeks after the start of treatment with AF37702 administered in place of the previous ESA by adjusting the dose in chronic renal failure patients on hemodialysis and on ESA treatment, demonstrating the long-term efficacy of AF Overall Conclusions The safety and efficacy of AF37702 administered intravenously once every 4 weeks for 52 weeks in place of the previous ESA in chronic renal failure patients on hemodialysis and on ESA treatment were evaluated in an open-label manner. With regard to safety, no clinically significant AF37702-specific events were reported,

10 indicating that there will be no significant safety concern with AF37702 if warning notes are issued as are with conventional ESAs. With regard to efficacy, Hgb values were consistently maintained within the target range on a long-term basis. In conclusion, it was demonstrated that AF37702 administered intravenously once every 4 weeks for 52 weeks was safe and effective with no significant concern, and could be well tolerated. Date of Report: January 30, 2012