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AF37702 Page 1 of 11 1 SYNOPSIS Title of Study: A Study of AF37702 in Chronic Renal Failure Patients on Peritoneal Dialysis Name of Sponsor: Takeda Pharmaceutical Co., Ltd. Study Drug: AF37702 Trade Name: Not yet determined Investigator(s) and Study Site(s): A total of 30 study sites including Meiyokai Medical Corporation Narita Memorial Hospital (Takaaki Obayashi, Director, Department of Nephrology) (See Appendix 16.1.4) Publication: None Study Period: Development Phase: Date first subject signed consent: May 24, 2010 Phase 3 Date last subject had last visit: May 7, 2011 Objectives: To evaluate efficacy, safety, and pharmacokinetics of AF37702 following subcutaneous or intravenous multiple administration, once every 4 weeks in chronic renal failure patients on peritoneal dialysis in an open-label manner. Study Design: This study was a multicenter, open-label study for evaluation of efficacy, safety, and pharmacokinetics of AF37702 following multiple administration in chronic renal failure patients on peritoneal dialysis. (1) Study population and its design This study consisted of 4 treatment groups comprising different subjects and dosing regimens. In the 0.025 mg/kg SC group, study drug was administered subcutaneously to subjects who had not been on treatment with an erythropoiesis stimulating agent (ESA). In the CF0.066 SC/SC group, study drug was administered subcutaneously to subjects who were on subcutanous ESA treatment. In the CF0.066 IV/SC group, study drug was administered subcutaneously to subjects who were on intravenous ESA treatment. In the CF0.066 IV/IV group, study drug was administered intravenously to subjects who were on intravenous ESA treatment. In the 0.025 mg/kg SC group, subjects who met the following criteria were included in the study: continuous peritoneal dialysis since before the start of the Screening Phase with no history of ESA treatment after the initiation of peritoneal dialysis or with no history of ESA treatment within 12 weeks (84 days) before start of the study drug administration, and hemoglobin (Hgb) values of less than 10.0 g/dl at 2 measurement time points within 8 weeks (56 days) from the day
AF37702 Page 2 of 11 before the initiation of study treatment. In the CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups, subjects who met the following criteria were included in the study: continuous peritoneal dialysis for at least 3 months (90 days) before the start of the Screening Phase and on ESA treatment (epoetin beta, epoetin alfa, or darbepoetin alfa) for at least 8 weeks (56 days) before start of the study drug administration, and Hgb values of 10.0 to 12.0 g/dl at 2 measumement time points within 8 weeks (56 days) from the day before the initiation of study treatment. The planned number of subjects in the study was approximately 80 subjects treated with study drug (0.025 mg/kg SC group, 5 subjects; CF0.066 SC/SC group, 25 subjects; CF0.066 IV/SC group, 25 subjects; CF0.066 IV/IV group, 25 subjects). The total study duration was 26 to 28 weeks (up to 6 doses of the study drug) consisting of the Screening Phase (2 to 4 weeks) and Treatment Phase (24 weeks). The tests/examinations and observations specified in the protocol were performed during the study period. (2) Dosage and mode of administration The initial dose in the 0.025 mg/kg SC group was the predetermined doses (1.0, 1.25, 1.5, 2.0, and 2.5 mg/4 weeks) based on the subjects body weight at Week 0. Subsequent doses were adjusted (unchanged, 1-step decrease, 1-step increase, or delayed) within the range of 0.5 to 6.0 mg every 4 weeks based on Hgb values of individual subjects. The second administration was delayed if the Hgb value exceeded 13.0 g/dl in any of the specified time points following initial treatment (except for the day of initial treatment), while the subsequent administration was delayed when the Hgb value exceeded 12.5 g/dl in any of the specified time points following the preceding treatment (except for the day of the preceding treatment). Administration of the study drug was resumed at 1-step decreased dose and continued every 4 weeeks, from the first even-numbered week after the Hgb value firstly decreased to 12.5 g/dl or less for the delay of 2nd adminitsration and from the first even-numbered week after the value firstly decreases to 12.0 g/dl or less for the dalay of subsequent administration. The initial dose in the CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups was the predetermined doses (0.75, 1.0, 1.25, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, and 8.0 mg/4 weeks) specified according to prescribed ESA doses within the 2 weeks before start of the study drug administration. The subsequent doses were adjusted (unchanged, 1-step decreased, 1-step increased, 2-step increased, or delayed) at a range of 0.5 to 20.0 mg every 4 weeks based on individual Hgb value. Administration was delayed when the Hgb value exceeded 12.5 g/dl in any of the specified time points following the preceding treatment (except for the day of the preceding treatment), and administration of AF37702 was resumed at a 1-step decreased dose and continued every 4 weeks from the first even-numbered week after the Hgb value first decreased to 12.0 g/dl or less. When switching from ESA preparation to study drug, the dosing interval was to be determined according to the dose frequency of ESA preparation before the switching; at least 2 days (twice or thrice per week administration), at least 7 days (once per week administration), at least 14 days (once per 2-week administration), or at least 28 days (every 4 weeks) since the day of final
AF37702 Page 3 of 11 administration of ESA. (3) Study schedule Subjects visited study sites every week until Week 4, and thereafter every other week during the period to Week 24. Laboratory tests, electrocardiogram (ECG) tests, observation of subjective symptoms/objective findings, and others were performed on the day of the test/examination specified in the protocol. Blood sampling for analysis of plasma drug concentration was also performed in subjects given the study drug intravenously. A schematic of the study design is shown below. Informed consent (prior to the Screening Phase) Start of Screening Phase Enrollment Final examination Screening Treatment (without dose delay) Weeks -4 to -2 Week 0 Note2) Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Note 1) Not on ESA treatment 0.025 mg/kg SC group: 5 subjects AF37702 subcutaneous administration On ESA treatment (subcutaneous administration) On ESA treatment (intravenous administration) Note 1), Note 2) CF0.066 SC/SC group: 25 subjects AF37702 subcutaneous administration Note 1), Note 2) CF0.066 IV/SC group: 25 subjects AF37702 subcutaneous administration Note 1), Note 2) CF0.066 IV/IV group: 25 subjects AF37702 intravenous administration 1st administration 2nd 3rd 4th 5th 6th Number of Subjects: Planned: Note 1): Doses were adjusted according to individual Hgb value. Note 2): When switching from ESA preparation to study drug, the dosing interval was at least 2 days (twice or thrice per week administration), at least 7 days (once per week administration), at least 14 days (once per 2-week administration), or at least 28 days (every 4 weeks) since the day of final administration of ESA. A schematic of the study design Number of subjects who were to receive the study drug administration: Approximately 80 subjects Analyzed: 0.025 mg/kg SC group: 5 subjects CF0.066 SC/SC group: 25 subjects CF0.066 IV/SC group: 25 subjects CF0.066 IV/IV group: 25 subjects Full Analysis Set (FAS): 101 subjects (10 in the 0.025 mg/kg SC group, 28 in the CF0.066 SC/SC group, 29 in the CF0.066 IV/SC group, and 34 in the CF0.066 IV/IV group) Per Protocol Set (PPS): 93 subjects (9 in the 0.025 mg/kg SC group, 27 in the CF0.066 SC/SC group, 26 in the CF0.066 IV/SC group, and 31 in the CF0.066 IV/IV group)
AF37702 Page 4 of 11 Inclusion Criteria: (1) All treatment groups 1) Those aged 20 or more at the time of obtaining the informed consent 2) Male or females 3) Those who had serum ferritin level of 100 ng/ml or more, or had transferrin saturation of 20% or more at the Screening Phase 4) Among those who were capable of giving consent to participate in the study, and understanding the informed consent form and other explanatory documents, those who had given written consent (2) Subjects not on ESA treatment (0.025 mg/kg SC group) 5) Those who had received peritoneal dialysis continuously since before the Screening Phase 6) Those who had not received ESA treatment after the start of peritoneal dialysis or within 12 weeks (84 days) before start of the study drug administration 7) Those who had the 2 most recent Hgb values (with an interval of not less than 5 days between 2 measurements, and one of the measurements performed within 14 days before start of the study drug administration) of less than 10.0 g/dl within 8 weeks (56 days) before start of the study drug administration (3) Subjects on ESA treatment (CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups) 8) Those who had received peritoneal dialysis continuously for 3 months (90 days) or more prior to the Screening Phase 9) Those who had received ESA treatment (epoetin beta, epoetin alfa, or darbepoetin alfa) continuously for 8 weeks (56 days) or more before start of the study drug administration; however, the change in regimen is not allowed within 2 weeks (14 days) before start of the study drug administration 10) Those who had the 2 most recent Hgb values (with an interval of not less than 5 days between 2 measurements, and one of the measurements performed within 14 days before start of the study drug administration) of 10.0 to 12.0 g/dl within 8 weeks (56 days) before start of the study drug administration. Exclusion Criteria: 1) Those who were known to be intolerant to any ESA 2) Those who were known to be intolerant to iron preparations 3) Those who received red blood cell or whole blood transfusion within 12 weeks (84 days) before start of the study drug administration 4) Those having hemoglobinopathy (sickle cell disease, thalassemia, etc.) 5) Those who had present or past history of any hemolytic disease 6) Those having poorly controlled inflammatory disease (rheumatoid arthritis, systemic lupus erythematosus, etc.) 7) Those who had suffered from moderate to severe infection within 2 weeks (14 days) before start of the study drug administration 8) Those having poorly controlled secondary hyperparathyroidism 9) Those having poorly controlled hypertension 10) Those with a history of epileptic seizure within 6 months (180 days) before start of the
AF37702 Page 5 of 11 study drug administration 11) Those who had a present or past history of chronic heart failure (class III or IV according to NYHA classification) 12) Those who had present or past history of malignant tumor within past 5 years before start of the study drug administration 13) Those who had a plan to undergo a surgery with a massive hemorrhage during the study period 14) Those who were pregnant, lactating, or potentially pregnant, and those of child-bearing potential and using no contraceptive measure 15) Those who had a present or past history of drug or alcohol abuse 16) Those who had a present or past history of hypersensitivity or allergy to peptide preparations, PEG, or protein preparations 17) Those who had suffered peritonitis or catheter infection that would interfere with continuous peritoneal dialysis within 8 weeks (56 days) prior to the study treatment 18) Those who had received hemodialysis concurrently (except for emergency management) 19) Those who were expected to receive maintenance hemodialysis during the study period (including combination therapy with peritoneal dialysis) 20) Those who had previous exposure to any study drug (including that used in post-marketing clinical studies) within 12 weeks (84 days) before start of the study drug administration 21) Those who had previous exposure to AF37702 22) Those who were likely to drop out early from the study or discontinue the study (for example, subjects who showed the following diseases or conditions within 1 year prior to the 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, a past history of serious allergy to multiple drugs, or other clinically serious diseases or conditions that were judged by the investigator or subinvestigator to be difficult for safety, evaluation, or follow-up of the subject) 23) Those who were considered ineligible to participate in this study by the investigator or subinvestigator Test Product, Dose, Mode of Administration, and Lot Number: Dosage form and content: AF37702 injection (10 mg/1 ml): An injectable solution containing 10 mg of AF37702 per vial (1 ml). The additives include sorbitol (47 mg), sodium dihydrogenphosphate (2.99 mg), anhydrous disodium phosphate (0.117 mg), sodium hydroxide (appropriate amount), polysorbate 20 (0.03 L), and water for injection (1 ml in total). AF37702 diluent (1 ml): An injectable solution containing the following ingredients per vial (1 ml): Sorbitol (47 mg), sodium dihydrogenphosphate (2.99 mg), anhydrous disodium phosphate (0.117 mg), sodium hydroxide (appropriate amount), polysorbate 20 (0.03 L), and water for injection (1 ml in total) Dosage and regimen: (1) 0.025 mg/kg SC group
AF37702 Page 6 of 11 Every 4 weeks, subcutaneous administration Initial dose: 1.0 to 2.5 mg (determined based on the subject s body weight at Week 0) Subsequent doses (after Week 4): Doses were adjusted within the range of 0.5 to 6.0 mg based on the Hgb value of individual subjects. (2) CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups CF0.066 SC/SC and CF0.066 IV/SC groups: Every 4 weeks, subcutaneous administration CF0.066 IV/IV group: Every 4 weeks, intravenous administration Initial dose: 0.75 to 8.0 mg (determined according to the prescribed ESA dose within 2 weeks before study treatment initiation) Subsequent doses (after Week 4): Doses were adjusted within the range of 0.5 to 20.0 mg based on the Hgb value of individual subjects. * Up to 6 doses of the study drug were to be given. Batch/Lot No. Study Drug Batch/Lot Number Expiration Date AF37702 injection (AF37702 diluent) AF37702 injection (AF37702 diluent) (for additional delivery) Z3773171 (Z377Q01) September 2011 Z3773175 (Z377Q03) January 2012 Z3773172 (Z377Q01) September 2011 Z3773176 (Z377Q03) January 2012 Period of Evaluation: Screening Phase (2 to 4 wks) + Treatment Phase (24 wks)(if there is no dose delay)
AF37702 Page 7 of 11 Main Endpoints: (1) Efficacy Primary endpoint; Proportion of subjects (%) whose mean Hgb values from Week 16 to Week 24 were within a range of 10.0 to 12.0 g/dl Secondary endpoint; Changes from baseline of mean Hgb values from Week 16 to Week 24 Other endpoints; Proportion of subjects (%) whose mean Hgb values from Week 16 to Week 24 were within a range of 11.0 to 12.0 g/dl Time profiles of Hgb value Time profiles of the Hgb changes from baseline Proportion of subjects (%) with no dose adjustment Pharmacodynamic parameters (reticulocyte count [absolute], RBC count, hematocrit, serum ferritin concentration, transferrin saturation, transferrin receptor protein) (2) Safety Adverse events (AEs) Laboratory test results ECG Vital signs (3) Pharmacokinetics Plasma concentrations of unchanged AF37702
AF37702 Page 8 of 11 Statistical Methods: Frequency distribution was presented per treatment group using the FAS for the proportion of subjects whose mean Hgb values from Week 16 to Week 24 were within a range of 10.0 to 12.0 g/dl. SUMMARY OF RESULTS Subject Disposition: A total of 135 subjects provided informed consent for this study. Of these, 101 subjects received study drug. Of the subjects who received the study drug, 89 subjects completed the study, consisting of 8 subjects in the 0.025 mg/kg SC group, 26 subjects in the CF0.066 SC/SC group, 26 subjects in the CF0.066 IV/SC group, and 29 subjects in the CF0.066 IV/IV group. Efficacy Conclusions: In the 0.025 mg/kg SC group, including the subjects not on ESA treatment, the proportion of subjects (%) whose mean Hgb values from Week 16 to Week 24 were within a range of 10.0 to 12.0 g/dl (2-sided 95% confidence interval [CI]), defined as the primary endpoint, was 88.9% (8/9) (51.750, 99.719). The mean Hgb change from baseline during the period from Week 16 through Week 24 (mean standard deviation [SD]), defined as the secondary endpoint, was 2.285 0.5329 g/dl. The results of the other endpoints were as follows: the proportion of subjects (%) whose mean Hgb values from Week 16 to Week 24 were within a range of 11.0 to 12.0 g/dl was 55.6% (5/9), and the Hgb changes from baseline at Week 4 were 2.0 g/dl (0.5 g/dl/week) or less in all subjects. For the time profiles of Hgb values, the time point when the mean Hgb value first exceeded 10.0 g/dl was Week 6. Thereafter, the mean Hgb value was maintained within the range of 10.0 to 12.0 g/dl at all dosing points. For the time profiles of Hgb changes from baseline, the time points when the mean Hgb changes from baseline first exceeded 1.0 g/dl and 2.0 g/dl were Weeks 6 and 14, respectively. The AF37702 doses (mean SD) were 1.500 0.3118 mg for the first administration and 1.500 0.4787 mg for the sixth administration. The AF37702 dose (mean SD) administered during the period from Week 16 through Week 24 was 1.375 0.5116 mg. Based on the above results, it was indicated that, in chronic renal failure patients who were on peritoneal dialysis and not on ESA treatment, AF37702 started at the initial dose determined based on the 0.025 mg/kg dose and adjusted appropriately at subsequent doses was able to achieve and maintain Hgb values within the target range (10.0 to 12.0 g/dl), without a rapid Hgb increase. In the CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups, including subjects on ESA treatment, the proportion of subjects (%) whose mean Hgb values from Week 16 to Week 24 were within a range of 10.0 to 12.0 g/dl (2-sided 95% CI), defined as the primary endpoint, was 77.8% (21/27) (57.742, 91.378), 85.2% (23/27) (66.269, 95.811), and 87.1% (27/31) (70.166, 96.370), respectively. Mean Hgb changes from baseline during the period from Week 16 through Week 24 (mean SD), defined as the secondary endpoint, were 0.582 0.6408 g/dl, 0.229 0.7299 g/dl, and 0.121 0.7513 g/dl in the CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups, respectively.
AF37702 Page 9 of 11 The results of the other endpoints were as follows: the proportion of subjects (%) whose mean Hgb values from Week 16 to Week 24 were within a range of 11.0 to 12.0 g/dl was 59.3% (16/27), 59.3% (16/27), and 64.5% (20/31) in the CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups, respectively. The proportion of subjects (%) whose Hgb changes from baseline were within 1.0 g/dl from Week 16 through Week 24 was 77.8% (21/27), 74.1% (20/27), and 90.3% (28/31) in the CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups, respectively. For the time profiles of the Hgb values, mean Hgb values were maintained within the range of 10.0 to 12.0 g/dl throughout the study period in all groups. For the time profiles of Hgb changes from baseline, mean Hgb changes from baseline were maintained at 1.0 g/dl or less throughout the study period in all groups except for Week 10 in the CF0.066 SC/SC group. The AF37702 doses (mean SD) in the CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups were 3.357 0.9114 mg, 4.241 2.1166 mg, and 3.500 2.3557 mg, respectively, for the first administration, and 2.663 1.1536 mg, 3.724 2.8123 mg, and 2.690 1.8934 mg, respectively, for the sixth administration. The AF37702 doses (mean SD) administered during the period from Week 16 through Week 24 were 2.514 1.0933 mg, 3.620 2.4048 mg, and 2.841 1.8735 mg in the CF0.066 SC/SC, CF0.066 IV/SC, and CF0.066 IV/IV groups, respectively. Based on the above results, it was indicated that, in patients with chronic renal failure who were on peritoneal dialysis and on ESA treatment, when switching from subcutaneous or intravenous ESA treatment to subcutaneous or intravenous AF37702 administration, AF37702 started at the initial switching dose determined based on the conversion factor of 0.066 and adjusted appropriately at subsequent doses was able to maintain Hgb values within the target range (10.0 to 12.0 g/dl) stably. Safety Conclusions: The incidence of adverse events (AEs) was 80.0% (8/10, 45 events) in the 0.025 mg/kg SC group, 89.3% (25/28, 103 events) in the CF0.066 SC/SC group, 89.7% (26/29, 90 events) in the CF0.066 IV/SC group, and 85.3% (29/34, 128 events) in the CF0.066 IV/IV group. Of all the AEs, those occurring in 2 or more subjects in all treatment groups were nasopharyngitis and hypertension. Of these, hypertension in 13 subjects (0.025 mg/kg SC group, 1 subject; CF0.066 SC/SC group, 2 subjects; CF0.066 IV/SC group, 5 subjects; and CF0.066 IV/IV group, 5 subjects) were considered to be related to study drug. However, since all events were mild in severity, study treatment was continued. There was no clear trend noted in the incidence of AEs by period in any of the groups or in the incidence of individual AEs by period. The incidence of AEs considered to be related to study drug was 30.0% (3/10, 5 events) in the 0.025 mg/kg SC group, 32.1% (9/28, 13 events) in the CF0.066 SC/SC group, 27.6% (8/29, 11 events) in the CF0.066 IV/SC group, and 29.4% (10/34, 16 events) in the CF0.066 IV/IV group. Of these, AEs considered to be related to study drug occurring in 2 subjects or more in any of the treatment groups were hypertension, blood pressure increased, and blood alkaline phosphatase
AF37702 Page 10 of 11 increased. The incidence of these AEs was as follows: hypertension: 10.0% (1/10) in the 0.025 mg/kg SC group, 7.1% (2/28) in the CF0.066 SC/SC group, 17.2% (5/29) in the CF0.066 IV/SC group, and 14.7% (5/34) in the CF0.066 IV/IV group; blood pressure increased: 7.1% (2/28) in the CF0.066 SC/SC group only; and blood alkaline phosphatase increased: 5.9% (2/34) in the CF0.066 IV/IV group only. All of these events were mild in severity and study treatment was continued. The majority of AEs were mild or moderate in severity, and severe AEs were observed only in the CF0.066 IV/IV group (8.8% (3/34, 4 events)). Details of severe AEs were 1 event each of dehydration, peritonitis, sepsis, and rectal ulcer haemorrhage (sepsis and rectal ulcer haemorrhage occurred in the same subject). All of these were assessed as not related to study drug. There was no AE leading to death during the study period. Serious adverse events (SAEs) occurred in 4 subjects (5 events) in the 0.025 mg/kg SC group, 3 subjects (5 events) in the CF0.066 SC/SC group, 4 subjects (9 events) in the CF0.066 IV/SC group, and 7 subjects (11 events) in the CF0.066 IV/IV group. Of these, SAEs considered to be related to study drug were acute myocardial infarction (1 subject) in the CF0.066 SC/SC group, thrombotic cerebral infarction and cardiac failure (occurred in the same subject) in the CF0.066 IV/SC group, and somnolence (1 subject) in the CF0.066 IV/IV group. Each of these events was also considered to be related to subject background characteristics or concomitant medications. The incidence of AEs leading to discontinuation of study treatment was 30.0% (3/10, 3 events) in the 0.025 mg/kg SC group, 3.6% (1/28, 1 event) in the CF0.066 SC/SC group, 13.8% (4/29, 5 events) in the CF0.066 IV/SC group, and 11.8% (4/34, 7 events) in the CF0.066 IV/IV group. There was no AE leading to discontinuation of study treatment that occurred in 2 subjects or more in any of the treatment groups. AEs leading to discontinuation of study treatment that were considered to be related to the study drug were hepatic function abnormal in the 0.025 mg/kg SC group, acute myocardial infarction in the CF0.066 SC/SC group, lymphadenopathy, thrombotic cerebral infarction, cardiac failure, and hypertension in the CF0.066 IV/SC group, and somnolence and macular oedema in the CF0.066 IV/IV group. All of these occurred in 1 subject each (of these, thrombotic cerebral infarction and cardiac failure in the CF0.066 IV/SC group occurred in the same subject). For laboratory tests, vital signs, and ECG, several time points were assessed as abnormal and clinically significant for 12-lead ECG findings in only 1 subject in the CF0.066 SC/SC group (subject number: 1213-002). These findings were diagnosed as acute myocardial infarction and were reported as an SAE related to the study drug. Except these, there were no clinically significant changes, and no clinically significant AEs associated with these were reported. None of the subjects received red blood cell transfusion during the period from study treatment initiation to study completion or discontinuation. Anti-AF37702 antibody was detected in 2 subjects (CF0.066 SC/SC group, 1 subject; CF0.066 IV/SC group, 1 subject). There was no decrease in Hgb values or occurrence of relevant AEs in either of these subjects after antibody detection. In addition, the antibodies detected in these 2 subjects showed no neutralization activity or cross-reaction with erythropoietin (EPO). The
AF37702 Page 11 of 11 anti-af37702 antibody testing was confirmed to have reverted to negative during the study period in 1 subject and during the follow-up period in the other subject. Based on the above results, it was considered that there was no significant safety concern with subcutaneous or intravenous multiple administrations of AF37702 in chronic renal failure patients on peritoneal dialysis. OVERALL CONCLUSIONS The efficacy, safety, and pharmacokinetics following subcutaneous or intravenous multiple administration of AF37702 every 4 weeks were evaluated in chronic renal failure patients on peritoneal dialysis in an open-label manner. With regard to efficacy, it was considered that, in patients with chronic renal failure who were on peritoneal dialysis and not on ESA treatment, AF37702 started at the initial dose determined based on the 0.025 mg/kg dose and adjusted appropriately at subsequent doses was able to achieve and maintain Hgb values within the target range (10.0 to 12.0 g/dl), without a rapid Hgb increase. It was also considered that, in patients with chronic renal failure who were on peritoneal dialysis and on ESA treatment, when switching from subcutaneous or intravenous ESA treatment to subcutaneous or intravenous AF37702 administration, AF37702 started at the initial switching dose determined based on the conversion factor of 0.066 and adjusted appropriately at subsequent doses was able to maintain Hgb values within the target range (10.0 to 12.0 g/dl) stably. With regard to safety, it was considered that there was no significant safety concern with subcutaneous or intravenous multiple administrations of AF37702 in chronic renal failure patients on peritoneal dialysis. Based on the above results, it was considered that, in chronic renal failure patients on peritoneal dialysis, every 4 weeks subcutaneous or intravenous multiple administration of AF37702 could gradually increase Hgb values to achieve and stably maintain within target Hgb values for patients not on ESA treatment, and also could be switched from other ESA treatment without large fluctuation of Hgb values and maintain Hgb values stably for patients on ESA treatment. Date of Report: January 30, 2012