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 AF37702 Page 3 of SYNOPSIS Title of Study: Phase III Double-blind Comparative Study of AF37702 in Chronic Renal Failure Patients on Hemodialysis and on rhuepo treatment Name of Sponsor: Takeda Pharmaceutical Co., Ltd. Study Drug: AF37702 Trade Name: Not yet determined Investigator(s) and Study Site(s): A total of 25 study sites including Akagaki Clinic (Dr Yoji Akagaki, Internal Medicine, Hospital Director) (See Appendix ) Publication: None Study Period: Development Phase: Date first subject signed consent: February 22, 2010 Phase 3 Date last subject had last visit: November 22, 2010 Objectives: To evaluate the efficacy and safety of AF37702 administered intravenously once every 4 weeks in chronic renal failure patients on hemodialysis and on rhuepo treatment compared with rhuepo agent (epoetin beta) in a multi-center, randomized, double blind manner. Study Design: This study was a phase III, multicenter, double blind, randomized, comparative study for evaluation of efficacy and safety of AF37702 compared with recombinant human erythropoietin (rhuepo) agent (epoetin beta) in chronic renal failure patients on hemodialysis and on rhuepo (epoetin alfa or beta) treatment. Among the chronic renal failure patients on rhuepo treatment at least once every week during 8 weeks before start of the study drug administration who had been receiving hemodialysis for 6 months or more prior to signing informed consent and also receiving hemodialysis 3 times per week for 12 weeks or more prior to signing informed consent, those who had 3 hemoglobin (Hgb) values with a mean 10.0 g/dl or more and 12.0 g/dl or less during the Screening Phase were included in the study. The planned number of subjects in the study was a total of 150 subjects who started to receive the study drug administration (AF37702 treatment group: 75 subjects, rhuepo treatment group: 75 subjects). The study duration was a total of 27 weeks consisting of the Screening Phase (3 weeks) and the Treatment Phase (24 weeks). During the study period, specified tests/examinations and observations were performed. This study was conducted using dynamic allocation procedure. Allocation factor was the dosage amount of rhuepo administered within 2 weeks prior to start of study drug administration. The

3 AF37702 Page 4 of 185 study drug administration was performed using double dummy method. In AF37702 treatment group, AF37702 Injection (10 mg/1 ml), EPOGIN Injection ampoule 1500 (placebo), and EPOGIN Injection ampoule 3000 (placebo) were used. In rhuepo treatment group, AF37702 Injection (placebo), EPOGIN Injection ampoule 1500 (1500 IU/0.5 ml), and EPOGIN Injection ampoule 3000 (3000 IU/0.5 ml) were used. The starting dose of AF37702 was predetermined doses (2.0, , 4.0, 5.0, 6.0 mg/4 wks) based on the subject s prescribed rhuepo dose per week during the 2 weeks prior to the start of study drug administration and AF37702 was administered intravenously once every 4 weeks on up to 6 occasions. From 2nd dose onwards, the dose was adjusted once every 4 weeks (unchanged, one-step increased, two-step increased, one-step decreased, delayed) at dose range of 1.5 to 10.0 mg based on the individual subject s Hgb value. The dose was delayed if Hgb value exceeded 12.5 g/dl and was restarted when Hgb value decreased to 12.0 g/dl or less. AF37702 was administered up to 6 occasions. The starting dose and frequency of epoetin beta were the same dose per week (3000, 3750, 4500, 6000, 7500, 9000 IU/wk) and frequency (1 to 3 times per week) as that received during the 2 weeks before start of the study drug administration. From Week 2 onwards, the dose was adjusted once every 4 weeks (at the time of administration of AF37702) (unchanged, one-step increased, two-step increased, one-step decreased, delayed) at dose range of 2250 to IU/wk based on the individual subject s Hgb value. The dose was delayed if Hgb value exceeded 12.5 g/dl and was restarted when Hgb value decreased to 12.0 g/dl or less. The investigators assessed whether the subjects met the criteria for dose delay every week. When switching from rhuepo agent to the study drug, there was to be an interval of 2 days or more (inclusive of the administration day) from the final dose of rhuepo agent. Study site visits were scheduled every week until Week 24 (final visit) after 1 st dose. On the specified test/examination day, laboratory test, ECG, and observation of subjective/objective symptoms were performed. Number of Subjects: Planned: Number of subjects who were to receive the study drug administration: 75 subjects per cohort 150 subjects in total Number of subjects who were to be evaluable for the primary endpoint: 60 subjects per cohort 120 subjects in total Analyzed: Full Analysis Set (FAS): 154 subjects (AF37702 group: 79 subjects, rhuepo group: 75 subjects) Per Protocol Set (PPS): 139 subjects (AF37702 group: 70 subjects, rhuepo group: 69 subjects) Safety Analysis Set: 154 subjects (AF37702 group: 79 subjects, rhuepo group: 75 subjects)

4 AF37702 Page 5 of 185 Inclusion Criteria: 1) Those aged 20 or more at the time of the informed consent. 2) Males or females 3) Those who had been receiving hemodialysis for 6 months (180 days) or more prior to signing informed consent and were clinically stable 4) Those who had been receiving hemodialysis 3 times per week for 12 weeks (84 days) or more prior to signing informed consent 5) Those who had 3 Hgb values with a mean 10.0 g/dl or more and 12.0 g/dl or less from 3 measurements during the Screening Phase (blood sampling was to be performed prior to 1st dialysis session of each week) 6) Those with a serum ferritin level of 100 ng/ml or more, or transferrin saturation of 20% or more at the Screening Phase 7) Those who had been receiving maintenance therapy with rhuepo agent (3000, 3750, 4500, 6000, 7500, or 9000 IU/wk) at least once a week during 8 weeks (56 days) before start of the study drug administration (change of dosage and regimen was not to be acceptable within 2 weeks (14 days) before start of the study drug administration) 8) Among those who were capable of giving consent to participation in the study, and understanding the informed consent form and other explanatory documents, those who had given written consent Exclusion Criteria: 1) Those who were known to be intolerant to any ESAs 2) Those who had a history of antibody production to the ESAs or a history of pure red cell aplasia 3) Those who were known to be intolerant to an iron preparation 4) Those who received red blood cell or whole blood transfusion within 12 weeks (84 days) before start of the study drug administration 5) Those having hemoglobinopathy (sickle cell disease, thalassemia, etc.) 6) Those who had present or past history of any hemolytic disease 7) Those having poorly controlled inflammatory disease (rheumatoid arthritis, systemic lupus erythematosus, etc.) 8) Those who had suffered from moderate to severe infection within 2 weeks (14 days) before start of the study drug administration 9) Those with evident coagulation disorder found clinically or based on the test/examination at Screening Phase (APTT and INR examined prior to dialysis session) 10) Those having no vascular access for maintenance hemodialysis 11) Those having poorly controlled secondary hyperparathyroidism 12) Those having poorly controlled hypertension 13) Those with a history of epileptic seizure within 6 months (180 days) before start of the study drug administration 14) Those who had present or past history of chronic heart failure (class III or IV according to

5 AF37702 Page 6 of 185 NYHA classification) 15) Those who had present or past history of malignant tumor within past 5 years before start of the study drug administration 16) Those who were planned to undergo a surgery with a massive hemorrhage during the study period 17) Those who were pregnant, lactating, or potentially pregnant, or those of child-bearing potential and using no contraceptive measure 18) Those who had present or past history of drug or alcohol abuse 19) Those who had present or past history of hypersensitivity or allergy to peptide preparation, PEG, or other protein preparation 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 AF ) 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 before start of 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 abnormality, neurological abnormality, 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 were judged by the investigator 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 and Mode of Administration, Lot Number: Dosage form and content 1 AF37702 AF37702 Injection (10 mg/1 ml): An injection solution containing 10 mg of AF37702 per vial (1 ml). List of excipients is as follows: sorbitol (47 mg); sodium phosphate monobasic, dihydrate (2.99 mg); sodium phosphate dibasic, anhydrous (0.117 mg); sodium hydroxide (appropriate amount); polysorbate 20 (0.03 L); Water for Injection (1 ml in total). AF37702 Injection (placebo): An injection solution without AF37702 per vial (1 ml). List of excipients is as follows: sorbitol (47 mg); sodium phosphate monobasic, dihydrate (2.99 mg); sodium phosphate dibasic, anhydrous (0.117 mg); sodium hydroxide (appropriate amount); polysorbate 20 (0.03 L); Water for Injection (1 ml in total). The above 2 types of Injection were unidentifiable by appearance. 2 Epoetin beta EPOGIN Injection ampoule 1500 (1500 IU/0.5 ml): An injection solution containing 1500 Unit of epoetin beta per ampoule (0.5 ml). List of

6 AF37702 Page 7 of 185 excipients is as follows: L-Histidine hydrochloride monohydrate (0.675 mg); polyoxyethylene [160] polyoxypropylene [30] glycol (0.250 mg); tonicity agent (sodium chloride); ph adjuster (dibasic sodium phosphate hydrate; sodium hydroxide; dilute hydrochloric acid). EPOGIN Injection ampoule 3000 (3000 IU/0.5 ml): An injection solution containing 3000 Unit of epoetin beta per ampoule (0.5 ml). List of excipients is as follows: L-Histidine hydrochloride monohydrate (0.675 mg); polyoxyethylene [160] polyoxypropylene [30] glycol (0.250 mg); tonicity agent (sodium chloride); ph adjuster (dibasic sodium phosphate hydrate; sodium hydroxide; dilute hydrochloric acid). EPOGIN Injection ampoule 1500 (placebo): An injection solution without epoetin beta per ampoule (0.5 ml). List of excipients is as follows: physiological saline. EPOGIN Injection ampoule 3000 (placebo): An injection solution without epoetin beta per ampoule (0.5 ml). List of excipients is as follows: physiological saline. The above 4 types of ampoules (EPOGIN Injection ampoule 1500 (1500 IU/0.5 ml), EPOGIN Injection ampoule 1500 (placebo), EPOGIN Injection ampoule 3000 (3000 IU/0.5 ml), EPOGIN Injection ampoule 3000 (placebo)) were unidentifiable by appearance. Dosage and administration A double-dummy method was applied in this study, thus AF37702 and epoetin beta (placebo) were administered in the AF37702 group, and Epoetin beta and AF37702 (placebo) were administered in the rhuepo group. 1 AF37702 AF37702 (Initial dose: mg/4 wks, 2nd dose onwards: mg/4 wks) was administered intravenously once every 4 weeks. 2 Epoetin beta Epoetin beta (Initial dose: IU/wk, 2nd dose onwards: IU/wk) was administered intravenously for 1 to 3 times per week. Study Drug Batch/Lot Number Expiration Date AF37702 DB (Injection) DB January 2011 AF37702 DB (Injection) for additional DB377R012 January 2011 Batch/Lot number Period of Evaluation: Screening Phase (3 wks)+treatment Phase (24 wks) (if there is no dose delay) Main Endpoints: 1 Efficacy Primary endpoint;

7 AF37702 Page 8 of 185 Changes of mean Hgb values from baseline from Week 16 to Week 24 Secondary endpoints; Proportion of subjects (%) whose mean Hgb values from Week 16 to Week 24 were 10.0 to 12.0 g/dl Proportion of subjects (%) whose changes of mean Hgb values from baseline from Week 16 to Week 24 were within ±1.0 g/dl Other endpoints; Time profiles of Hgb values Time profiles of changes of mean Hgb values from baseline Proportion of subjects (%) with no dose adjustment Pharmacodynamic parameters (red blood cell count, hematocrit, serum ferritin concentration, transferrin saturation, transferrin receptor protein) 2 Safety Adverse events, clinical laboratory test results, ECG, body weight and vital signs Statistical Methods: Following analysis was performed using FAS. Descriptive statistics by cohort were calculated, and mean values and standard deviation (SD) were shown by cohort with regard to the primary endpoint of changes of mean Hgb values from baseline from Week 16 to Week 24. Point estimation and a two-sided 95% confidence interval were calculated for the difference between the AF37702 group and the rhuepo group (AF37702 group minus rhuepo group). If the two-sided 95% confidence interval was within equivalence margin of ±1.0 g/dl, AF37702 group was considered to be equivalent to the rhuepo group. SUMMARY OF RESULTS Subject Disposition: Of the subjects who were randomized (156 subjects), 154 subjects received the study treatment, consisting of 79 subjects in the AF37702 group and 75 subjects in the rhuepo group. Two subjects (rhuepo group: 2 subjects) did not receive the study drug ; the reasons were a major protocol deviation (because the subject was found to have not satisfied the inclusion criterion 7 [the subject has been receiving maintenance therapy with rhuepo agent (3000, 3750, 4500, 6000, 7500, or 9000 IU/week) at least once a week during 8 weeks (56 days) before start of the study drug administration] after randomization) in 1 subject and other (the subject was found to have not undergone laboratory tests at Week 0 piror to the start of dialysis before the study drug administration after randomization) in 1 subject. Of those who received the study drug, 137 subjects completed the study, consisting of 70 subjects in the AF37702 group and 67 subjects in the rhuepo group. Seventeen subjects were withdrawn from the study; the reasons were pretreatment events/aes in 11 subjects (AF37702 group: 7 subjects and rhuepo group: 4 subjects), voluntary withdrawal in 3 subjects (rhuepo group: 3 subjects), based on the dose adjustment criteria (prolonged dose interruption) in 2 subjects (AF37702 group: 2 subjects) and other (impossible to receive the study drug administration due to initiaion of dialysis at another hospital) in 1 subject (rhuepo group: 1

8 AF37702 Page 9 of 185 subject). Efficacy Conclusions: For the primary endpoint, the change (mean SD) of the mean Hgb values from baseline from Week 16 to Week 24 was g/dl and g/dl in the AF37702 group and rhuepo group, respectively. Point estimation (95% CI) for the difference between the treatment groups was ( , ). Since both of the upper and lower 95% CI limits were within the equivalence margin ( 1.0) predefined in the protocol, equivalence between the AF37702 group and rhuepo group was demonstrated. For the secondary endpoints, the proportion of subjects (%) whose mean Hgb values from baseline from Week 16 to Week 24 were 10.0 to 12.0 g/dl was lower in the AF37702 group than in the rhuepo group, whereas the proportion of subjects (%) whose changes of mean Hgb values from baseline from Week 16 to Week 24 were within 1.0 g/dl was higher in the AF37702 group than in the rhuepo group. The proportion of subjects (%) whose mean Hgb values from Week 16 to Week 24 were 9.5 to 12.0 g/dl was not significantly different between the treatment groups. The mean Hgb values were 10.0 to 12.0 g/dl through the study period in both groups. In both groups, the mean values of changes in Hgb values from baseline were maintained within 1.0 g/dl throughout the study period. Change of Hgb values from baseline at Week 24 was smaller in the AF37702 group than in the rhuepo group. The mean values of the difference between maximum and minimum Hgb values in 4-week intervals were less than 1.0 g/dl at all the 4-week intervals before and after start of the study drug administration in both treatment groups. The proportion of subjects in whom the difference between maximum and minimum Hgb values in 4-week intervals was more than 1.0 g/dl tended to be higher in the AF37702 group than in the rhuepo group, however, the proportion was higher at all the 4-week intervals after start of the study drug administration than during the 4-week interval before start of the study drug administration in both groups. The mean values of the changes in Hgb values from the preceding week were within 0.5 g/dl at all the time points before and after start of the study drug administration in both treatment groups. After start of the study drug administration, the proportion of subjects in whom the change in Hgb values from the preceding week increased by more than 0.5 g/dl tended to be higher in the AF37702 group than in the rhuepo group, however, among all the time points after start of the study drug administration, the number of time points when the proportion was higher than the highest proportion among 3 time points before start of the study drug administration was higher in the rhuepo group than in the AF37702 group. Furthermore, after start of the study drug administration, the proportion of subjects in whom the change in Hgb values from the preceding week decreased by more than 0.5 g/dl tended to be higher in the AF37702 group than in the rhuepo group, however, among all the time points after start of the study drug administration, the number of time points after start of the study drug administration when the proportion was higher than the highest proportion among 3 time points before start of the study drug administration was not significantly different between the treatment groups.

9 AF37702 Page 10 of 185 The actual doses from Week 16 to Week 24 increased compared with those at baseline (Week 0) in both AF37702 and rhuepo groups. In summary, the equivalence of the AF37702 group and rhuepo group was demonstrated in terms of the primary endpoint, and Hgb values were stably maintained within the range of target levels during the study period in both groups. In terms of the secondary and other endpoints, there was no significant difference between the treatment groups, and generally comparable results were shown. Therefore, the efficacy of AF37702 was confirmed to be equivalent to that of rhuepo. Safety Conclusions: The incidence of AEs was 88.6% (70/79 subjects, 268 cases) in the AF37702 group and 88.0% (66/75 subjects, 286 cases) in the rhuepo group. Of AEs with an incidence of 5% or more in either the treatment group, 8 events had a 2-fold or more difference in the incidence between the treatment groups. Of these, 6 events more frequently occurred in the rhuepo group than in the AF37702 group. There was no significant difference in the incidence or the types of AEs occurred between the treatment groups. There was no evident trend for the onset period of AEs in either group or no significant difference between the treatment groups. Also, there was no evident trend for the onset period of individual AEs. The incidence of AEs which were considered to be related to the study drug was 7.6% (6/79 subjects, 8 cases) in the AF37702 group and 8.0% (6/75 subjects, 6 cases) in the rhuepo group. AEs considered to be related to the study drug that occurred in at least 2 subjects in either the treatment group were only hypertension. Its incidence was 2.5% (2/79 subjects) and 2.7% (2/75 subjects) in the AF37702 group and rhuepo group, respectively; there was no significant difference between the treatment groups. Most AEs were mild or moderate in intensity. Severe AEs occurred only in the AF37702 group and its incidence was 3.8% (3/79 subjects, 6 cases). None of the events was assessed as related to the study drug. One subject died in the AF37702 group. All the events leading to death were considered not to be related to the study drug. The incidence of SAEs including death was 13.9% (11/79 subjects, 18 cases) in the AF37702 group and 14.7% (11/75 subjects, 11 cases) in the rhuepo group. Of these, SAEs other than death which were considered to be related to the study drug were angina pectoris (1 subject), cardiac failure congestive and hypertensive heart disease (1 subject) in the AF37702 group, and prostate cancer (1 subject) and brain stem infarction (1 subject) in the AF37702 group. The incidence of AEs leading to study drug discontinuation was 8.9% (7/79 subjects, 9 cases) in the AF37702 group and 5.3% (4/75 subjects, 4 cases) in the rhuepo group. Of these, AEs which were considered to be related to the study drug were cardiac failure congestive and hypertensive heart disease (1 subject), and urticaria (1 subject) in the AF37702 group, and brain stem infarction (1 subject) in the rhuepo group. Laboratory tests, vital signs and ECG did not show any clinically significant changes, and no

10 AF37702 Page 11 of 185 relevant AEs which were clinically significant were reported. Anti-AF37702 antibody was detected in 1 subject after AF37702 treatment. However, even after the antibody became positive, there was no decrease in Hgb values or related AE has not occured in this subject. The antibodies detected in this subject did not show the neutralizing activity and they had no cross reactivity with EPO. A follow-up investigation confirmed that the anti-af37702 antibody became negative. In summary, there was no significant difference in safety after administration of AF37702 and rhuepo between the treatment groups. Overall Conclusions: A multicenter, double-blind, randomized, comparative study was conducted to evaluate the efficacy and safety of AF37702 compared with rhuepo in chronic renal failure patients on hemodialysis and on rhuepo treatment. With regard to efficacy, equivalence between the treatment groups was demonstrated for the primary endpoint, the change (mean SD) of mean Hgb value from baseline from Week 16 to Week 24. Hgb values were stably maintained within the target range during the study period in both groups. Therefore, the efficacy of AF37702 was confirmed to be equivalent to that of rhuepo for the treatment of anemia in chronic renal failure patients on hemodialysis and on rhuepo treatment. With regard to safety, there was no significant difference in the incidence or the types of AEs and AEs which were considered to be related to the study drug after AF37702 or rhuepo treatment between the treatment groups. Most of the AEs were mild or moderate in intensity. None of the severe AEs occurred in the AF37702 group were considered to be related. There was no significant difference in the incidence of SAEs or clinically significant AEs between the treatment groups. The death in the AF37702 group (1 subject)was considered not related to the study drug. Therefore, there was no significant difference in safety between the AF37702 group and rhuepo group. Date of Report: August 9, 2011