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Roxadustat (ASP1517) ISN 1517-CL-0302Renal anemiaCONFIDENTIAL

Name of Sponsor/Company: Astellas Pharma Inc.

Name of Finished Product: Not available

Name of Active Ingredient: Roxadustat (ASP1517)

Mar 2018 Astellas Synopsis of 18

SYNOPSIS

Title of Study: A Phase 3, Multi-center, Open-label Study of Intermittent Oral Dosing of ASP1517 in

Peritoneal Dialysis Chronic Kidney Disease Patients With Anemia (Protocol No. 1517-CL-0302)

Investigators/Coordinating Investigator: , , , Japan,

and others.

Study Center(s): 15 sites in Japan

Publication Based on the Study: None to date

Study Period: Approximately 1.1 years

Study Initiation Date (Date of First Informed Consent): 22 Jun 2016

Study Completion Date (Date of Last Evaluation): 02 Aug 2017

Phase of Development: Phase 3

Objectives:

To evaluate the safety and efficacy of ASP1517 in patients with renal anemia on peritoneal dialysis.

Methodology:

This study was conducted as a multi-center, randomized, open-label, non-comparative study.

After obtaining written informed consent from patients, the prescreening assessments were performed. After

confirming that the patients satisfied the inclusion/exclusion criteria, the screening assessments were performed

at least 1 week after the prescreening assessments. When the patients were confirmed to satisfy all the

inclusion/exclusion criteria by assessments performed within 10 weeks after the prescreening assessments, the

investigator or sub-investigator registered the eligible patients within 4 weeks after the screening assessments

(or on the same day), in principle, and transferred them to the treatment period. Patients receiving

erythropoiesis stimulating agent (ESA) were registered on the day when ESA had been administered

immediately after confirming that they satisfied the inclusion/exclusion criteria.

The investigator or sub-investigator prescribed ASP1517 based on the dose directions notified by the web

registration system.

The study drug was administered 3 times a week for a maximum of 24 weeks.



[Assignment method]

For patients receiving ESA, the dose of the study drug was determined on the basis of the patient’s dose of ESA

just before the registration.

For patients not receiving ESA, dynamic allocation was conducted using a biased-coin minimization approach

based on the following i) and ii) as assignment factors to minimize bias:

i) Study site

ii) Body weight measured just before the registration (less than 40 kg, 40 kg or more)

The patients not receiving ESA (n = 13) were randomized to the initial dose of 50 mg of ASP1517 (ASP1517

50-mg ESA untreated group) or 70 mg of ASP1517 (ASP1517 70-mg ESA untreated group). The patients

receiving ESA (n = 43) were allocated to the initial dose of 70 mg of ASP1517 (ASP1517 70-mg ESA treated

group) or 100 mg of ASP1517 (ASP1517 100-mg ESA treated group). A combination of the ASP1517 50-mg

ESA untreated group and the ASP1517 70-mg ESA untreated group was defined as pooled ESA untreated group

(n = 13). A combination of the ASP1517 70-mg ESA treated group and the ASP1517 100-mg ESA treated

group was defined as pooled ESA treated group (n = 43).

Number of Patients (Planned, Enrolled and Analyzed):

Planned: 50 patients in total

Randomized/registered: 56 patients (6 in the ASP1517 50-mg ESA untreated group, 7 in the ASP1517 70-mg

ESA untreated group, 23 in the ASP1517 70-mg ESA treated group and 20 in the ASP1517 100-mg ESA

treated group)

[Analysis sets]

● Safety analysis set (SAF): 56 patients (6 in the ASP1517 50-mg ESA untreated group, 7 in the ASP1517

70-mg ESA untreated group, 23 in the ASP1517 70-mg ESA treated group and 20 in the ASP1517 100-mg

ESA treated group)

● Full analysis set (FAS): 56 patients (6 in the ASP1517 50-mg ESA untreated group, 7 in the ASP1517 70-

mg ESA untreated group, 23 in the ASP1517 70-mg ESA treated group and 20 in the ASP1517 100-mg

ESA treated group)

● Pharmacokinetics analysis set (PKAS): 56 patients (6 in the ASP1517 50-mg ESA untreated group, 7 in

the ASP1517 70-mg ESA untreated group, 23 in the ASP1517 70-mg ESA treated group and 20 in the

ASP1517 100-mg ESA treated group)

Diagnosis and Main Criteria for Inclusion:

Patients with renal anemia on peritoneal dialysis were enrolled in this study. Patients who were candidates for

participation in the study were screened in accordance with the following inclusion criteria before enrollment

into the study.

1. Patients who had given written informed consent by themselves

2. Patients with chronic kidney disease (CKD) who had been receiving and were scheduled to undergo

peritoneal dialysis during the study period (excluding patients on concurrent hemodialysis, or those who

were scheduled to undergo hemodialysis during the study period)

3. Patients aged 20 years or more at informed consent acquisition



i) Patients not receiving ESA

4. Patients who had been on peritoneal dialysis for at least 4 weeks before prescreening assessments

5. Patients who had not received ESA after the start of peritoneal dialysis, or patients who had not received

ESA within 6 weeks before the prescreening assessments

6. The patient’s 2 most recent Hb levels just before registration during the screening period had to satisfy the

following (2 Hb levels had to be measured with at least a week interval):

● Mean of the 2 levels < 10.5 g/dL

● Absolute difference between the 2 levels ≤ 1.3 g/dL

7. Patients with either transferrin saturation (TSAT) of ≥ 5% or serum ferritin of ≥ 30 ng/mL during the

screening period

ii) Patients receiving ESA

8. Patients who had been receiving ESA within the doses approved in Japan for at least 8 weeks before

prescreening assessments after the start of peritoneal dialysis

9. The patient’s 2 most recent Hb levels just before registration during the screening period had to satisfy the

following (2 Hb levels had to be measured with at least a week interval):

● Mean of the 2 levels ≥ 10.0 g/dL and ≤ 12.0 g/dL

10. Patients with either TSAT of ≥ 20% or serum ferritin of ≥ 100 ng/mL during the screening period

Test Product, Dose and Mode of Administration, Batch Numbers:

<Test drug>

ASP1517 tablets were tablets containing 20 mg as ASP1517, tablets containing 50 mg as ASP1517 and tablets

containing 100 mg as ASP1517 (Lot No. of formulation: ASP1517 20-mg tablet: , ASP1517 50-mg

tablet: and ASP1517 100-mg tablet: )

<Dose and mode of administration >

The investigator or sub-investigator prescribed the study drug on the basis of (1) Initial dose notified by the web

registration system in registered patients. Patients receiving ESA were registered on the day when ESA would

have been administered immediately after confirming that they satisfied the inclusion/exclusion criteria.

Dose adjustment was managed on the web registration system on the basis of (2) Dose adjustment rule. The

dose was determined on the basis of the Hb level entered into the web registration system. The investigator or

sub-investigator prescribed the study drug on the basis of the dose notified by the web registration system.

(1) Initial dose


50 mg or 70 mg.


The dose was determined on the basis of the average weekly dose during 4 weeks prior to registration in

patients receiving recombinant human erythropoietin (rHuEPO) or darbepoetin alfa, or the average 4-week dose

during 8 weeks prior to registration in patients receiving epoetin beta pegol according to the following [Table

for dose conversion at start of ASP1517].



[Table for dose conversion at start of ASP1517]

rHuEPO(IU/week)

Darbepoetin alfa(μg/week)

Epoetin beta pegol(μg/4 weeks)

ASP1517(mg/time)

<4500 <20 ≤100 70≥4500 ≥20 >100 100

(2) Dose adjustment rule

Dose was adjusted according to Section “5.3.1.2 Increase or Reduction in Dose of the Study Drugs” so that the

Hb level was able to be maintained within the target range (10.0 to 12.0 g/dL).

According to the following rules, patients took the study drug 3 times a week for a maximum of 24 weeks:

● The first dosing was taken on the day or the next day of prescription.

● Patients took the study drug at 2- or 3-day intervals (Monday-Wednesday-Friday, Tuesday-Thursday-

Saturday, etc.; dosing days had to remain consistent) throughout the administration period. Only the last

dose was taken from the previous day of the week 24 visit to no later than the test and assessment on the

day of week 24 visit.

● When coadministered with phosphate binders such as bixalomer, sevelamer hydrochloride, precipitated

calcium carbonate, lanthanum carbonate hydrate, ferric citrate hydrate, sucroferric oxyhydroxide, patients

had to take the study drug at least 1 hour before or 1 hour after dosing phosphate binder.

<Increase or Reduction in Dose of the Study Drugs>

Follow the below instructions regarding dose adjustment of the study drugs after the start of administration.

[Dose adjustment rule]

1. A decision on whether to perform dose adjustment or not was made at every even-week visit from week 4,

if both the Hb level and the change in the Hb levels over the past 4 weeks (difference between the Hb

levels in the concerned week and 4 weeks earlier) met the criteria defined in the [Dose increase/reduction

rules], except as shown in [Dose adjustment in case of temporary dose hold] and [Dose adjustment in case

of excessive Hb elevation] below. Patients started taking the study drug at the post-adjustment dose on the

day of the next treatment.

2. If a dose reduction was required at the lowest dose or a dose increase was required at the highest dose, the

dose had to remain the same.

3. The dose for each patient was not permitted to be increased to more than 3.0 mg/kg.

4. If a dose increase or reduction was performed, the adjusted dose had to remain the same for at least 4

weeks (except in cases shown in [Dose adjustment in case of excessive Hb elevation] and [Dose

adjustment in case of temporary dose hold] below).

[Table for dose adjustment of the study drug]

Stage 1 2 3 4 5 6 7 8 9 10Dose (mg) 20 40 50 70 100 120 150 200 250 300

The highest dose was not permitted to exceed 3.0 mg/kg (dose calculation had to be made using the body weight just before registration at week 0).

[Example] The maximum dose of ASP1517 could be 150 mg in a patient weighing 60.0 kg just before registration at week 0.



[Dose increase/reduction rules] (weeks 4, 6, 8, 10, 12, 14, 16, 18, 20 and 22)

Dose increase/reduction had to be conducted if both the Hb level and the change in the Hb levels over the past 4

weeks (difference between the Hb levels in the concerned week and 4 weeks earlier) met the following rule.

Change of Hb levels from 4 weeks ago to the concerned week

Hb level in the week

<10.5 g/dL≥10.5 g/dL≤11.5 g/dL

>11.5 g/dL≤12.5 g/dL

<−1.0 g/dLOne-step dose

increaseOne-step dose

increaseNo change

≥−1.0 g/dL≤1.0 g/dL

One-step dose increase

No changeOne-step dose

reduction

>1.0 g/dL No changeOne-step dose

reductionOne-step dose

reduction

[Dose adjustment in case of temporary dose hold]

At any time when the Hb level was more than 12.5 g/dL, stopped dosing, then resumed dosing when the Hb

level was less than 11.0 g/dL at a dose that was reduced by 1 step.

[Dose adjustment in case of excessive Hb reduction]


If the Hb level decreased by above 1.0 g/dL from week 0 and was less than 9.5 g/dL at week 2, the dose had to

be increased by 1 step.


If the Hb level was less than 9.0 mg/dL at week 2, the dose had to be increased by 1 step.

[Dose adjustment in case of excessive Hb elevation]

If the Hb level increased by above 2.0 g/dL at any time within 4 weeks, the dose had to be reduced by 1 step. If

dose adjustment was performed on the basis of excessive Hb elevation, the adjusted dose had to remain the

same for at least 4 weeks.

Duration of Treatment:

A maximum of 24 weeks

Reference Product, Dose and Mode of Administration, Batch Numbers:

Not applicable.

Criteria for Evaluation:

<Efficacy endpoints>

● Maintenance rate of the target Hb level (proportion of patients who achieved the average Hb level of 10.0

to 12.0 g/dL for weeks 18 to 24)

● Response rate from baseline to end of treatment (Hb response defined as: Hb ≥ 10.0 g/dL and a Hb

increase from baseline by ≥ 1.0 g/dL in any patient with baseline)



● Response rate from baseline to end of treatment (Hb response defined as: Hb ≥ 10.5 g/dL and a Hb

increase from baseline by ≥ 1.0 g/dL in any patient with baseline)

● Average Hb levels of weeks 18 to 24

● Change of average Hb levels of weeks 18 to 24 from baseline

● Rate of rise in Hb levels (g/dL/week) from week 0 to at the earliest date of week 4, time of

discontinuation, or time of dose adjustment

● Proportion of measurement points that met the target Hb level (10.0 to 12.0 g/dL) after achievement of Hb

of 10.0 g/dL in each patient

● Proportion of patients who achieved the target Hb level (10.0 to 12.0 g/dL) at each week

● Proportion of patients who achieved, and time to achieve, the lower limit of the target Hb level (10.0 g/dL)

● Change of Hb levels from baseline to each week

● Hematocrit (Ht), reticulocyte (Ret), Fe, ferritin, transferrin, total iron binding capacity (TIBC), soluble

transferrin receptor (sTfR), TSAT and reticulocyte hemoglobin content (CHr)

● QOL survey (SF-36, EQ-5D-5L and FACT-An). The following scores were used.

- SF-36: Physical Functioning Subscore, Vitality Subscore, Physical Component Score, Mental

Component Score

- EQ-5D-5L: VAS Score, Mobility, Self-Care, Usual Activities, Pain/Discomfort, Anxiety/Depression

- FACT-An: Anemia Subscale Score, FACT-An Total Score

● Occurrence (number) of hospitalizations

<Pharmacokinetics>

● Plasma concentration of unchanged form of ASP1517

<Exploratory endpoint>

● Hepcidin

<Safety endpoints>

● Vital signs (blood pressure in sitting position, pulse rate)

● 12-lead electrocardiogram (ECG)

● Adverse events (AEs)

● Laboratory data (excluding Hb, Ht, Ret, Fe, ferritin, transferrin, TIBC, sTfR, TSAT and CHr)

Statistical Methods:

[Analysis of efficacy endpoints]

Analyses were performed on the FAS. Unless designated otherwise, analyses were performed in patients not

receiving ESA (initial dose: 50 mg or 70 mg), patients receiving ESA and the full study population.

[Analysis of pharmacokinetics]

Based on the separately prepared pharmacokinetic analysis plan, a list of unchanged drug concentrations in the

plasma was prepared for each patient.



[Analysis of exploratory endpoint]

Hepcidin

The summary statistics were calculated for each time period. The analysis results were to be reported in the

clinical study report or separately reported.

[Analysis of safety]

Analyses were performed using SAF as the target. Unless designated otherwise, analyses were performed in

patients not receiving ESA (initial dose: 50 mg or 70 mg), patients receiving ESA and the full study population.

Summary of Results/Conclusions:

Population:

A total of 69 patients gave informed consent and 13 patients discontinued before

randomization/registration due to screen failures [Figure 1]. A total of 56 patients were

randomized/registered. All 56 patients were treated with the study treatment. A total of 49 (87.5%)

patients completed the study and 7 (12.5%) patients discontinued [Table 1]. Of the 7 patients

discontinued, no patients of the pooled ESA untreated group and 7 (16.3%) patients of the pooled ESA

treated group discontinued.

Of the 56 patients included in the FAS, 36 (64.3%) patients were male and 20 (35.7%) patients were

female [Table 2]. The mean age was 64.3 years and the mean weight at prescreening was 63.86 kg. Mean

ages among all the groups were similar. The mean (SD) peritoneal dialysis vintage was 62.01 (41.94)

months in the ASP1517 50-mg ESA untreated group, 14.54 (13.67) months in the ASP1517 70-mg ESA

untreated group and 38.05 (38.14) months in the pooled ESA treated group. With respect to the other

baseline characteristics, treatment groups were similar.

Efficacy and Exploratory Endpoint Results:

● The maintenance rate of patients who achieved the target Hb level (10.0 to 12.0 g/dL) for weeks 18 to 24

in the FAS was 83.3% (95%CI: 35.9%, 99.6%) in the ASP1517 50-mg ESA untreated group, 100.0%

(95%CI: 59.0%, 100%) in the ASP1517 70-mg ESA untreated group and 74.4% (95%CI: 58.8%, 86.5%)

in the pooled ESA treated group [Table 3].

● The maintenance rate of patients who achieved the target Hb level (10.0 to 12.0 g/dL) with at least one Hb

value for weeks 18 to 24 in the FAS was 83.3% (5/6 patients, 95%CI: 35.9%, 99.6%) in the ASP1517 50-

mg ESA untreated group, 100.0% (7/7 patients, 95%CI: 59.0%, 100.0%) in the ASP1517 70-mg ESA

untreated group and 86.5% (32/37 patients, 95%CI: 71.2%, 95.5%) in the pooled ESA treated group

[Table 4].

● The cumulative response rates (Hb ≥ 10.0 g/dL and a Hb Increase from baseline by ≥ 1.0 g/dL) from

baseline to the end of treatment were 100% both in the ASP1517 50-mg ESA untreated group and in the

ASP1517 70-mg ESA untreated group.

● The cumulative response rates (Hb ≥ 10.5 g/dL and a Hb Increase from baseline by ≥ 1.0 g/dL) from

baseline to the end of treatment were 100% both in the ASP1517 50-mg ESA untreated group and in the

ASP1517 70-mg ESA untreated group.



● The mean average Hb levels of weeks 18 to 24 in the FAS was 11.07 g/dL in the ASP1517 50-mg ESA

untreated group, 11.03 g/dL in the ASP1517 70-mg ESA untreated group and 10.93 g/dL in the pooled

ESA treated group [Table 5].

● The mean change of average Hb levels of weeks 18 to 24 from baseline in the FAS was 1.50 g/dL (95%CI:

0.43, 2.57) in the ASP1517 50-mg ESA untreated group, 1.86 g/dL (95%CI: 0.82, 2.90) in the ASP1517

70-mg ESA untreated group and 0.14 g/dL (95%CI: −0.12, 0.39) in the pooled ESA treated group [Table

6].

● The mean (SD) rate of rise in Hb levels (g/dL/week) from baseline to at earliest date of week 4,

discontinuation or dose adjustment in the FAS was 0.193 (0.203) g/dL/week in the ASP1517 50-mg ESA

untreated group, 0.556 (0.408) g/dL/week in the ASP1517 70-mg ESA untreated group,

0.136 (0.217) g/dL/week in the ASP1517 70-mg ESA treated group and 0.286 (0.302) g/dL/week in the

ASP1517 100-mg ESA treated group.

● The proportion of patients with change in Hb exceeding 0.5 g/dL/week in the FAS was 0% in the

ASP1517 50-mg ESA untreated group, 42.9% in the ASP1517 70-mg ESA untreated group, 8.7% in the

ASP1517 70-mg ESA treated group and 20.0% in the ASP1517 100-mg ESA treated group.

● The mean Hb values in the ASP1517 50-mg ESA untreated group and the ASP1517 70-mg ESA untreated

group were increased through week 8 and then kept the target Hb level through the end of treatment

[Figure 2]. The mean Hb values in the pooled ESA treated group were increased and then decreased

through week 14, and then kept the target Hb level through the end of treatment [Figure 2].

● The mean changes in SF-36, EQ-5D-5L and FACT-An scores were small and no apparent trend was

observed during the study.

● The proportion of patients who were admitted to the hospital during treatment period in the ASP1517

50-mg ESA untreated group, the ASP1517 70-mg ESA untreated group and the pooled ESA treated group

was 50.0% (3/6 patients), 57.1% (4/7 patients) and 7.0% (3/43 patients), respectively. The common

reasons for hospitalization were peritoneal equilibration test and AEs.

● The mean hepcidin values in the ASP1517 50-mg ESA untreated group were decreased through week 4

and then stable through the end of treatment. The mean hepcidin values in the ASP1517 70-mg ESA

untreated group and the pooled ESA treated group were decreased and then slightly increased through

week 12, and then stable through the end of treatment [Figure 3].

Safety Results:

● The incidence of treatment-emergent adverse events (TEAEs) was 87.5% (49/56 patients) in total, 83.3%

(5/6 patients) in the ASP1517 50-mg ESA untreated group, 71.4% (5/7 patients) in the ASP1517 70-mg

ESA untreated group and 90.7% (39/43 patients) in the pooled ESA treated group.

● The common (incidence ≥ 5%) TEAEs in total were nasopharyngitis (25.0%), back pain (8.9%), catheter

site infection, diarrhea, vomiting (7.1% each), abdominal pain, conjunctivitis, constipation, nausea and

pruritus (5.4% each) [Table 7].

● The incidence of drug-related TEAEs in total was 37.5% (21/56 patients) [Table 8].

● No death was reported in any of the treatment groups.



● The incidence of serious TEAEs in total was 14.3% (8/56 patients) [Table 9]. The serious TEAE occurred

in 2 or more patients in total were peritonitis (3.6%, 2/56 patients).

● Of the 56 patients in all the treatment groups, 1 (1.8%) experienced drug-related serious TEAE of

rhabdomyolysis.

● The incidence of TEAEs leading to withdrawal of treatment in total was 7.1% (4/56 patients) [Table 10].

● The incidence of TEAEs occurring in time interval of ≥1 to ≤43 days was 57.1%, that of >43 to ≤85 days

was 56.6%, that of >85 to ≤127 days was 36.5%, that of >127 to ≤169 days was 34.0% and that of >169

days was 25.0%.

CONCLUSIONS:

● Treatment with oral ASP1517 3 times a week was able to correct Hb and to maintain Hb in the target range

in Japanese anemic peritoneal dialysis CKD patients not treated with ESA regardless of the initial dose;

similarly, Hb could be maintained in Japanese anemic peritoneal dialysis CKD patients pre-treated with

ESA and converted to treatment with ASP1517 3 times a week.

● Efficacy of ASP1517 was demonstrated by the persistence of an effect in the target Hb level, and ASP1517

showed well-tolerated safety profile demonstrating an AE profile similar to the underlying population of

patients with anemia and CKD.

Date of Report: 23 Mar 2018



Figure 1 Disposition of Patients

Informed consent n = 69

Randomized/registered and received the study drug

n = 56Discontinued before

randomization/registration †n = 13

ASP1517 50-mg ESA untreated n = 6

ASP1517 70-mg ESA untreated n = 7

ASP1517 70-mg ESA treated n = 23

ASP1517 100-mg ESA treated n = 20

Completed treatment n = 49 Discontinued n = 7

ASP1517 50-mg ESA untreated n = 6 ASP1517 50-mg ESA untreated n = 0

ASP1517 70-mg ESA untreated n = 7 ASP1517 70-mg ESA untreated n = 0

ASP1517 70-mg ESA treated n = 20 ASP1517 70-mg ESA treated n = 3

ASP1517 100-mg ESA treated n = 16 ASP1517 100-mg ESA treated n = 4

† Patients who signed informed consent but discontinued before first randomization/registration were screen failures.

Source: Table 12.1.1.1, Table 12.1.1.2, Table 12.1.1.3.2

Table 1 Study Discontinuation (All Registered Patients)

ESA Untreated ESA Treated

Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

Study Discontinuation

No 6 (100.0%) 7 (100.0%) 13 (100.0%) 20 (87.0%) 16 (80.0%) 36 (83.7%) 49 (87.5%)

Yes 0 0 0 3 (13.0%) 4 (20.0%) 7 (16.3%) 7 (12.5%)

Primary Reason for the Study Discontinuation †Completed 6 (100.0%) 7 (100.0%) 13 (100.0%) 20 (87.0%) 16 (80.0%) 36 (83.7%) 49 (87.5%)Adverse Event 0 0 0 2 (8.7%) 2 (10.0%) 4 (9.3%) 4 (7.1%)Death 0 0 0 0 0 0 0Lack of Efficacy 0 0 0 0 0 0 0Lost to Follow-up 0 0 0 0 0 0 0Progressive Disease 0 0 0 0 0 0 0Protocol Deviation 0 0 0 0 0 0 0Withdrawal by Patient 0 0 0 1 (4.3%) 1 (5.0%) 2 (4.7%) 2 (3.6%)Study Terminated by Sponsor

0 0 0 0 0 0 0

Non-Compliance with Study Drug

0 0 0 0 0 0 0

Recovery 0 0 0 0 0 0 0Pregnancy 0 0 0 0 0 0 0Site Terminated by Sponsor

0 0 0 0 0 0 0

Other‡ 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)

† Only the primary reason for discontinuation was collected.

‡ The patient was applicable to withdrawal criteria No.6 (The patient needed a change to hemodialysis or needed concomitant hemodialysis after the start of the study).

Source: Table 12.1.1.3.2, Appendix 13.2.1.2



Table 2 Demographic Characteristics (FAS)


Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

SexMale 4 (66.7%) 6 (85.7%) 10 (76.9%) 12 (52.2%) 14 (70.0%) 26 (60.5%) 36 (64.3%)Female 2 (33.3%) 1 (14.3%) 3 (23.1%) 11 (47.8%) 6 (30.0%) 17 (39.5%) 20 (35.7%)

Age(Years) [Informed Consent]n 6 7 13 23 20 43 56Mean 64.5 67.4 66.1 61.7 66.2 63.7 64.3SD 11.4 11.2 10.9 8.9 11.1 10.1 10.3Min 43 53 43 45 39 39 39Median 68.5 71.0 69.0 64.0 67.0 66.0 67.0Max 73 83 83 80 87 87 87

Age Group(Years) [Informed Consent]<65 2 (33.3%) 3 (42.9%) 5 (38.5%) 12 (52.2%) 7 (35.0%) 19 (44.2%) 24 (42.9%)≥65 4 (66.7%) 4 (57.1%) 8 (61.5%) 11 (47.8%) 13 (65.0%) 24 (55.8%) 32 (57.1%)

Height(cm) [Prescreening]n 6 7 13 23 20 43 56Mean 163.30 163.24 163.27 159.56 161.88 160.63 161.25SD 12.08 5.47 8.71 6.42 8.93 7.68 7.93Min 148.2 157.6 148.2 147.3 145.6 145.6 145.6Median 165.00 162.60 162.60 158.90 163.20 160.30 162.20Max 180.3 174.0 180.3 169.3 175.2 175.2 180.3

Weight(kg) [Prescreening]n 6 7 13 23 20 43 56Mean 59.25 63.76 61.68 64.80 64.20 64.52 63.86SD 8.68 6.22 7.50 14.12 10.17 12.30 11.37Min 48.4 55.6 48.4 48.3 42.1 42.1 42.1Median 56.05 61.20 61.10 59.90 64.10 62.70 61.15Max 70.2 74.0 74.0 104.5 82.7 104.5 104.5

Weight Group(kg) [Prescreening]<60 4 (66.7%) 2 (28.6%) 6 (46.2%) 12 (52.2%) 8 (40.0%) 20 (46.5%) 26 (46.4%)≥60 2 (33.3%) 5 (71.4%) 7 (53.8%) 11 (47.8%) 12 (60.0%) 23 (53.5%) 30 (53.6%)

Weight(kg) [Week 0]n 6 7 13 23 20 43 56Mean 59.48 63.79 61.80 65.10 64.17 64.67 64.00SD 9.16 5.46 7.41 14.04 9.69 12.08 11.18Min 48.5 55.4 48.5 48.4 42.9 42.9 42.9Median 55.75 62.70 62.10 60.80 64.15 63.50 62.40Max 72.1 72.4 72.4 102.6 82.5 102.6 102.6

Weight Group(kg) [Week 0]<60 4 (66.7%) 1 (14.3%) 5 (38.5%) 11 (47.8%) 7 (35.0%) 18 (41.9%) 23 (41.1%)>=60 2 (33.3%) 6 (85.7%) 8 (61.5%) 12 (52.2%) 13 (65.0%) 25 (58.1%) 33 (58.9%)

BMI(kg/m2) [Prescreening]n 6 7 13 23 20 43 56Mean 22.18 23.88 23.10 25.40 24.38 24.92 24.50SD 1.71 1.24 1.67 5.13 2.44 4.09 3.74Min 19.6 22.4 19.6 20.2 19.9 19.9 19.6Median 21.82 24.44 23.17 23.99 24.10 24.09 24.03Max 24.2 25.5 25.5 42.9 31.5 42.9 42.9

Duration of Anemia associated with CKD(Months)n 4 7 11 22 17 39 50Mean 57.57 35.70 43.65 50.56 46.75 48.90 47.75SD 35.86 31.03 32.94 32.36 26.25 29.54 30.05Min 8.1 5.6 5.6 4.0 12.2 4.0 4.0Median 64.76 26.15 32.30 47.29 43.20 45.01 44.11Max 92.6 97.5 97.5 121.7 91.9 121.7 121.7

Duration of Anemia associated with CKD Group (Months)<6 0 1 (14.3%) 1 (7.7%) 1 (4.3%) 0 1 (2.3%) 2 (3.6%)≥6 to <12 1 (16.7%) 0 1 (7.7%) 1 (4.3%) 0 1 (2.3%) 2 (3.6%)≥12 to <36 0 4 (57.1%) 4 (30.8%) 7 (30.4%) 7 (35.0%) 14 (32.6%) 18 (32.1%)≥36 to <60 1 (16.7%) 1 (14.3%) 2 (15.4%) 5 (21.7%) 5 (25.0%) 10 (23.3%) 12 (21.4%)≥60 to <120 2 (33.3%) 1 (14.3%) 3 (23.1%) 7 (30.4%) 5 (25.0%) 12 (27.9%) 15 (26.8%)≥120 to <240 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)≥240 0 0 0 0 0 0 0Unknown 2 (33.3%) 0 2 (15.4%) 1 (4.3%) 3 (15.0%) 4 (9.3%) 6 (10.7%)




Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

Primary Disease of CKDChronic Glomerular Nephritis

4 (66.7%) 4 (57.1%) 8 (61.5%) 6 (26.1%) 5 (25.0%) 11 (25.6%) 19 (33.9%)

Diabetic Nephropathy 2 (33.3%) 1 (14.3%) 3 (23.1%) 5 (21.7%) 5 (25.0%) 10 (23.3%) 13 (23.2%)Chronic Pyelonephritis 0 0 0 0 0 0 0 Polycystic Kidney 0 0 0 0 0 0 0 Nephrosclerosis 0 1 (14.3%) 1 (7.7%) 7 (30.4%) 8 (40.0%) 15 (34.9%) 16 (28.6%)Other 0 1 (14.3%) 1 (7.7%) 5 (21.7%) 2 (10.0%) 7 (16.3%) 8 (14.3%)

Duration of CKD (Months)n 3 6 9 18 12 30 39Mean 95.65 182.61 153.62 140.42 136.82 138.98 142.36SD 69.37 159.66 137.94 118.16 116.13 115.34 119.15Min 24.1 30.6 24.1 24.0 12.2 12.2 12.2Median 100.21 115.76 110.49 87.15 95.87 87.15 100.21Max 162.6 409.6 409.6 382.3 373.6 382.3 409.6

Duration of CKD Group (Months)<6 0 0 0 0 0 0 0 ≥6 to <12 0 0 0 0 0 0 0 ≥12 to <36 1 (16.7%) 1 (14.3%) 2 (15.4%) 2 (8.7%) 3 (15.0%) 5 (11.6%) 7 (12.5%)≥36 to <60 0 0 0 2 (8.7%) 1 (5.0%) 3 (7.0%) 3 (5.4%)≥60 to <120 1 (16.7%) 2 (28.6%) 3 (23.1%) 7 (30.4%) 3 (15.0%) 10 (23.3%) 13 (23.2%)≥120 to <240 1 (16.7%) 1 (14.3%) 2 (15.4%) 3 (13.0%) 2 (10.0%) 5 (11.6%) 7 (12.5%)≥240 0 2 (28.6%) 2 (15.4%) 4 (17.4%) 3 (15.0%) 7 (16.3%) 9 (16.1%)Unknown 3 (50.0%) 1 (14.3%) 4 (30.8%) 5 (21.7%) 8 (40.0%) 13 (30.2%) 17 (30.4%)

Peritoneal Dialysis Vintage (Months)n 6 7 13 23 20 43 56Mean 62.01 14.54 36.45 32.93 43.94 38.05 37.68SD 41.94 13.67 37.86 25.22 49.10 38.14 37.73Min 9.1 1.5 1.5 3.0 3.2 3.0 1.5Median 60.88 12.02 17.28 33.02 36.11 33.02 31.33Max 131.7 42.5 131.7 102.8 189.8 189.8 189.8

Peritoneal Dialysis Vintage Group (Months)<6 0 2 (28.6%) 2 (15.4%) 5 (21.7%) 4 (20.0%) 9 (20.9%) 11 (19.6%)≥6 to <12 1 (16.7%) 1 (14.3%) 2 (15.4%) 1 (4.3%) 4 (20.0%) 5 (11.6%) 7 (12.5%)≥12 to <36 1 (16.7%) 3 (42.9%) 4 (30.8%) 9 (39.1%) 2 (10.0%) 11 (25.6%) 15 (26.8%)≥36 to <60 1 (16.7%) 1 (14.3%) 2 (15.4%) 5 (21.7%) 6 (30.0%) 11 (25.6%) 13 (23.2%)≥60 to <120 2 (33.3%) 0 2 (15.4%) 3 (13.0%) 2 (10.0%) 5 (11.6%) 7 (12.5%)≥120 to <240 1 (16.7%) 0 1 (7.7%) 0 2 (10.0%) 2 (4.7%) 3 (5.4%)≥240 0 0 0 0 0 0 0

Source: Table 12.1.2.1.2



Table 3 Maintenance Rate of Target Hb Level (Average Hb Level of 10.0 to 12.0 g/dL for Weeks 18 to 24) (FAS)


Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

Average Hb Levels of Weeks 18 to 24Number of PatientsWho Maintain Target Hb Level †

5 (83.3%) 7 (100.0%) 12 (92.3%) 19 (82.6%) 13 (65.0%) 32 (74.4%) 44 (78.6%)

95% CI of Maintenance Rate ‡

(35.9%, 99.6%)

(59.0%, 100.0%)

(64.0%, 99.8%)

(61.2%, 95.0%)

(40.8%, 84.6%)

(58.8%, 86.5%)

(65.6%, 88.4%)

Hb values in analysis visit windows at weeks 18, 20, 22 and 24 were used for calculating the average of weeks 18 to 24.

The denominator about the maintenance rate is the number of FAS.

† Defined as average Hb level of 10.0 to 12.0 g/dL for weeks 18 to 24.

‡ Clopper-Pearson method

Source: Table 12.3.1.1

Table 4 Maintenance Rate of Target Hb Level (Average Hb Level of 10.0 to 12.0 g/dL for Weeks 18 to 24) For Patients With at Least One Hb Value During Weeks 18 to 24 (FAS)


Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517

(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517

(N=43)Average Hb Levels of Weeks 18 to 24Number of PatientsWho Maintain Target Hb Level †

5/6 (83.3%) 7/7 (100.0%) 12/13 (92.3%) 19/20 (95.0%) 13/17 (76.5%) 32/37 (86.5%) 44/50 (88.0%)

95% CI of Maintenance Rate ‡

(35.9%, 99.6%)

(59.0%, 100.0%)

(64.0%, 99.8%)

(75.1%, 99.9%)

(50.1%, 93.2%)

(71.2%, 95.5%)

(75.7%, 95.5%)


† Defined as Average Hb Level of 10.0 to 12.0 g/dL for weeks 18 to 24.

‡ Clopper-Pearson method


Table 5 Average Hb Levels of Weeks 18 to 24 (FAS)


Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

Average Hb Levels of Weeks 18 to 24 (g/dL)n 6 7 13 20 17 37 50Mean 11.07 11.03 11.05 10.90 10.96 10.93 10.96SD 0.81 0.46 0.62 0.42 0.79 0.61 0.61Min 9.5 10.3 9.5 9.9 9.7 9.7 9.5Median 11.30 11.10 11.20 10.90 10.90 10.90 11.00Max 11.7 11.5 11.7 11.6 12.3 12.3 12.395% CI (10.22, 11.92) (10.60, 11.46) (10.67, 11.42) (10.70, 11.10) (10.56, 11.37) (10.73, 11.13) (10.79, 11.13)


Source: Table 12.3.4



Table 6 Change of Average Hb Levels of Weeks 18 to 24 From Baseline (FAS)

ESA Untreated ESA TreatedASP1517

50 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517

(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517

(N=43)Change of Average Hb Levels of Weeks 18 to 24 From Baseline (g/dL)

n 6 7 13 20 17 37Mean 1.50 1.86 1.69 0.11 0.17 0.14SD 1.02 1.13 1.05 0.66 0.89 0.76Min -0.2 0.3 -0.2 -1.1 -1.1 -1.1Median 1.75 2.00 2.00 -0.10 0.10 0.00Max 2.7 3.5 3.5 1.1 1.9 1.995% CI (0.43, 2.57) (0.82, 2.90) (1.06, 2.33) (-0.20, 0.41) (-0.28, 0.63) (-0.12, 0.39)


Source: Table 12.3.5

Figure 2 Mean-Standard Deviation Plot of Hemoglobin (FAS)

PSC: Prescreening, SC: Screening, EOT: End of Treatment, ULN: upper limit of normal, LLN: lower limit of normal

Source: Figure 12.3.2.1



Figure 3 Mean-Standard Deviation Plot of Hepcidin (FAS)

EOT: End of Treatment

Source: Figure 12.3.15.1

Table 7 Common (≥ 5% in total) Treatment-emergent Adverse Events (SAF)

MedDRA Version 19.0System Organ Class

Preferred Term


Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

Overall 5 (83.3%) 5 (71.4%) 10 (76.9%) 21 (91.3%) 18 (90.0%) 39 (90.7%) 49 (87.5%)Gastrointestinal disorders 1 (16.7%) 0 1 (7.7%) 8 (34.8%) 10 (50.0%) 18 (41.9%) 19 (33.9%)

Diarrhoea 0 0 0 2 (8.7%) 2 (10.0%) 4 (9.3%) 4 (7.1%)Vomiting 0 0 0 2 (8.7%) 2 (10.0%) 4 (9.3%) 4 (7.1%)Abdominal pain 0 0 0 2 (8.7%) 1 (5.0%) 3 (7.0%) 3 (5.4%)Constipation 0 0 0 0 3 (15.0%) 3 (7.0%) 3 (5.4%)Nausea 0 0 0 2 (8.7%) 1 (5.0%) 3 (7.0%) 3 (5.4%)

Infections and infestations 4 (66.7%) 3 (42.9%) 7 (53.8%) 10 (43.5%) 11 (55.0%) 21 (48.8%) 28 (50.0%)Nasopharyngitis 0 0 0 6 (26.1%) 8 (40.0%) 14 (32.6%) 14 (25.0%)Catheter site infection 0 0 0 2 (8.7%) 2 (10.0%) 4 (9.3%) 4 (7.1%)Conjunctivitis 1 (16.7%) 1 (14.3%) 2 (15.4%) 0 1 (5.0%) 1 (2.3%) 3 (5.4%)

Musculoskeletal and connective tissue disorders

0 3 (42.9%) 3 (23.1%) 5 (21.7%) 3 (15.0%) 8 (18.6%) 11 (19.6%)

Back pain 0 3 (42.9%) 3 (23.1%) 0 2 (10.0%) 2 (4.7%) 5 (8.9%)Skin and subcutaneous tissue disorders

1 (16.7%) 2 (28.6%) 3 (23.1%) 3 (13.0%) 2 (10.0%) 5 (11.6%) 8 (14.3%)

Pruritus 0 0 0 1 (4.3%) 2 (10.0%) 3 (7.0%) 3 (5.4%)




Table 8 Drug-related Treatment-emergent Adverse Events (SAF)


Preferred Term


Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

Overall 3 (50.0%) 1 (14.3%) 4 (30.8%) 7 (30.4%) 10 (50.0%) 17 (39.5%) 21 (37.5%)Cardiac disorders 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Palpitations 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)Eye disorders 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)

Conjunctivitis allergic 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)Gastrointestinal disorders 1 (16.7%) 0 1 (7.7%) 0 7 (35.0%) 7 (16.3%) 8 (14.3%)

Constipation 0 0 0 0 3 (15.0%) 3 (7.0%) 3 (5.4%)Diarrhoea 0 0 0 0 2 (10.0%) 2 (4.7%) 2 (3.6%)Chronic gastritis 1 (16.7%) 0 1 (7.7%) 0 0 0 1 (1.8%)Duodenitis 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)Dyspepsia 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)Gastritis 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)Gastrooesophageal reflux disease

0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)

Nausea 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)Vomiting 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)

General disorders and administration site conditions

1 (16.7%) 1 (14.3%) 2 (15.4%) 2 (8.7%) 0 2 (4.7%) 4 (7.1%)

Oedema 1 (16.7%) 1 (14.3%) 2 (15.4%) 0 0 0 2 (3.6%)Drug interaction 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)Oedema peripheral 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Infections and infestations 1 (16.7%) 1 (14.3%) 2 (15.4%) 0 0 0 2 (3.6%)Conjunctivitis 1 (16.7%) 1 (14.3%) 2 (15.4%) 0 0 0 2 (3.6%)

Investigations 0 0 0 2 (8.7%) 1 (5.0%) 3 (7.0%) 3 (5.4%)Alanine aminotransferase increased

0 0 0 2 (8.7%) 0 2 (4.7%) 2 (3.6%)

Aspartate aminotransferase increased

0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Blood creatine phosphokinase increased

0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)

Blood alkaline phosphatase increased

0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Metabolism and nutrition disorders

0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Hyperphosphataemia 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)Musculoskeletal and connective tissue disorders

0 1 (14.3%) 1 (7.7%) 2 (8.7%) 0 2 (4.7%) 3 (5.4%)

Back pain 0 1 (14.3%) 1 (7.7%) 0 0 0 1 (1.8%)Muscular weakness 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)Rhabdomyolysis 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Nervous system disorders 0 0 0 1 (4.3%) 1 (5.0%) 2 (4.7%) 2 (3.6%)Vocal cord paralysis 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)Restless legs syndrome 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Reproductive system and breast disorders

0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Gynaecomastia 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)Respiratory, thoracic and mediastinal disorders

1 (16.7%) 0 1 (7.7%) 1 (4.3%) 2 (10.0%) 3 (7.0%) 4 (7.1%)

Cough 0 0 0 1 (4.3%) 1 (5.0%) 2 (4.7%) 2 (3.6%)Epistaxis 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)Vocal cord polyp 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)Allergic cough 1 (16.7%) 0 1 (7.7%) 0 0 0 1 (1.8%)

Skin and subcutaneous tissue disorders

1 (16.7%) 0 1 (7.7%) 1 (4.3%) 2 (10.0%) 3 (7.0%) 4 (7.1%)

Pruritus 0 0 0 1 (4.3%) 2 (10.0%) 3 (7.0%) 3 (5.4%)Miliaria 1 (16.7%) 0 1 (7.7%) 0 0 0 1 (1.8%)




Preferred Term


Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

Vascular disorders 0 1 (14.3%) 1 (7.7%) 1 (4.3%) 0 1 (2.3%) 2 (3.6%)Hypertension 0 1 (14.3%) 1 (7.7%) 0 0 0 1 (1.8%)Labile blood pressure 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)


Table 9 Serious Treatment-emergent Adverse Events (SAF)


Preferred Term


Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

Overall 2 (33.3%) 1 (14.3%) 3 (23.1%) 3 (13.0%) 2 (10.0%) 5 (11.6%) 8 (14.3%)Cardiac disorders 1 (16.7%) 0 1 (7.7%) 0 0 0 1 (1.8%)

Atrioventricular block second degree

1 (16.7%) 0 1 (7.7%) 0 0 0 1 (1.8%)

General disorders and administration site conditions

0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)

General physical health deterioration

0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)

Infections and infestations 0 0 0 1 (4.3%) 1 (5.0%) 2 (4.7%) 2 (3.6%)Peritonitis 0 0 0 1 (4.3%) 1 (5.0%) 2 (4.7%) 2 (3.6%)

Injury, poisoning and procedural complications

0 1 (14.3%) 1 (7.7%) 0 0 0 1 (1.8%)

Head injury 0 1 (14.3%) 1 (7.7%) 0 0 0 1 (1.8%)Metabolism and nutrition disorders

1 (16.7%) 0 1 (7.7%) 0 0 0 1 (1.8%)

Hyperglycaemia 1 (16.7%) 0 1 (7.7%) 0 0 0 1 (1.8%)Musculoskeletal and connective tissue disorders

0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Rhabdomyolysis 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)Surgical and medical procedures

0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Benign tumour excision 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)




Table 10 Treatment-emergent Adverse Events Leading to Withdrawal of Treatment (SAF)


Preferred Term


Total(N=56)

ASP151750 mg(N=6)

ASP151770 mg(N=7)

PooledASP1517(N=13)

ASP151770 mg(N=23)

ASP1517100 mg(N=20)

PooledASP1517(N=43)

Overall 0 0 0 2 (8.7%) 2 (10.0%) 4 (9.3%) 4 (7.1%)Cardiac disorders 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Palpitations 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)Gastrointestinal disorders 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)

Dyspepsia 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)Investigations 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Alanine aminotransferase increased

0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Aspartate aminotransferase increased

0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Musculoskeletal and connective tissue disorders

0 0 0 2 (8.7%) 0 2 (4.7%) 2 (3.6%)

Muscular weakness 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)Rhabdomyolysis 0 0 0 1 (4.3%) 0 1 (2.3%) 1 (1.8%)

Skin and subcutaneous tissue disorders

0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)

Pruritus 0 0 0 0 1 (5.0%) 1 (2.3%) 1 (1.8%)


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