Roxadustat (FG-4592/ASP1517) ISN 1517-CL-0543 Renal Anemia … · 2019-09-27 · Renal Anemia CONFIDENTIAL EudraCT number 2015-002565-28 Aug2018 Astellas Synopsis Page 3of 30 In treatment

Roxadustat (FG-4592/ASP1517) ISN 1517-CL-0543Renal AnemiaCONFIDENTIAL EudraCT number 2015-002565-28

Name of Sponsor/Company:Astellas Pharma Global Development, Inc.

Name of Finished Product:Roxadustat (FG-4592/ASP1517)

Name of Active Ingredient:Roxadustat (FG-4592/ASP1517)

Aug 2018 Astellas Synopsis Page 1 of 30

SYNOPSIS

Title of Study:

A Phase 1 Study to Evaluate the Pharmacokinetics of Roxadustat in Subjects with Different Degrees of Renal

Function (1517-CL-0543)

Investigators/Coordinating Investigator:

, MD (Site Number ) and (Site Number )

Study Center(s):

UK (Site Number ) and , Germany (Site Number )

Publication Based on the Study:

Not applicable

Study Period:

4Q2016 to 4Q2017

Study Initiation Date (Date of First Evaluation):

12 Dec 2016

Study Completion Date (Date of Last Evaluation):

11 Dec 2017

Phase of Development:

Phase 1

Objectives:

Primary Objectives

Subjects with Normal Renal Function or Severely Impaired Renal Function

● To evaluate the pharmacokinetics of roxadustat and its main metabolites in plasma and urine

Subjects with End-stage Renal Disease on Continuous Ambulatory Peritoneal Dialysis or Automated Peritoneal

Dialysis

● To evaluate the pharmacokinetics of roxadustat and its main metabolites in plasma, urine and dialysate



Subjects with End-stage Renal Disease on Hemodialysis or Hemodiafiltration

● To evaluate the pharmacokinetics of roxadustat and its main metabolites in plasma, urine and dialysate

● To evaluate the effect of dialysis on the pharmacokinetics of roxadustat and its main metabolites

Secondary Objectives

● To evaluate the safety and tolerability of roxadustat

● To evaluate the pharmacodynamics of roxadustat

Exploratory Objective

● To compare the pharmacokinetics of roxadustat and its main metabolites in subjects with severely

impaired renal function or end-stage renal disease (ESRD) relative to the pharmacokinetics of roxadustat

in subjects with normal renal function

Methodology:

This study was a phase 1 study to investigate the pharmacokinetics, metabolic profile, pharmacodynamics,

safety and tolerability of a single dose of roxadustat in subjects with severely impaired renal function or ESRD.

The pharmacokinetics, metabolic profile, pharmacodynamics, safety and tolerability of a single dose of

roxadustat were also investigated in subjects with normal renal function and the results compared to subjects

with severely impaired renal function or ESRD.

Subjects with Normal Renal Function or Severely Impaired Renal Function and Subjects with End-stage Renal

Disease on Continuous Ambulatory Peritoneal Dialysis or Automated Peritoneal Dialysis

Screening took place from days -30 to -3 and the subjects were admitted to the clinical unit on day -2. The

treatment period lasted 8 days, during which the subjects received a single oral dose of 100 mg roxadustat in the

morning of day 1.

Pharmacokinetics of roxadustat and its main metabolites (O-glucuronide-, O-glucoside- and sulphate of

hydroxy-roxadustat) in plasma, urine and dialysate were assessed. In addition, plasma protein binding of

roxadustat was assessed on day 1.

Subjects completed the treatment period on day 6, provided that all required assessments had been performed

and there were no medical reasons for a prolonged follow-up. The study was completed with an end-of-study

visit (ESV), which took place between 5 and 9 days after the last treatment period-defined assessment (or after

early withdrawal).


A 2-period, single-sequence design was used for subjects with ESRD on hemodialysis (HD) or

hemodiafiltration (HDF). Screening took place from days -30 to -3 and the subjects completed 2 treatment

periods in order to evaluate the pharmacokinetics of roxadustat with dosing after and before dialysis:

● In treatment period 1, subjects were admitted to the clinical unit on the day of the first dialysis session of

the week (e.g., Mon if subject was on a Mon-Wed-Fri-regimen or Tue if subject was on a

Tue-Thu-Sat-regimen) (day -2). The subjects received a single oral dose of 100 mg roxadustat 2 hours

after completion of hemodialysis on day 1 of treatment period 1.



● In treatment period 2, subjects were admitted to the clinical unit the day before the second dialysis session

of the week (e.g., Tue if subject was on a Mon-Wed-Fri regimen or Wed if subject was on a

Tue-Thu-Sat-regimen) (day -1). The subjects received a single oral dose of 100 mg roxadustat 2 hours

prior to the start of hemodialysis on day 1 of treatment period 2.

The washout between treatment periods 1 and 2 was minimally 1 week and maximally 3 weeks, between day 6

of treatment period 1 and day -1 of treatment period 2.

In both treatment periods the pharmacokinetics of roxadustat and its main metabolites (O-glucuronide-,

O-glucoside- and sulphate of hydroxy-roxadustat) in plasma and urine (for all subjects with residual urine

production) were assessed. The pharmacokinetics of roxadustat and its main metabolites (O-glucuronide-,

O-glucoside- and sulphate of hydroxy-roxadustat) in dialysate was assessed in treatment period 2 only. In

addition, plasma protein binding of roxadustat was assessed on day 1 of treatment periods 1 and 2.

Subjects completed the treatment period on day 6 of treatment period 2, provided that all required assessments

had been performed and there were no medical reasons for a prolonged follow-up. The study was completed

with an ESV, which took place between 5 and 9 days after the last treatment period 2-defined assessment (or

after early withdrawal).

HD and HDF subjects could have used low flux and high flux dialysis filters.

All Subjects

Erythropoietin (EPO) was not assessed for subjects who were on treatment with long-acting

erythropoiesis-stimulating agents (ESAs) (i.e., darbepoetin and MPG-EPO) at that time. Continuous heart rate

measurement was performed for 24 hours prior to dosing (after completion of dialysis on day -2 in HD/HDF

subjects) and for 24 hours after dosing (only in treatment period 1 in HD/HDF subjects). An optional

biobanking sample may have been taken for potential exploratory, retrospective, gene polymorphism analysis.

Roxadustat plasma, urine and dialysate samples were stored for potential exploratory metabolic profiling or

exploratory biomarker analysis after the study.

Number of Patients (Planned, Enrolled and Analyzed):

A sufficient number of subjects were enrolled to evaluate the pharmacokinetics of roxadustat and its main

metabolites in subjects with different degrees of renal function in this exploratory clinical pharmacokinetic

study.

The remaining 34 (46.6%) subjects were enrolled (registered) into the study and received roxadustat. Only 1 of

these subjects was in the ESRD on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal

dialysis (APD) renal function group. The recruitment of the full number of required subjects for the ESRD on

CAPD or APD renal function group was difficult and not possible within the given time frame.

Of the 34 enrolled subjects, 28 subjects were enrolled at the site in Germany and 6 subjects were enrolled at the

site in the UK

All registered subjects completed the study as per the protocol. All registered subjects that received roxadustat

were included in the safety, pharmacokinetic and pharmacodynamics analysis sets.



Diagnosis and Main Criteria for Inclusion:

Male or female subjects with a body weight within the range of 45 to 160 kg (inclusive [screening]), who

provided written informed consent and to whom all of the inclusion and none of the exclusion criteria applied

were eligible for inclusion in this study.

If a subject with impaired renal function was being treated with short acting ESAs, the subject had to agree to

discontinue treatment for at least 14 days prior to admission.

Subjects who had any condition which, in the investigator’s opinion, made the subject unsuitable for clinical

study participation were excluded from the study.

Specific Inclusion Criteria for Subjects with Normal Renal Function

Subject was aged 40 to 75 years (inclusive [screening]) and had a predose estimated glomerular filtration rate

(eGFR) value based on the Modification of Diet in Renal Disease (MDRD) method (screening) of ≥ 90 mL/min

per 1.73 m2.

Specific Inclusion Criteria for Subjects with Severely Impaired Renal Function

Subject was aged 18 to 75 years (inclusive [screening]), had a predose eGFR value based on the abbreviated

MDRD method (screening) of < 30 mL/min/1.73 m2 and was not on dialysis.

Specific Inclusion Criteria for Subjects with End-stage Renal Disease on Continuous Ambulatory Peritoneal

Dialysis or Automated Peritoneal Dialysis

Subject was aged 18 to 75 years (inclusive [screening]) and was on CAPD or APD treatment with the same

mode of dialysis for at least 4 months prior to admission to the clinical unit.

Specific Inclusion Criteria for Subjects with End-stage Renal Disease on Hemodialysis or Hemodiafiltration

Subject was aged 18 to 75 years (inclusive [screening]), was on HD or HDF treatment with the same mode of

dialysis for at least 4 months prior to admission to the clinical unit and should have had dialysis sessions 3 times

weekly.

Specific Exclusion Criteria for Subjects with Normal Renal Function

Subject used any prescribed or nonprescribed drugs within 2 weeks (or 5 half-lives, whichever was longer) prior

to admission to the clinical unit, except for occasional use of paracetamol (up to 2 g per day) and oral

contraceptives or hormone replacement therapy.

Specific Exclusion Criteria for Subjects with Impaired Renal Function (Including Severely Impaired Renal

Function and End-stage Renal Disease)

Subject had used immunosuppressant drugs or drugs used to treat malignancies (including corticosteroids at

doses > 10 mg prednisolone per day or equivalent) within 3 months prior to admission to the clinical unit.

Subject had an anticipated use of the following prohibited medication during the treatment and/or follow-up of

the study:

● Oral multivalent cation-containing drugs and mineral supplements, anion-exchange resins, sucralfate or

magnesium- or aluminium-containing antacids, phosphate binders and iron-chelating agents were not

allowed from 24 hours before until 48 hours after dosing.



● Short-acting intravenous or subcutaneous ESA were not allowed within 2 weeks prior to admission to the

clinical unit until the ESV.

● Dapsone in any dose amount or anticipated chronic use of paracetamol > 2 g per day or nonsteroidal

anti-inflammatory drugs, except for low dose aspirin/acetylsalicylic acid, were not allowed from admission

to the clinical unit until the ESV.

Subject had not been on a stable dose of concomitant medication to treat concurrent chronic conditions for at

least 2 weeks (or 5 half-lives of the drug, whichever was longer) prior to admission to the clinical unit (minor

dose changes were allowed in agreement with the sponsor). Doses of statins should not have exceeded the

capped maximum daily doses at admission to the clinical unit. Rosuvastatin use was not allowed.

Subject had used any nonessential prescribed and nonprescribed drugs within 2 weeks (or 5 half-lives,

whichever was longer) prior to admission to the clinical unit.

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

Roxdustat was provided as 100 mg tablets (lot number: and expiry/re-evaluation date: 31 Aug 2018).

A single dose of 100 mg roxadustat was administered orally on day 1 under the following conditions:

Subjects with Normal Renal Function or Severely Impaired Renal Function

On the day of dosing the subject started with a breakfast (completed within 30 minutes), after which the subjects

refrained from water and food intake until dosing. Approximately 2.5 hours after completion of the breakfast

the roxadustat tablet was taken with 150 mL of water. After dosing the subject refrained from water and food

intake for at least 2 hours. Lunch may have been provided at any time after the fasting period.

Subjects with End-stage Renal Disease on Continuous Ambulatory Peritoneal Dialysis or Automated Peritoneal

Dialysis

Dosing of roxadustat took place after the first dwelling cycle of the day and before the second dwelling cycle.

Breakfast was served approximately 3 hours before dosing and needed to be completed within 30 minutes, after

which the subjects refrained from water and food intake until dosing. The roxadustat tablet was taken with

150 mL of water. After dosing, the subject refrained from water and food intake for at least 2 hours. Lunch

may have been provided at any time after the fasting period and dialysis procedures were to be taken into

consideration. Prior to a dwelling period, the dialysate was drained for approximately 20 minutes and dialysis

fluid was infused for approximately 10 minutes.


Treatment Period 1

On the day of dosing the subject started with a breakfast (completed within 30 minutes). Dialysis was initiated

approximately 1 hour after completion of the breakfast.

Lunch was provided during the dialysis session (completed within 30 minutes), after which subjects refrained

from water and food intake until dosing. Approximately 2 hours after completion of dialysis, the roxadustat

tablet was taken with 150 mL of water. After dosing, the subject refrained from water and food intake for at

least 2 hours. Dinner may have been provided at any time after the fasting period.



Treatment Period 2

On the day of dosing the subject started with a breakfast (completed within 30 minutes), after which the subjects

refrained from water and food intake until dosing. Approximately 2.5 hours after completion of the breakfast

the roxadustat tablet was taken with 150 mL of water. After dosing, the subject refrained from water and food

intake for 2 hours. Dialysis was initiated approximately 2 hours after study drug intake. Lunch was provided

during the dialysis session.

Duration of Treatment (or Duration of Study, if applicable):

Subjects with Normal Renal Function or Severely Impaired Renal Function and Subjects with End-stage Renal

Disease on Continuous Ambulatory Peritoneal Dialysis or Automated Peritoneal Dialysis

After a screening period of up to 30 days prior to study drug administration, eligible subjects were residential

for at least 5 days/4 nights. Subjects were admitted to the clinical unit on day -2 and received a single oral dose

of 100 mg roxadustat in the morning of day 1. The study was completed with an ESV, which took place

between 5 and 9 days after the last treatment period-defined assessment (or after early withdrawal).


After a screening period of up to 30 days prior to study drug administration, eligible subjects were residential

for at least 5 days/4 nights in each of the 2 treatment periods. The washout between treatment periods 1 and 2

was minimally 1 week and maximally 3 weeks, between day 6 of treatment period 1 and day -1 of treatment

period 2.

In each treatment period, subjects were admitted to the clinical unit on day -2 and received a single oral dose of

100 mg roxadustat in the morning of day 1. The study was completed with an ESV, which took place between 5

and 9 days after the last treatment period 2-defined assessment (or after early withdrawal).

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

Not applicable

Criteria for Evaluation:

Pharmacokinetics

The pharmacokinetic parameters assessed included the following:

● Pharmacokinetics of roxadustat in plasma: Cmax, Cmax,u, AUCinf, AUCinf,u, AUClast, AUClast,u, CL/F, CLu/F,

fu, tmax, t½, Vz/F and Vz,u/F

● Pharmacokinetics of roxadustat metabolites (O-glucuronide-, O-glucoside- and sulphate of

hydroxy-roxadustat) in plasma: Cmax, AUCinf, AUClast, tlag, tmax, t½ and metabolite to parent ratio (MPR)

● Pharmacokinetics of roxadustat in urine (where possible): CLR, CLR,u, Aeinf, Aeinf%, Aelast and Aelast%

● Pharmacokinetics of roxadustat metabolites (O-glucuronide-, O-glucoside-, and sulphate of

hydroxy-roxadustat) in urine (where possible): CLR, Aeinf, Aelast and MPR based on Aeinf



The following additional pharmacokinetic parameters were also calculated, as these were deemed necessary:

● Effective t½ for roxadustat in plasma

● Total exposure ratio (TER) for roxadustat and its metabolites (O-glucuronide-, O-glucoside-, and sulphate

of hydroxy-roxadustat) in plasma

● Aeinf% for roxadustat metabolites in urine (O-glucuronide-, O-glucoside- and sulphate of

hydroxy-roxadustat)

Additional Endpoint for End-stage Renal Disease Subjects on Continuous Ambulatory Peritoneal Dialysis or

Automated Peritoneal Dialysis and for End-stage Renal Disease Subjects on Hemodialysis or Hemodiafiltration

(Treatment Period 2 Only)

The pharmacokinetic parameters in dialysate fluid included the following:

Dialysis clearance (CLD) for roxadustat and its main metabolites

Fraction of dose cleared by dialysis (fD) for roxadustat

All of the pharmacokinetic parameters assessed were considered primary endpoints.

Pharmacodynamics

The pharmacodynamic parameters assessed included the following:

● Pharmacodynamics (EPO): Emax, Emax-baseline, AUCE,last, AUCE,last(baseline-corrected) and tmax,EPO

All of the pharmacodynamic parameters assessed were considered secondary endpoints.

Safety

The safety parameters assessed included the following:

● Nature, frequency and severity of adverse events (AEs)

● Vital signs

● Clinical laboratory tests: hematology, biochemistry and urinalysis

● Routine 12-lead electrocardiogram (ECG)

● Continuous heart rate measurement

All of the safety parameters assessed were considered secondary endpoints.

Statistical Methods:

Pharmacokinetics

Concentrations (plasma, urine and dialysate) and pharmacokinetic parameters of roxadustat and its metabolites

(O-glucuronide-roxadustat, O-glucoside-roxadustat and the sulphate of hydroxy-roxadustat) were summarized

using descriptive statistics by renal function group and treatment period (when applicable). Plasma

concentrations and pharmacokinetic parameters for roxadustat and its metabolites were plotted (as applicable).

An evaluation of the effect of renal function on the pharmacokinetics of roxadustat and its main metabolites was

undertaken by consideration of descriptive statistics and plots of pharmacokinetic parameters.



Statistical assessments included:

● The effect of dialysis on the pharmacokinetics of roxadustat and its metabolites

● The relationship between total and unbound pharmacokinetic parameters of roxadustat and its metabolites

and eGFR

● Effect of renal function group on pharmacokinetics of roxadustat and its metabolites

Pharmacodynamics

EPO plasma concentrations and pharmacodynamic parameters were summarized using descriptive by renal

function group, treatment period and time point (for concentrations). EPO plasma concentrations were plotted.

Safety

AEs were coded using MedDRA version 19.0. The number and percentage of subjects with treatment-emergent

AEs (TEAEs) were summarized by SOC and preferred term. Descriptive statistics were used to summarize vital

signs, clinical laboratory tests and continuous cardiac monitoring and changes from baseline. Vital signs and

continuous cardiac monitoring were plotted graphically and time-matched changes from baseline.

Summary of Results/Conclusions:

Populations:

Subject classification and analysis sets can be found in Table 1 and demographic and baseline characteristics

can be found in [Table 2].

Pharmacokinetic Results:

● Relative to subjects with normal renal function, the geometric least squares mean ratio for AUCinf of

roxadustat was 223% and 195% in subjects with severely impaired renal function or with ESRD on HD or

HDF, respectively.

● Roxadustat mean Cmax and terminal t½ were comparable between subjects with severely impaired renal

function or with ESRD on HD or HDF and subjects with normal renal function. Mean tmax was delayed in

subjects with severely impaired renal function but not in subjects with ESRD on HD or HDF [Table 3].

● The mean fu of roxadustat in plasma was 1.06% in subjects with severely impaired renal function and

1.10% to 1.16% in subjects with ESRD on HD or HDF, compared with 0.871% in subjects with normal

renal function [Table 3].

● The mean effective t½ for accumulation of roxadustat was 9.71 hours in subjects with normal renal function,

14.9 hours in subjects severely impaired renal function and 15.1 to 15.9 hours in subjects with ESRD on

HD or HDF, calculated for a dosing interval τ of 48 hours [Table 3].

● No metabolite was present in the plasma of subjects with normal renal function, severely impaired renal

function or ESRD on HD or HDF at a mean AUCinf greater than 10% of total drug-related material

[Table 3], [Table 5], [Table 7] and [Table 9].

● Linear regression analysis indicated that CL/F of roxadustat and CLR of roxadustat and metabolites

generally decreased with decreasing eGFR.



● Roxadustat and metabolites were not significantly cleared by HD or HDF in a 4-hour dialysis session

[Table 4], [Table 6], [Table 8], [Table 10], [Table 15], [Table 16], [Table 17] and [Table 18].

● The percentage of the dose recovered in urine of subjects with normal renal function was 0.978% as

roxadustat, 20.3% as O-glucuronide-roxadustat, 7.21% as O-glucoside-roxadustat and 2.00% as the

sulphate of hydroxy-roxadustat. The urinary excretion of roxadustat and metabolites decreased with

deteriorating renal function [Table 11], [Table 12], [Table 13] and [Table 14].

● One subject with ESRD on CAPD or APD was enrolled in this study and was not used for comparison.

Pharmacodynamic Results:

In subjects with severely impaired renal function or ESRD on HD or HDF, baseline-corrected maximum EPO

values were higher with respect to AUC and Emax than in subjects with normal renal function. Median tmax of

EPO concentrations between 8 and 12 hours did not differ between renal function groups. EPO levels returned

to near baseline at 24 hours postdose in subjects with normal renal function but remained above baseline in

subjects with renal impairment until 36 to 48 hours postdose. Administration of roxadustat in treatment

period 2 (administration before dialysis) resulted in a higher mean AUC and Emax of EPO than administration in

treatment period 1 (administration after dialysis) [Table 19].

Safety Results:

There were no deaths or TEAEs that led to the withdrawal of treatment reported during the conduct of the study.

The highest number and percentage of TEAEs were reported for subjects with normal renal function (12 TEAEs

were reported for 8 [66.7%] subjects). The most commonly reported TEAEs were diarrhea and headache

Table 20 . All TEAEs reported were mild in severity, except for moderate TEAEs of diarrhea, anemia, urinary

tract infection and asthenia. TEAEs considered by the investigator to have a possible or probable relationship to

the study drug comprised tachycardia, diarrhea, nausea, urinary tract infection, headache and maculo-papular

rash.

A serious AE (SAE) of anemia, an SAE (not treatment-emergent) of hyperkalemia and a TEAE of blood

creatine phosphokinase increased were reported during the study. There were no other clinical laboratory

abnormalities that were considered potentially clinically significant by the investigator for any of the clinical

laboratory analyses. Two subjects had alkaline phosphatase values > 1.5 X upper limit of normal; however,

there were no laboratory values that met the criteria for hepatotoxicity or concomitant elevations in alanine

aminotransferase or aspartate aminotransferase with total bilirubin.

Changes reflecting normal diurnal variation were observed for mean systolic blood pressure, diastolic blood

pressure and pulse. One subject with normal renal function had a TEAE of tachycardia. No other individual

vital sign findings were considered by the investigator to be clinically significant.

ECG abnormalities were observed across renal function groups and time points; however, none of these

abnormalities were considered to be clinically significant. For continuous cardiac monitoring, there were no

clinically relevant changes in mean heart rate at time-matched time points on day 1 compared with baseline

(day -1).



CONCLUSIONS:

Overall, the pharmacokinetics of roxadustat and its main metabolites in subjects with different degrees of renal

function were well characterized. In subjects with severely impaired renal function or with ESRD on HD or

HDF, mean roxadustat plasma exposure (AUC) was approximately double compared with subjects with normal

renal function, whereas Cmax was not significantly changed. The mean TER of roxadustat metabolites was

similar in subjects with severely impaired renal function, with ESRD on HD or HDF and normal renal function

and was not greater than 10% of total drug-related material exposure for any of the circulating metabolites.

Roxadustat and metabolites were not significantly cleared by HD or HDF in a 4-hour dialysis session. A single

dose of 100 mg roxadustat was safe and well tolerated in subjects with different degrees of renal function.

Date of Report: 01 Aug 2018



Table 1 Subject Classification and Analysis Sets by Renal Function Group (All Registered Subjects)

Analysis Sets

Normal(n = 12)n (%)

Severe(n = 9)n (%)

ESRD on CAPD or APD

(n = 1)n (%)

ESRD on HD or HDF

(n = 12)n (%)

Total

(n = 34)n (%)

Registered 12 (100) 9 (100) 1 (100) 12 (100) 34 (100)

Safety Analysis Set† 12 (100) 9 (100) 1 (100) 12 (100) 34 (100)

Pharmacokinetic Analysis Set‡ 12 (100) 9 (100) 1 (100) 12 (100) 34 (100)

Pharmacodynamic Analysis Set§ 12 (100) 9 (100) 1 (100) 12 (100) 34 (100)

Treatment Discontinuation 0 0 0 0 0

Investigational Period Discontinuation

0 0 0 0 0

Follow-up Discontinuation 0 0 0 0 0

APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration.

† All enrolled subjects who received at least 1 dose of study drug (roxadustat).

‡ A subset of the safety analysis set for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.

§ A subset of the safety analysis set population for which sufficient pharmacodynamics data was available to facilitate derivation of at least 1 pharmacodynamic parameter and for whom the time of dosing on the day of sampling was known.

Source: End-of-Text Tables 12.1.1.1, 12.1.1.3.1, 12.1.1.4 and 12.1.1.5

Table 2 Summary of Demographic and Baseline Characteristics by Renal Function Group (All Registered Subjects)

ParameterCategory/Statistics

Normal(n = 12)

Severe(n = 9)

ESRD on CAPD or APD

(n = 1)

ESRD on HD or HDF

(n = 12)

Total

(n = 34)

Sex, n (%)

Male 5 (41.7) 6 (66.7) 1 (100) 9 (75.0) 21 (61.8)

Female 7 (58.3) 3 (33.3) 0 3 (25.0) 13 (38.2)

Race, n (%)

White 12 (100) 9 (100) 1 (100) 12 (100) 34 (100.0)

Black or African American 0 0 0 0 0

Asian 0 0 0 0 0

American Indian or Alaska Native

0 0 0 0 0

Native Hawaiian or Other Pacific Islander

0 0 0 0 0

Other 0 0 0 0 0

Age (years)

Mean (SD) 60.1 (11.4) 64.3 (6.6) 56.0 (NA) 56.3 (10.8) 59.8 (10.1)

Median 62.0 65.0 56.0 53.0 61.0

Min - Max 45 - 75 55 - 73 56 - 56 37 - 75 37 - 75

EudraCT Age Category, n (%)

≥ 18 years to ≤ 64 years 8 (66.7) 4 (44.4) 1 (100) 10 (83.3) 23 (67.6)

≥ 65 years to ≤ 84 years 4 (33.3) 5 (55.6) 0 2 (16.7) 11 (32.4)

≥ 85 years 0 0 0 0 0

Table continued on next page




Normal(n = 12)

Severe(n = 9)

ESRD on CAPD or APD

(n = 1)

ESRD on HD or HDF

(n = 12)

Total

(n = 34)

Weight (kg)

Mean (SD) 77.73 (12.40) 90.46 (21.08) 72.60 (NA) 76.78 (14.58) 80.61 (16.33)

Median 78.50 98.00 72.60 76.55 80.20

Min - Max 57.2 - 98.4 52.1 - 114.2 72.6 - 72.6 50.7 - 107.2 50.7 - 114.2

Height (cm)

Mean (SD) 169.2 (9.1) 173.6 (9.3) 182.0 (NA) 169.2 (7.7) 170.7 (8.7)

Median 166.0 173.0 182.0 170.0 170.5

Min - Max 158 - 183 158 - 186 182 - 182 155 - 181 155 - 186

BMI (kg/m2)

Mean (SD) 27.38 (5.52) 30.35 (8.37) 21.92 (NA) 26.72 (4.10) 27.77 (6.01)

Median 26.67 28.83 21.92 26.27 26.82

Min - Max 21.0 - 39.4 16.4 - 45.8 21.9 - 21.9 21.1 - 33.8 16.4 – 45.8

eGFR (mL/min/1.73 m2)

Mean (SD)105.74 (12.32)

16.91 (6.45) 8.76 (NA) 8.59 (2.87) 45.09 (46.28)

Median 102.49 14.22 8.76 8.10 14.14

Min - Max 92.4 - 128.9 9.7 - 27.1 8.8 - 8.8 3.8 - 13.4 3.8 – 128.9

All eligible (i.e., not screen failures) subjects.

APD: automated peritoneal dialysis; BMI: body mass index (weight [kg]/height2 [m2]); CAPD: continuous ambulatory peritoneal dialysis; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; max: maximum; min: minimum; NA: not applicable.

Source: End-of-Text Table 12.1.2.1

Table 3 Plasma Pharmacokinetic Parameters of Roxadustat by Renal Function Group(Pharmacokinetic Analysis Set)


Normal(n = 12)

Severe(n = 9)

ESRD on CAPD or APD(n = 1)

ESRD on HD or HDF

Treatment Period 1(n = 12)

ESRD on HD or HDF


Cmax (ng/mL)

Mean (SD) 6780 (1460) 6730 (1310) 6010 (NA) 6950 (1850) 6910 (1290)

%CV 21.6 19.5 NA 26.6 18.6

Median 6780 6750 6010 7140 7440

Min - Max 4740 – 9400 4540 – 9250 6010 – 6010 3090 – 9700 4890 – 8540

AUCinf (h•ng/mL)

Mean (SD) 39800 (8780) 82500 (18300) 74900 (NA) 77400 (29500) 76600 (28200)

%CV 22.1 22.2 NA 38.1 36.9

Median 38300 78500 74900 73000 73200

Min - Max 28400 – 59200 61300 – 116000 74900 – 74900 43900 – 134000 43100 – 130000

AUClast (h•ng/mL)

Mean (SD) 39600 (8600) 81900 (18200) 74800 (NA) 76300 (28100) 75500 (26800)

%CV 21.7 22.2 NA 36.8 35.4

Median 38200 77900 74800 71300 72700

Min - Max 28400 – 58400 61200 – 116000 74800 – 74800 43800 – 131000 43000 – 125000





Normal(n = 12)

Severe(n = 9)


ESRD on HD or HDF


ESRD on HD or HDF


CL/F (L/h)

Mean (SD) 2.62 (0.536) 1.26 (0.268) 1.34 (NA) 1.45 (0.472) 1.47 (0.510)

%CV 20.4 21.2 NA 32.6 34.7

Median 2.62 1.27 1.34 1.37 1.37

Min - Max 1.69 – 3.52 0.859 – 1.63 1.34 – 1.34 0.745 – 2.28 0.769 – 2.32

tmax (h)

Median 1.00 3.00 3.00 2.00 1.00

Min - Max 0.983 – 3.00 1.00 – 4.00 3.00 – 3.00 0.967 – 5.00 0.967 – 4.00

t½ (h)

Mean (SD) 16.0 (6.75) 18.5 (4.41) 12.5 (NA) 17.2 (6.97) 16.8 (5.55)

%CV 42.3 23.8 NA 40.4 33.0

Median 13.8 17.2 12.5 15.3 15.0

Min - Max 8.31 – 33.0 13.1 – 24.8 12.5 – 12.5 11.3 – 33.0 9.57 – 28.2

Vz/F (L)

Mean (SD) 57.2 (15.2) 33.8 (10.5) 24.1 (NA) 33.8 (11.4) 33.1 (8.22)

%CV 26.6 31.1 NA 33.8 24.9

Median 52.9 35.7 24.1 35.7 33.1

Min - Max 32.6 – 80.5 20.9 – 49.9 24.1 – 24.1 18.6 – 54.9 18.1 – 47.2

Effective t½ 48 hours (h)

Mean (SD) 9.71 (1.35) 14.9 (2.97) 13.3 (NA) 15.9 (4.56) 15.1 (4.14)

%CV 13.9 19.9 NA 28.7 27.4

Median 9.88 13.7 13.3 14.6 14.3

Min - Max 7.47 – 12.2 10.3 – 19.5 13.3 – 13.3 11.1 – 22.7 11.3 – 25.5

Effective t½ 56 hours (h)

Mean (SD) 10.3 (1.60) 15.3 (2.98) 13.2 (NA) 16.1 (4.52) 15.5 (4.25)

%CV 15.6 19.5 NA 28.1 27.4

Median 10.1 14.1 13.2 15.0 14.7

Min - Max 7.53 – 13.3 10.7 – 19.8 13.2 – 13.2 11.4 – 22.6 11.5 – 25.7

fu

Mean (SD) 0.00871 (0.000653) 0.0106 (0.00121) 0.00880 (NA) 0.0110 (0.000859) 0.0116 (0.00114)

%CV 7.5 11.4 NA 7.8 9.8

Median 0.00877 0.0106 0.00880 0.0115 0.0113

Min - Max 0.00765 – 0.00985 0.00834 – 0.0127 0.00880 – 0.00880 0.00962 – 0.0118 0.00998 – 0.0135

Cmax,u (ng/mL)

Mean (SD) 59.1 (13.4) 70.6 (10.3) 52.9 (NA) 76.3 (21.1) 80.0 (16.4)

%CV 22.6 14.6 NA 27.7 20.4

Median 59.2 72.7 52.9 72.8 84.5

Min - Max 36.3 – 82.1 47.2 – 83.2 52.9 – 52.9 36.6 – 109 51.0 – 102

AUCinf,u (h•ng/mL)

Mean (SD) 348 (85.1) 872 (203) 659 (NA) 850 (333) 898 (372)

%CV 24.5 23.3 NA 39.2 41.4

Median 345 857 659 746 859

Min - Max 237 – 520 653 – 1190 659 – 659 513 – 1570 430 – 1600





Normal(n = 12)

Severe(n = 9)


ESRD on HD or HDF


ESRD on HD or HDF


AUClast,u (h•ng/mL)

Mean (SD) 346 (83.7) 864 (198) 658 (NA) 838 (319) 886 (353)

%CV 24.2 22.9 NA 38.1 39.9

Median 344 849 658 728 855

Min - Max 236 – 513 651 – 1180 658 – 658 512 – 1530 429 – 1520

CLu/F (L/h)

Mean (SD) 303 (71.8) 120 (25.6) 152 (NA) 132 (41.3) 130 (54.6)

%CV 23.7 21.3 NA 31.3 41.9

Median 290 117 152 134 116

Min - Max 192 – 423 84.2 – 153 152 – 152 63.7 – 195 62.4 – 233

Vz,u/F (L)

Mean (SD) 6620 (1890) 3160 (855) 2740 (NA) 3110 (1130) 2900 (856)

%CV 28.6 27.1 NA 36.5 29.6

Median 6180 3150 2740 3220 2740

Min - Max 3630 – 9150 2090 – 4800 2740 – 2740 1600 – 5400 1600 – 4740

All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known.

For the ESRD on HD or HDF renal function group: in treatment period 1 subjects received roxadustat after completion of HD and in treatment period 2 subjects received roxadustat prior to the start of HD.

APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; NA: not applicable.

Source: End-of-Text Table 12.4.2.1.1

Table 4 Statistical Assessment of the Effect of Dialysis on Plasma Pharmacokinetics of Roxadustat in Subjects With End-stage Renal Disease on Hemodialysis or Hemodiafiltration (Pharmacokinetic Analysis Set)

Parameter

Treatment Period 1 Treatment Period 2 Geometric LS Mean Ratio

(%)90% CI of Ratio (%)n

Geometric LS Mean n

Geometric LS Mean

AUCinf (h∙ng/mL) 12 72900 12 72200 98.95 (92.40, 105.96)

Cmax (ng/mL) 12 6690 12 6790 101.62 (90.78, 113.76)

AUCinf,u (h∙ng/mL) 12 799 12 831 103.92 (95.43, 113.16)

Cmax.u (ng/mL) 12 73.3 12 78.2 106.72 (92.60, 123.01)


Assessment based on an analysis of variance performed on natural logarithmic-transformed parameters with treatment period as a fixed effect and subject as a random effect.

Ratios and CIs are transformed back to raw scale and values are expressed as percentages.


ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; LS: least squares.




Table 5 Plasma Pharmacokinetic Parameters of O-glucuronide-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)


Normal(n = 12†)

Severe(n = 9)


ESRD on HD or HDF


ESRD on HD or HDF

Treatment Period 2(n = 12‡)

Cmax (ng/mL)

Mean (SD) 49.9 (16.0) 38.1 (19.9) 18.3 (NA) 59.2 (50.9) 55.1 (43.9)

%CV 32.0 52.4 NA 85.9 79.8

Median 46.9 30.8 18.3 37.2 36.5

Min - Max 30.4 – 86.9 23.6 – 89.1 18.3 – 18.3 17.1 – 167 21.2 – 157

AUCinf (h•ng/mL)

Mean (SD) 286 (88.2) 533 (320) 253 (NA) 1080 (1490) 924 (1240)

%CV 30.8 60.1 NA 137.5 133.9

Median 263 446 253 449 382

Min - Max 186 – 491 240 – 1320 253 – 253 181 – 5040 156 – 4420

AUClast (h•ng/mL)

Mean (SD) 277 (87.7) 516 (320) 235 (NA) 1040 (1460) 887 (1190)

%CV 31.6 62.0 NA 140.0 134.0

Median 257 428 235 427 353

Min - Max 174 – 481 228 – 1300 235 – 235 157 – 4980 146 – 4220

tlag (h)

Median 0 0.500 1.00 0 0

Min - Max 0 – 0.500 0 – 1.05 1.00 – 1.00 0 – 1.00 0 – 1.00

tmax (h)

Median 2.00 3.00 4.00 2.00 2.01

Min - Max 1.00 – 3.00 3.00 – 5.00 4.00 – 4.00 1.00 – 8.00 1.95 – 5.00

t½ (h)

Mean (SD) 8.10 (1.86) 15.9 (5.35) 11.1 (NA) 17.5 (9.19) 17.2 (5.97)

%CV 23.0 33.6 NA 52.6 34.7

Median 8.36 14.6 11.1 14.1 16.0

Min - Max 4.54 – 10.5 9.46 – 23.6 11.1 – 11.1 10.0 – 39.8 9.93 – 27.7

MPR

Mean (SD) 0.00495 (0.00159) 0.00432 (0.00224) 0.00225 (NA) 0.00779 (0.00743) 0.00666 (0.00607)

%CV 32.2 51.9 NA 95.3 91.1

Median 0.00463 0.00369 0.00225 0.00451 0.00371

Min - Max 0.00252 – 0.00803 0.00229 – 0.00941 0.00225 – 0.00225 0.00206 – 0.0250 0.00242 – 0.0227

TER

Mean (SD) 0.00478 (0.00156) 0.00402 (0.00203) 0.00214 (NA) 0.00704 (0.00652) 0.00641 (0.00547)

%CV 32.6 50.5 NA 92.6 85.4

Median 0.00457 0.00339 0.00214 0.00414 0.00357

Min - Max 0.00240 – 0.00765 0.00210 – 0.00860 0.00214 – 0.00214 0.00197 – 0.0218 0.00229 – 0.0199



MPR and TER were calculated according to Astellas NCA manual version 2.0; MPR = AUCcorr(M)/AUC(P)and TER = AUClast(corr)(M)/(AUC[P] + sum of AUClast(corr) [M] for all 3 metabolites quantified).

Footnotes continued on next page



APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; MPR: metabolite to parent ratio; NA: not applicable; NCA: noncompartmental analysis; TER: total exposure ratio.

† n = 10 for TER

‡ n = 11 for TER


Table 6 Statistical Assessment of the Effect of Dialysis on Plasma Pharmacokinetics of O-glucuronide-roxadustat in Subjects With End-stage Renal Disease on Hemodialysis or Hemodiafiltration (Pharmacokinetic Analysis Set)

Parameter



Geometric LS Mean n

Geometric LS Mean

AUCinf (h∙ng/mL) 12 610 12 545 89.41 (80.92, 98.78)

Cmax (ng/mL) 12 44.9 12 43.9 97.73 (87.83, 108.74)





APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; LS: least squares.


Table 7 Plasma Pharmacokinetic Parameters of O-glucoside-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)


Normal(n = 12†)

Severe(n = 9)


ESRD on HD or HDF


ESRD on HD or HDF


Cmax (ng/mL)

Mean (SD) 18.3 (9.85) 27.6 (9.98) 10.8 (NA) 21.7 (12.4) 21.9 (11.7)

%CV 53.7 36.1 NA 57.4 53.6

Median 15.9 24.3 10.8 18.5 18.7

Min - Max 8.80 – 39.7 15.8 – 45.7 10.8 – 10.8 8.01 – 52.0 5.41 – 49.9

AUCinf (h•ng/mL)

Mean (SD) 146 (87.8) 495 (296) 164 (NA) 369 (346) 375 (391)

%CV 60.3 59.7 NA 93.7 104.4

Median 109 470 164 241 231

Min - Max 74.4 – 347 158 – 1080 164 – 164 115 – 1320 72.2 – 1410





Normal(n = 12†)

Severe(n = 9)


ESRD on HD or HDF


ESRD on HD or HDF


AUClast (h•ng/mL)

Mean (SD) 121 (84.2) 477 (294) 149 (NA) 347 (338) 342 (370)

%CV 69.6 61.6 NA 97.3 108.1

Median 94.6 440 149 224 203

Min - Max 44.2 – 328 150 – 1050 149 – 149 93.7 – 1280 65.7 – 1380

tlag (h)

Median 0.475 0.500 1.00 0.492 0

Min - Max 0 – 1.00 0 – 1.05 1.00 – 1.00 0 – 2.00 0 – 2.03

tmax (h)

Median 2.99 3.00 4.00 3.00 3.00

Min - Max 1.97 – 3.00 3.00 – 4.00 4.00 – 4.00 2.00 – 8.00 1.95 – 12.0

t½ (h)

Mean (SD) 8.48 (2.97) 15.2 (3.56) 12.7 (NA) 14.6 (5.99) 15.4 (4.36)

%CV 35.0 23.4 NA 41.1 28.3

Median 7.84 15.6 12.7 13.2 15.1

Min - Max 5.89 – 15.4 10.3 – 19.7 12.7 – 12.7 8.35 – 28.8 6.71 – 21.8

MPR

Mean (SD) 0.00246 (0.00126) 0.00406 (0.00195) 0.00150 (NA) 0.00297 (0.00159) 0.00296 (0.00193)

%CV 51.3 48.0 NA 53.5 65.3

Median 0.00218 0.00427 0.00150 0.00237 0.00242

Min - Max 0.000861 – 0.00526 0.00120 – 0.00643 0.00150 – 0.00150 0.00135 – 0.00673 0.00115 – 0.00743

TER

Mean (SD) 0.00228 (0.00114) 0.00378 (0.00179) 0.00143 (NA) 0.00270 (0.00137) 0.00269 (0.00169)

%CV 50.0 47.4 NA 50.7 62.8

Median 0.00208 0.00405 0.00143 0.00219 0.00218

Min - Max 0.000822 – 0.00480 0.00117 – 0.00594 0.00143 – 0.00143 0.00129 – 0.00586 0.00109 – 0.00653



MPR and TER were calculated according to Astellas NCA manual version 2.0; MPR = AUCcorr(M)/AUC(P)and TER = AUClast(corr),(M)/(AUC[P] + sum of AUClast(corr) [M] for all 3 metabolites quantified).


† n = 10 for AUCinf, t½, MPR and TER

‡ n = 11 for AUCinf, t½, MPR and TER




Table 8 Statistical Assessment of the Effect of Dialysis on Plasma Pharmacokinetics of O-glucoside-roxadustat in Subjects With End-stage Renal Disease on Hemodialysis or Hemodiafiltration (Pharmacokinetic Analysis Set)

Parameter



Geometric LS Mean n

Geometric LS Mean

AUCinf (h∙ng/mL) 12 281 11 253 89.91 (79.93, 101.13)

Cmax (ng/mL) 12 18.8 12 19.1 101.33 (91.61, 112.07)







Table 9 Plasma Pharmacokinetic Parameters of Sulphate of Hydroxy-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)


Normal(n = 12†)

Severe(n = 9)


ESRD on HD or HDF


ESRD on HD or HDF


Cmax (ng/mL)

Mean (SD) 635 (230) 453 (225) 435 (NA) 623 (222) 627 (193)

%CV 36.2 49.7 NA 35.6 30.8

Median 561 460 435 622 614

Min - Max 303 – 1140 226 – 866 435 – 435 285 – 903 232 – 915

AUCinf (h•ng/mL)

Mean (SD) 3590 (1150) 6390 (2840) 4590 (NA) 8310 (5910) 7720 (4690)

%CV 32.1 44.4 NA 71.1 60.8

Median 3250 6170 4590 7190 6460

Min - Max 1690 – 5620 2560 – 10500 4590 – 4590 2820 – 20700 2940 – 17700

AUClast (h•ng/mL)

Mean (SD) 3540 (1160) 6330 (2810) 4530 (NA) 8140 (5700) 7560 (4510)

%CV 32.6 44.4 NA 70.0 59.6

Median 3220 6110 4530 7160 6400

Min - Max 1670 – 5590 2530 – 10500 4530 – 4530 2780 – 19700 2900 – 17100

tlag (h)

Median 0 0.500 1.00 0 0

Min - Max 0 – 0.500 0 – 1.05 1.00 – 1.00 0 – 1.00 0 – 1.00

tmax (h)

Median 2.02 5.00 4.00 2.00 2.00

Min - Max 1.97 – 4.00 3.00 – 6.00 4.00 – 4.00 1.97 – 12.0 1.95 – 5.98





Normal(n = 12†)

Severe(n = 9)


ESRD on HD or HDF


ESRD on HD or HDF


t½ (h)

Mean (SD) 15.9 (6.12) 18.6 (6.72) 12.8 (NA) 18.2 (6.59) 18.7 (5.74)

%CV 38.4 36.1 NA 36.2 30.7

Median 14.1 17.4 12.8 17.5 16.9

Min - Max 9.00 – 26.3 11.7 – 35.0 12.8 – 12.8 12.0 – 31.8 11.7 – 30.2

MPR

Mean (SD) 0.0725 (0.0227) 0.0606 (0.0227) 0.0482 (NA) 0.0779 (0.0256) 0.0747 (0.0208)

%CV 31.3 37.4 NA 32.8 27.8

Median 0.0743 0.0710 0.0482 0.0725 0.0745

Min - Max 0.0391 – 0.106 0.0253 – 0.0849 0.0482 – 0.0482 0.0449 – 0.123 0.0472 – 0.107

TER

Mean (SD) 0.0643 (0.0194) 0.0563 (0.0202) 0.0458 (NA) 0.0710 (0.0212) 0.0702 (0.0173)

%CV 30.2 35.9 NA 29.8 24.7

Median 0.0687 0.0656 0.0458 0.0672 0.0697

Min - Max 0.0373 – 0.0893 0.0246 – 0.0779 0.0458 – 0.0458 0.0428 – 0.107 0.0444 – 0.0942



MPR and TER were calculated according to Astellas NCA manual version 2.0; MPR = AUCcorr(M)/AUC(P)and TER = AUClast(corr)(M)/(AUC[P] + sum of AUClast(corr) [M] for all 3 metabolites quantified).


† n = 10 for TER

‡ n = 11 for TER


Table 10 Statistical Assessment of the Effect of Dialysis on Plasma Pharmacokinetics of Sulphate of Hydroxy-roxadustat in Subjects With End-stage Renal Disease on Hemodialysis or Hemodiafiltration (Pharmacokinetic Analysis Set)

Parameter



Geometric LS Mean n

Geometric LS Mean

AUCinf (h∙ng/mL) 12 6890 12 6610 96.05 (89.53, 103.04)

Cmax (ng/mL) 12 580 12 594 102.32 (90.39, 115.82)












Table 11 Urine Pharmacokinetic Parameters of Roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)


Normal(n = 12)

Severe(n = 9†)


ESRD on HD or HDFTreatment Period 1

(n = 12‡)


(n = 12‡)

CLR (L/h)

Mean (SD) 0.0260 (0.0159) 0.00949 (0.00648) 0.00613 (NA) 0.00138 (0.00131) 0.00118 (0.00112)

%CV 61.4 68.3 NA 94.7 94.7

Median 0.0231 0.00775 0.00613 0.00139 0.000891

Min - Max 0.00492 – 0.0585 0.00271 – 0.0252 0.00613 – 0.00613 0.0000195 – 0.00398 0.0000344 – 0.00355

Aeinf (mg)

Mean (SD) 0.978 (0.531) 0.773 (0.588) 0.459 (NA) 0.1000 (0.101) 0.104 (0.145)

%CV 54.3 76.0 NA 100.4 139.3

Median 0.948 0.734 0.459 0.0897 0.0613

Min - Max 0.202 – 2.04 0.264 – 2.27 0.459 – 0.459 0.00111 – 0.303 0.00233 – 0.450

Aeinf%

Mean (SD) 0.978 (0.531) 0.773 (0.588) 0.459 (NA) 0.1000 (0.101) 0.104 (0.145)

%CV 54.3 76.0 NA 100.4 139.3

Median 0.948 0.734 0.459 0.0897 0.0613

Min - Max 0.202 – 2.04 0.264 – 2.27 0.459 – 0.459 0.00111 – 0.303 0.00233 – 0.450

Aelast (mg)

Mean (SD) 0.965 (0.525) 0.791 (0.607) 0.450 (NA) 0.0927 (0.0895) 0.0979 (0.133)

%CV 54.4 76.7 NA 96.5 135.7

Median 0.935 0.679 0.450 0.0836 0.0589

Min - Max 0.200 – 2.03 0.257 – 2.24 0.450 – 0.450 0.00107 – 0.264 0.00226 – 0.414

Aelast%

Mean (SD) 0.965 (0.525) 0.791 (0.607) 0.450 (NA) 0.0927 (0.0895) 0.0979 (0.133)

%CV 54.4 76.7 NA 96.5 135.7

Median 0.935 0.679 0.450 0.0836 0.0589

Min - Max 0.200 – 2.03 0.257 – 2.24 0.450 – 0.450 0.00107 – 0.264 0.00226 – 0.414

CLR,u (L/h)

Mean (SD) 2.99 (1.81) 0.947 (0.815) 0.697 (NA) 0.126 (0.114) 0.105 (0.0932)

%CV 60.5 86.1 NA 90.2 88.9

Median 2.62 0.692 0.697 0.128 0.0819

Min - Max 0.562 – 6.45 0.280 – 3.02 0.697 – 0.697 0.00172 – 0.340 0.00263 – 0.296

Footnotes appear on next page





APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; CV: coefficient of variation; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration; Max: maximum; Min: minimum; MPR: metabolite to parent ratio; NA: not applicable.

† n = 8 for Aelast and Aelast%

‡ n = 8 for CLR, Aeinf, Aeinf%, Aelast, Aelast% and CLR,u


Roxadustat (FG-4592/ASP1517) ISN 1517 CL-0543Renal AnemiaCONFIDENTIAL EudraCT number 2015-002565-28


Table 12 Urine Pharmacokinetic Parameters of O-glucuronide-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)


Normal(n = 12)

Severe(n = 9†)


ESRD on HD or HDF


ESRD on HD or HDF


CLR (L/h)Mean (SD) 114 (44.3) 30.5 (21.0) 18.9 (NA) 2.58 (2.96) 2.12 (2.57)%CV 38.7 68.8 NA 114.7 121.2Median 130 20.4 18.9 0.998 0.825Min - Max 44.6 – 167 7.18 – 61.9 18.9 – 18.9 0.00618 – 7.14 0.000461 – 7.45

Aeinf (mg)Mean (SD) 30.5 (8.53) 12.8 (6.69) 4.77 (NA) 1.29 (1.27) 1.02 (1.05)%CV 28.0 52.3 NA 98.6 103.8Median 34.5 9.64 4.77 1.02 0.717Min - Max 11.4 – 37.3 6.82 – 26.7 4.77 – 4.77 0.00221 – 3.70 0.000154 – 3.20

Aeinf%Mean (SD) 20.3 (5.69) 8.52 (4.46) 3.18 (NA) 0.861 (0.849) 0.677 (0.703)%CV 28.0 52.3 NA 98.6 103.8Median 23.0 6.43 3.18 0.678 0.478Min - Max 7.61 – 24.9 4.55 – 17.8 3.18 – 3.18 0.00148 – 2.47 0.000103 – 2.13

Aelast (mg)Mean (SD) 31.2 (8.73) 12.8 (6.42) 4.79 (NA) 1.17 (1.08) 0.954 (0.934)%CV 28.0 50.1 NA 91.9 97.9Median 35.8 10.8 4.79 1.00 0.722Min - Max 11.9 – 37.6 6.49 – 24.4 4.79 – 4.79 0.00166 – 3.17 0.000115 – 2.85

MPR Based on Aeinf

Mean (SD) 26.2 (14.8) 12.9 (5.47) 6.92 (NA) 11.1 (13.4) 9.16 (9.79)%CV 56.4 42.6 NA 120.2 106.8Median 20.3 11.7 6.92 5.10 4.66Min - Max 12.2 – 62.0 6.08 – 24.3 6.92 – 6.92 1.01 – 38.0 0.0440 – 27.9




† n = 8 for Aelast

‡ n = 8 for CLR, Aeinf, Aeinf%, Aelast and MPR based on Aeinf




Table 13 Urine Pharmacokinetic Parameters of O-glucoside-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)


Normal(n = 12†)

Severe(n = 9‡)


ESRD on HD or HDF

Treatment Period 1(n = 12§)

ESRD on HD or HDF

Treatment Period 2(n = 12¶)

CLR (L/h)

Mean (SD) 99.8 (49.2) 13.3 (13.8) 10.4 (NA) 1.77 (1.61) 1.86 (2.59)

%CV 49.3 104.0 NA 91.0 139.3

Median 101 5.52 10.4 1.23 1.20

Min - Max 33.4 – 181 4.15 – 41.5 10.4 – 10.4 0.00355 – 4.81 0.000505 – 7.49

Aeinf (mg)

Mean (SD) 10.5 (3.28) 4.13 (1.91) 1.71 (NA) 0.410 (0.316) 0.394 (0.511)

%CV 31.2 46.2 NA 77.1 129.4

Median 11.4 3.31 1.71 0.329 0.264

Min - Max 3.87 – 14.6 1.59 – 6.54 1.71 – 1.71 0.000989 – 0.999 0.000158 – 1.41

Aeinf%

Mean (SD) 7.21 (2.25) 2.83 (1.31) 1.17 (NA) 0.281 (0.217) 0.270 (NA)

%CV 31.2 46.2 NA 77.1 NA

Median 7.81 2.27 1.17 0.226 0.181

Min - Max 2.65 – 10.0 1.09 – 4.48 1.17 – 1.17 0.000677 – 0.684 0.000108 – 0.966

Aelast (mg)

Mean (SD) 10.5 (3.15) 4.07 (1.90) 1.68 (NA) 0.404 (0.338) 0.339 (0.479)

%CV 30.1 46.5 NA 83.8 141.3

Median 11.1 4.31 1.68 0.314 0.239

Min - Max 3.88 – 15.1 1.52 – 6.40 1.68 – 1.68 0.000893 – 1.08 0.000148 – 1.39

MPR Based on Aeinf

Mean (SD) 10.2 (6.54) 4.15 (1.36) 2.55 (NA) 3.35 (3.03) 3.98 (4.45)

%CV 64.4 32.7 NA 90.4 111.8

Median 8.88 4.12 2.55 2.05 2.83

Min - Max 3.63 – 25.1 1.97 – 5.74 2.55 – 2.55 0.612 – 8.33 0.0465 – 12.6




† n = 10 for Aeinf, Aeinf% and MPR based on Aeinf

‡ n = 8 for Aelast

§ n = 7 for CLR, Aeinf, Aeinf%, Aelast and MPR based on Aeinf

¶ n = 7 for CLR and Aelast and n = 6 for Aeinf, Aeinf% and MPR based on Aeinf




Table 14 Urine Pharmacokinetic Parameters of Sulphate of Hydroxy-roxadustat by Renal Function Group (Pharmacokinetic Analysis Set)


Normal(n = 12)

Severe(n = 9†)



(n = 12‡)


(n = 12‡)

CLR (L/h)

Mean (SD) 0.735 (0.210) 0.0852 (0.0452) 0.0354 (NA) 0.0121 (0.00685) 0.00895 (0.00865)

%CV 28.6 53.0 NA 56.6 96.7

Median 0.780 0.0667 0.0354 0.0117 0.00802

Min - Max 0.326 – 0.948 0.0533 – 0.191 0.0354 – 0.0354 0.0000517 – 0.0192 0.00000777 – 0.0237

Aeinf (mg)

Mean (SD) 2.55 (0.949) 0.506 (0.291) 0.163 (NA) 0.0756 (0.0527) 0.0486 (0.0547)

%CV 37.2 57.6 NA 69.7 112.5

Median 2.55 0.430 0.163 0.0662 0.0341

Min - Max 1.28 – 4.16 0.217 – 1.18 0.163 – 0.163 0.000386 – 0.160 0.0000534 – 0.143

Aeinf%

Mean (SD) 2.00 (0.746) 0.397 (0.229) 0.128 (NA) 0.0594 (0.0414) 0.0382 (0.0429)

%CV 37.2 57.6 NA 69.7 112.5

Median 2.00 0.338 0.163 0.0520 0.0268

Min - Max 1.01 – 3.27 0.171 – 0.926 0.128 – 0.128 0.000303 – 0.126 0.0000420 – 0.112

Aelast (mg)

Mean (SD) 2.51 (0.932) 0.509 (0.277) 0.154 (NA) 0.0640 (0.0468) 0.0449 (0.0505)

%CV 37.0 54.5 NA 73.1 112.5

Median 2.51 0.432 0.154 0.0572 0.0335

Min - Max 1.27 – 4.10 0.200 – 1.10 0.154 – 0.154 0.000372 – 0.136 0.0000411 – 0.134

MPR Based on Aeinf

Mean (SD) 2.81 (2.26) 0.724 (0.603) 0.278 (NA) 0.774 (0.750) 0.648 (0.632)

%CV 80.3 83.2 NA 96.9 97.5

Median 1.89 0.559 0.278 0.645 0.582

Min - Max 1.08 – 8.20 0.125 – 2.09 0.278 – 0.278 0.138 – 2.38 0.0180 – 1.52







† n = 8 for Aelast

‡ n = 7 for CLR, Aeinf, Aeinf%, Aelast and MPR based on Aeinf




Table 15 Dialysate Pharmacokinetic Parameters of Roxadustat (Pharmacokinetic Analysis Set)


ESRD on CAPD or APD(n = 1†)


(n = 12)

CLD (L/h)

Mean (SD) NA (NA) 0.128 (0.0584)

%CV NA 45.6

Median NA 0.143

Min – Max NA – NA 0.0186 – 0.195

fD

Mean (SD) 0.00371 (NA) 0.0234 (0.0126)

%CV NA 54.0

Median 0.00371 0.0266

Min – Max 0.00371 – 0.00371 0.00229 – 0.0450

All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient plasma concentration data was available to facilitate derivation of at least 1 pharmacokinetic parameter and for whomthe time of dosing on the day of sampling was known.


Dialysate pharmacokinetic parameters account for the incorrect volume unit for 1 subject with ESRD on HD or HDF.


† n = 0 for CLD


Table 16 Dialysate Pharmacokinetic Parameters of O-glucuronide-roxadustat (Pharmacokinetic Analysis Set)




(n = 12)

CLD (L/h)

Mean (SD) NA (NA) 0.00300 (0.00133)

%CV NA 44.2

Median NA 0.00335

Min – Max NA – NA 0.000435 – 0.00474





† n = 0 for CLD




Table 17 Dialysate Pharmacokinetic Parameters of O-glucoside-roxadustat (Pharmacokinetic Analysis Set)




(n = 12)

CLD (L/h)

Mean (SD) NA (NA) 0.00363 (0.00161)

%CV NA 44.3

Median NA 0.00391

Min – Max NA – NA 0.000520 – 0.00585





† n = 0 for CLD


Table 18 Dialysate Pharmacokinetic Parameters of Sulphate of Hydroxy-roxadustat (Pharmacokinetic Analysis Set)




(n = 12)

CLD (L/h)

Mean (SD) NA (NA) 0.0000528 (0.0000268)

%CV NA 50.6

Median NA 0.0000508

Min – Max NA – NA 0.00000671 – 0.000104





† n = 0 for CLD




Table 19 Plasma Pharmacodynamic Parameters of Erythropoietin by Renal Function Group(Pharmacodynamic Analysis Set)


Normal(n = 12)

Severe(n = 8)

ESRD on CAPDor APD(n = 1)

ESRD on HD or HDF


ESRD on HD or HDF


AUCE,last (h∙mU/mL)

Mean (SD) 2650 (1150) 15200 (25400) 6100 (NA) 4870 (3190) 7370 (4040)

%CV 43.5 167.3 NA 65.4 54.8

Median 2240 3490 6100 4500 8410

Min - Max 1490 – 5650 1030 – 75100 6100 – 6100 666 – 9900 889 – 12600

AUCE,last(baseline corrected) (h∙mU/mL)

Mean (SD) 1580 (1110) 13000 (24600) 5250 (NA) 4210 (3230) 5940 (3810)

%CV 70.3 189.1 NA 76.7 64.1

Median 1390 2510 5250 3430 6050

Min - Max 378 – 4410 420 – 72600 5250 – 5250 416 – 9190 479 – 11100

Emax (mU/mL)

Mean (SD) 170 (128) 337 (324) 470 (NA) 260 (200) 409 (225)

%CV 75.7 96.0 NA 77.0 55.1

Median 135 200 470 201 407

Min - Max 30.8 – 501 38.6 – 750 470 – 470 22.6 – 551 35.0 – 702

Emax–baseline (mU/mL)

Mean (SD) 161 (128) 316 (307) 462 (NA) 253 (201) 386 (224)

%CV 80.0 97.2 NA 79.5 58.1

Median 128 191 462 187 350

Min - Max 20.2 – 491 32.9 – 721 462 – 462 20.5 – 544 31.7 – 692

tmax,EPO (h)

Median 8.00 12.00 8.00 10.0 12.0

Min - Max 6.00 – 8.00 8.00 – 24.0 8.00 – 8.00 8.00 – 12.0 8.00 – 12.0

All enrolled subjects who received at least 1 dose of study drug (roxadustat) for which sufficient pharmacodynamic data were available to facilitate derivation of at least 1 pharmacodynamic parameter and for whom the time of dosing on the day of sampling was known.






Table 20 Number and Percentage of Treatment-emergent Adverse Events by Renal Function Group (Safety Analysis Set)

MedDRA v19.0

System Organ Class

Preferred Term

Normal(n = 12)n (%)

Severe(n = 9)n (%)

ESRD on CAPD or

APD(n = 1)n (%)

ESRD on HD or HDFTreatment Period 1(n = 12)n (%)

ESRD on HD or HDFTreatment Period 2(n = 12)n (%)

Overall 8 (66.7) 2 (22.2) 0 4 (33.3) 3 (25.0)

Blood and Lymphatic System Disorders 0 1 (11.1) 0 0 0

Anaemia 0 1 (11.1) 0 0 0

Cardiac Disorders 1 (8.3) 0 0 0 0

Tachycardia 1 (8.3) 0 0 0 0

Gastrointestinal Disorders 2 (16.7) 1 (11.1) 0 3 (25.0) 0

Diarrhoea 1 (8.3) 1 (11.1) 0 2 (16.7) 0

Nausea 0 1 (11.1) 0 1 (8.3) 0

Flatulence 1 (8.3) 0 0 0 0

General Disorders and Administration Site Conditions

0 2 (22.2) 0 1 (8.3) 1 (8.3)

Asthenia 0 0 0 1 (8.3) 1 (8.3)

Pyrexia 0 1 (11.1) 0 0 0

Vessel puncture site haematoma 0 1 (11.1) 0 0 0

Infections and Infestations 2 (16.7) 1 (11.1) 0 0 0

Urinary tract infection 1 (8.3) 1 (11.1) 0 0 0

Nasopharyngitis 1 (8.3) 0 0 0 0

Injury, Poisoning and Procedural Complications

0 0 0 0 1 (8.3)

Skin abrasion 0 0 0 0 1 (8.3)

Traumatic haematoma 0 0 0 0 1 (8.3)

Investigations 1 (8.3) 0 0 0 0

Blood creatine phosphokinase increased 1 (8.3) 0 0 0 0

Musculoskeletal and Connective Tissue Disorders

0 0 0 1 (8.3) 0

Musculoskeletal pain 0 0 0 1 (8.3) 0

Nervous System Disorders 3 (25.0) 1 (11.1) 0 2 (16.7) 1 (8.3)

Headache 3 (25.0) 0 0 2 (16.7) 1 (8.3)

Dizziness 0 1 (11.1) 0 0 0

Psychiatric Disorders 1 (8.3) 0 0 0 0

Bradyphrenia 1 (8.3) 0 0 0 0

Skin and Subcutaneous Tissue Disorders 1 (8.3) 0 0 0 0

Rash maculo-papular 1 (8.3) 0 0 0 0

All enrolled subjects who received at least 1 dose of study drug (roxadustat).

A treatment-emergent adverse event was defined as a newly occurring or worsening adverse event observed after starting administration of study drug up until the end-of-study visit, inclusive.

Sorting order: ascending order by SOC code and ascending order by preferred term code was applied.

Adverse events for ESRD subjects on HD/HDF were assigned to treatment periods according to start date/time of adverse event. Adverse events started in treatment period 1 (with no end date/time or end date/time in treatment period 2) were only assigned to treatment period 1 unless they worsened in treatment period 2.

APD: automated peritoneal dialysis; CAPD: continuous ambulatory peritoneal dialysis; ESRD: end-stage renal disease; HD: hemodialysis; HDF: hemodiafiltration.


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Roxadustat (FG-4592/ASP1517) ISN 1517-CL-0543 Renal Anemia … · 2019-09-27 · Renal Anemia CONFIDENTIAL EudraCT number 2015-002565-28 Aug2018 Astellas Synopsis Page 3of 30 In treatment