rhEPO
/1

6 12
(rhEPO) Epoetin
Epoetin alfa

2014
(US Food and Drug Administration, FDA)


DNA
1





Eprex® 3


1 st Generation
Eprex® Epoetin alfa
Recormon® Epoetin beta


RegMed 2015 Vol. 62 3
(Pharmaceutical and Medical Devices Agency, PMDA)
Teruyo Arato 2011 [4]

Substance) Brand Name Company
2 Hospira/Stada 12/18/2007
[JCR]
2. Retacrit
Duration
Route/
HX 575 (EU)
period (wk 25~28)
response* during wk
( Erypo® group as
interval validity only)
Duration
Route/
SB 309 (EU)
1. Mean weekly
The 95% CI
45 IU/kg/wk)
dose /kg during DB
period
dosage ±14 IU/kg/wk
2. Hb ± 0.6g/dl
04-46 safety trial
with historical data
04-14 safety trial
evaluation period
on HD/n=143
DB: double blind; RD: randomized; MC: multicenter; wk: week; CRF: chronic renal failure
HDHemodialysisIVIntravenous injectionSCSubcutaneous injection
* Hb response was defined as an increase in Hb concentration of 2g/dl from the mean value from the screen/baseline period in the
absence of RBC transfusion during the preceding 4 weeks
# 30%The assumed placebo rate (10%) plus half the difference between active treatment and placebo (20%)
HX-575 (Epoetinalfahexal ® / Binocrit
Novartis AG Hexal Epoetin alfa

/(Pharmacokinetic/Pharmacodynamics, PK/PD)
() /(PK/PD)
Eprex ®(PD effect)
(reticulocyte count)
97%~103%
Study N Route Reference Study Design
INJ-4 6 SC/IV Eprex® /Erypo ® Single dose; pilot study
INJ-5 76 IV Eprex® / Erypo ® Multiple dose (100ug/kg t.i.w. for 4wk);
pivotal study
INJ-6 72 SC Neorecormon® Multiple dose (100ug/kg t.i.w. for 4wk);
characterization of PK
4wk);supportive data for PK
INJ-12 74 SC Eprex® / Erypo ® Multiple dose (100ug/kg t.i.w. for 4wk);
Pivotal study requested by the CHMP
SC IV; t.i.w 3
()
(INJ-9)
Erypo ® 10~13 g/dl 2:1
Erypo ®
( 1~24 )( 25~28 )
Erypo ®(
RegMed 2015 Vol. 62 6
±0.5 g/dl) PP Population ITT Population
ITT Population ± 0.5 g/dl
Epoetin (Change in Epoetin Dose)
56
Primary Endpoint: Mean Absolute Change in Hb (PP Population)
HX575 (n=207) Erypo® (n=118)
Least square means (g/dl) 0.147 ± 0.092 0.063 ± 0.117
Difference 0.084, 95% CI [-0.170; 0.338]
Within Predefined Margin [-0.5; +0.5]
INJ-11 12 91 2:1
Erypo ®
Erypo ®(Internal Validity)
HX575 5-12
≥ 2.0 g/dl
4 HX575 30% (
10%20%)
HX575 61.7%
(37/60)95% 30% ()Erypo®
44.1%
Primary Endpoint: Response Rate
Anti-Epoetin Antibody 4-8
RegMed 2015 Vol. 62 7
6
(
[ 1] 2
(Erypo® /Eprex® )
Eprex® / Erypo ® /

)(
(PRCA)
1) INJ13
2) INJ14
3) INJ17
6
1 Eprex® 2002
2006 coated rubber stopper
(additional pharmacovigilance measure)
85% Epoetin alpha
Biosimilar (:EMA
11/3/2015)
IV
IV
Autologous Predonation
Orthopaedic Surgery SC SC SC*
SCIV # EMA Epoetinalfa HEXAL “ # ”

( 07-08)
(NCT01693029) Procrit ® 2015 3
(week -4~day 1)( 21~28 )

/Silapo
) Epoetin zeta Epoetin alfa
Hospiral Inc.STADA BIOCEUTICALS 2007 12
Epoetin alfa
Retacrit
/Silapo
EMA [3](PK) III

() (PK)
Epoetin (Correction of Epoetin Serum
Concentrations Based on the Protein Content of the Used Batches Erypo ®
(PK profile)
(Equivalence Margin) EMA CHMP (Committee for Medicinal Products for
Human Use) AUC 80-125%Cmax 70-143%

05-05-0000 24 IV Erypo ® Single Dose, Two-Period Cross Over
03-09-0001 48 SC/IV Erypo ® Single Dose, Three-Period Cross Over


Guideline

24
EPO (Hemoglobin) 9 (1:1)
Erypo ®
RegMed 2015 Vol. 62 10
SB3098.07 g/dlErypo® 8.04g/dl(Coprimary Endpoint)
1) 4 EPO (
95%± 14 IU/kg/wk )2) 4
( 95%± 1g/dl )
4 SB309 Erypo®
() 4 EPO (SB309-
Erypo® ) 95%(35.34IU/Kg/wk) 14IU/Kg/wk
Erypo® ()SB309 4 Erypo®
10%
SB309 Erypo®
Mean Weekly Dosage of EPO/kg During the Last 4 wk (IU/Kg/wk)
95% CI Difference
Mean Hb During the Last 4 wk (g/dl)
95% CI Difference
Within predefined [-1; +1]
(±14 IU/kg/wk)
3
45 IU/kg/wk ( EPO Dynepo® EMA
) 40 IU/kg/wk
1 g/dl 95% 35.34
IU/Kg/wk()

04-04 24 12 16
RegMed 2015 Vol. 62 11
(Crossover Design)313
Erypo® 10.5 12.5 g/dl
Erypo® Erypo®
SB309
Erypo® ) 95%± 0.6 g/dl
SB309 Erypo® ()
SB309 04-04 [3]
SB309 Erypo®
Intra-Individual Change (Test-Reference) in Mean Weekly EPO Dose /kg during DB
Period (IU/Kg/wK)
Intra-Individual Change (Test-Reference) in Mean Hb during DB Period (g/dl)
95% CI Difference
(Carry-Over Effect)
4
52
2 12 EPO

12 12
8.7±0.92 g/dl 11.4±1.98 2.7g/dl Epoetin alfa
RegMed 2015 Vol. 62 12
( 12-28 11.3-12g/dl
1.8-3.3g/dl) Epoetin 502.7~598.7IU/Kg
() 12-24 618
745 52 208
(PRCA)
()


EMA Guideline

2014 12 16
1) 4 (21~24 )
2) 4 EPO
RegMed 2015 Vol. 62 13
JR-103, Epoetin Kappa (Epoetinalfa BS [JCR]
)

()
ESPO® ()
Healthy Volunteers 24 IV Placebo Controlled Single Dose
(Exploratory)
Renal Anemia
Patients on
()
II/III 24 329
ESPO®

(52 ) Anti-Epoetin
Antibody
RegMed 2015 Vol. 62 14
PMDA PMDA
1) 500 5 2)
Anemia of Prematurity 3)





1041403614 )
3. EMA. (2007) Retacrit (SB309, epoetin zeta)EPAR-Scientific Discussion.
4. TeruyoA, Teruhide Y., et alExperience of Reviewing the Follow-on Biologics including
Somatropin and Erythropoietin in Japan. Biological 39 (2011)289-292.
5. EMA (2010) Guideline on Non-Clinical and Clinical Development of Similar Biological
Medicinal Products Containing Recombinant Erythropoietins (Revision).