Biochemical, Functional, Pharmacological and Toxicological Characterization …€¦ · ·...

Biochemical, Functional, Pharmacological and Toxicological Characterization of

RIXUBIS: A Novel Recombinant Human Factor IX Product

PROPRIETARY - DO NOT COPY OR DISTRIBUTE - Baxter Healthcare Corp.

Factor IX Product

Dr. Peter L. TurecekSenior Director

Biologics R&D – Drug DevelopmentBaxter BioScience, Vienna, Austria

WCBP, Jan. 30, 2014 1

RIXUBIS – Regulatory Background

PHARMACEUTICAL FORM

Powder and solvent for solution for injection (for intravenous use)

PRODUCT NAME

Company Code: BAX326

Trade Name: Rixubis (global name, accepted by US/FDA and NRG [EMA/CHMP])

INN proposed: nonacog gamma


Powder and solvent for solution for injection (for intravenous use)STRENGTHS

250, 500, 1000, 2000, 3000 IU/vial

PACK SIZE (1 CARTON)

1 Vial Rixubis, 1 Vial SWFI (5 ml), 1 BaxJect II

PROPOSED INDICATION(S)

Treatment and prophylaxis of bleeding in patients with hemophilia B (congenital factor IX deficiency).Rixubis is indicated in all age groups.

WCBP, Jan. 30, 2014 2

Agenda

� CMC� Manufacturing

� Biochemical, structural and functional characteriza tion

� Pharmacological and toxicological characterization


� Pharmacological and toxicological characterization

� Differentiation to other FIX products� Relevance of FIXa impurity

� Clinical development

WCBP, Jan. 30, 2014 3

Expression system for rFIX

• Chinese hamster ovary (CHO) cell line

• Co-expression of rFIX with rFurin: enhanced proteolytic cleavage of the FIX propeptide

• No materials of animal or human origin

Why using the CHO cell line?• Extensively studied and well characterized• Platform for the production of several recombinant therapeutic proteins


– Advate & Recombinate (hemophilia A), EPO (anemia), t-PA (acute myocardial infarction), IFN-β1a (relapsing multiple sclerosis), DNase (cystic fibrosis)

• Capable of all post-translational modifications in FIX• Resistant to infection by a wide variety of human viruses

– Adenovirus, Coxsackie, Echovirus, Rhinovirus, Herpesvirus group, Influenza, Paramyxovirus group, Reovirus Group

• Scalable to large volumes• Morfini M et al., Haemophilia (2012), 18, 431–436

− “Production of rFVIIa in CHO-cell cultures eliminates the need for serum products in the culture medium (which can be undefined and of variable qual ity), and facilitates a modern biopharmacologic production process.“

WCBP, Jan. 30, 2014 4

Rixubis (rFIX) Manufacturing Process

Upstream process

Harvest & filtration

Chemostat

Inoculum buildup

InoculumCell bank


Downstream process

Concentration & preformulation

2nd virus inactivation

Purification chromatography

1st virus inactivation

Capture chromatography

Formulation, lyophilization

FDPPreformulated

BDS

WCBP, Jan. 30, 2014 5

Biochemical and pre-clinical studies

Parameters evaluated:

• Physicochemical properties

• Biochemical function


• Biochemical function

• Efficacy (functional analysis)

• Safety (toxicity/tolerability)in animal models

WCBP, Jan. 30, 2014 6

Physico-chemical and biochemicalcharacterization program

Primary structureAmino acid analysis, N-terminal sequencing, and peptide mapping

Glycosylation analysesMonosaccharidesSialic acidN-glycans and O-glycans

GLA analysis High performance anion exchange chromatography

Phosphorylation andsulfation

Acidic modifications of activation peptide


sulfationAcidic modifications of activation peptide

Protein composition

Mass analysis of native protein (MALDI-MS)Size exclusion HPLCHPLC analysis of activated and reduced proteinReducing and non-reducing SDS-PAGE

Higher-order structure FTIR and DLS

Functionality

One-stage clotting assay ; chromogenic assay

Thrombin generation assay

Kinetics of activation by FXIa and FVIIa

Phospholipid binding (Surface plasmon resonance)

WCBP, Jan. 30, 2014 7

The activator reagent used for the one-stage clott ing assay may impact the FIX assay result

• In course of the development of RIXUBIS a number of aPTT reagents were screened and their impact on the assay result was analyzed.

– In general, two types of activator reagents are available (silica based and ellagic acid type reagents)

aPTT reagent Manufacturer Phospholipid Activator type

Stago PTTa Stago Animal Silica

Triniclot automated APTT

Trinity Biotech / Stago Rabbit brain Silica


APTT

DAPTTIN Technoclone Not disclosed Silica

Pathromtin SL Siemens Plant Silica

Cephen Hyphen Biomed Plant Silica

APTT SP Instrumentation Laboratory Synthetic Silica

SynthASil Instrumentation Laboratory Synthetic Silica

Kontact Pacific Hermostasis Rabbit brain Silica

APTT Dutch Diagnostics Animal Silica

Actin FS Siemens Soy Ellagic acid

Actin FSL Siemens Soy, rabbit brain Ellagic acid

APTT ES Helena Rabbit brain Ellagic acid

WCBP, Jan. 30, 2014 8

The one-stage clotting activity of a rFIX product is dependent on the aPTT reagent

60

80

100

120

140

160

180

FIX

(% r

elat

ive

to la

bel)

Triniclot Automated aPTT

Actin FS

Actin FSL

Pathromtin SL

APTT ES (Helena)

SynthASil

Cephen

Dapttin

Stago aPTT


• Two rFIX products (one batch each) were analyzed with the one-stage clotting assay using a panel of aPTT reagents. Reference was the 4th IS for FIX concentrates.

• Factor IX potency results can be affected by the type of aPTT reagent and reference standard used in the assay; differences of up to 40% have been observed

0

20

40

FIX

(% r

elat

ive

to la

bel)

Stago aPTT

APTT SP (IL)

Kontact

Dutch Diagnostic aPTT

Commercial rFIX RIXUBIS

WCBP, Jan. 30, 2014 9

RIXUBIS and commercial rFIX: Variability in FIX recove ry in FIX-deficient plasma when using different aPTT reagents

0

20

40

in v

itro

reco

very

(%

var

iabi

lity)

• RIXUBIS and commercial rFIX (3 lots each) were spiked into immunodepleted FIX-deficient plasma and FIX activity was measured using 8 different aPTT reagents. Reference was a human plasma pool.

• Data illustrate the variability around the mean FIX activity obtained with a panel of different aPTT reagents


� RIXUBIS and a commercial rFIX product show the same degree of variability in FIX activity when measured with one- stage clotting assay in human FIX-deficient plasma

2/10/2014 10Internal use statement goes here.

-40

-20

0

Rixubis Commercial rFIX

in v

itro

reco

very

(%

var

iabi

lity)

Reagents: Silica type: Stago PTTa, Triniclot automated APTT, DAPTTIN, Pathromtin SL, Cephen, APTT SP, Synthasil; Ellagic acid: Actin FS

0

20

40

60

80

100

120

FIX

chr

om (

% r

elat

ive

to

labe

led

clot

ting

act.)

Comparison of clotting and chromogenic potencies ofFIX products

Agreement of chromogenic FIX activity with labeled clotting potency

Chromogenic assay kits:

• Light bars: Hyphen Biophen• Dark bars: Rossix

label


0

• For RIXUBIS the labeled one-stage clotting potency is in good agreement with the chromogenic FIX activity (86 – 104 %)

• The other commercial rFIX product resulted in lower chromogenic FIX activities (65 – 89 %) as compared to the label

• Chromogenic activity was analyzed using test kits from two manufacturers

#A

Commercial rFIXRIXUBIS

#B #C #A #B #C #D #E #F #G

WCBP, Jan. 30, 2014 11

FIX assay sensitive for FIXa

FIX+ FXIa, FX, FVIII, PL-vesicles and CaCl2

FXIa mediated FIX activationFVIIIa/FX complex formation FXa generation

Subsamples (1 - 40 min) + chromogenic substrate

measurement ofFXa concentration CH3OCO-D-CHA-Gly-Arg -pNA

X

Xa

XIa

IX IXa

Ca++

VIII

IXaCa++


FXa concentration

Kinetics of FXa generation depends on - rate of FIX activation- rate of FIXa-FVIII-PL complex assembly- rate of FX activation

FXa generation curve vs.time

0

2

4

6

8

10

0 5 10 15 20 25 30 35 40

Time (min)

FX

a ge

nera

tion

(nM

)

1 U/ml FIX

0.75 U/ml FIX

0.5 U/ml FIX

0.25 U/ml FIX

0.125 U/ml FIX

0 U/ml FIX

CH3OCO-D-CHA-Gly-Arg -pNA

In the absence of FXIa only the effect of the endogenous FIXa is measured

WCBP, Jan. 30, 2014 12

RIXUBIS: Results in FIX assay sensitive for FIXa

Enhanced FIX assaywithout FXIa

1,0

1,5

2,0

FX

a g

ener

atio

n (n

M)

Rixubis (n=13)

commercial rFIX (n=3)

commercial pdFIX (n=1)


� Measurable FIXa levels in the commercial pd FIX and rFIX

� Much less in RIXUBIS

0,0

0,5

1,0

0 10 20 30 40 50

FX

a g

ener

atio

n (n

M)

Time (min)

WCBP, Jan. 30, 2014 13

Influence of FIXa on FIX one-stage clotting assay

10

15

20F

IX c

lotti

ng a

ctiv

ity (

IU/m

L)

7

8

9

10

0 0.2 0.4 0.6 0.8 1 1.2 1.4FIX

clo

ttin

g ac

tivity

(I

U/m

L)% FIXa / FIX


5

10

0 5 10 15 20 25 30 35 40 45

FIX

clo

tting

act

ivity

(IU

/mL)

% FIXa / FIX

� Adding FIXa to RIXUBIS (0.03 to 43% FIXa/FIX) influen ced the FIX 1-stage clotting activity determination

� Clotting activity increased continuously with FIXa c oncentration

WCBP, Jan. 30, 2014 14

Influence of FIXa on non-activated partial thromboplastin time (NAPTT)

100

150

200

250N

AP

TT

clo

ttin

g tim

e (s

ec)

0

50

100

150

200

250

0.0 0.4 0.8 1.2 1.6

NA

PT

T c

lott

ing

time

(sec

)

% FIXa / FIX


0

50

0 5 10 15 20 25 30 35 40 45

NA

PT

T c

lott

ing

time

(sec

)

% FIXa / FIX

� Increasing the FIXa content in RIXUBIS significantly shortened NAPTT

� Rapid decrease in clotting time found from 0 to 0.3 % FIXa/FIX

WCBP, Jan. 30, 2014 15

Influence of FIXa on TGA - thrombin generation assay

150

200

250

300

350P

eak

Thr

ombi

n (n

M)

BAX 326

BAX 326 spiked with 144 mU/mL FIXa (0.2%)

BAX 326 spiked with 14.4 mU/mL FIXa (0.02%)

licensed rFIX


� Adding FIXa to RIXUBIS (0.02 and 0.2% FIXa/FIX) resulted in higherpeak thrombin levels

0

50

100

0 0.2 0.4 0.6 0.8 1

Pea

k T

hrom

bin

(nM

)

FIX in FIX-deficient plasma (IU/mL)

WCBP, Jan. 30, 2014 16

Summary in vitro characterization

• Polypeptide sequence identical to that of commercial rFIX

• Posttranslational modifications are comparable to those of commercial rFIX

• Purity (specific activity) in the same range as of commercial rFIX

• Activation kinetics by FXIa and FVIIa/TF comparable to commercial rFIX


• Binding to synthetic phospholipids comparable for rFIXand commercial rFIX

• RIXUBIS and a commercial rFIX product show the same degree of variability in FIX activity when measured with one-stage clotting assay in human FIX-deficient plasma

• FIXa content (0.01%) about 10-times lower than in commercial rFIX

WCBP, Jan. 30, 2014 17

Nonclinical Animal GLP program

PharmacologyGeneral safety pharmacology in macaquesSafety pharmacology in ratsThrombogenicity/Wessler in rabbits

Primary Pharmacodynamics

Tail tip bleeding in miceCOM (Carotid occlusion model) in miceTEG (Thromboelastography)

PharmacokineticsPK in micePK in rats


Pharmacokinetics PK in ratsPK in macaques

Tox

Single dose toxicity in miceSingle dose toxicity in macaquesRepeated dose toxicity in ratsRepeated dose toxicity in macaquesLocal tolerance in rabbits

Immunology Comparative immunogenicity in mice

WCBP, Jan. 30, 2014 18

Nonclinical Animal Studies – Results Summary /1

Baxter’s nonclinical testing strategy was based on the assumption that Rixubis will not differ significantly to commercial rFIX regarding safety and efficacy.

Study Results

Primary Pharmacodynamics

In vitro aPTT in plasma (rat, macaque, human)

Rixubis can shorten the aPTT of human, macaque and rat plasma.

In vivo mouse modelsTail tip bleeding The primary pharmacodynamic


Pharmacodynamics Tail tip bleeding The primary pharmacodynamic effects of Rixubis were similar to those of commercial rFIX and commercial pdFIX

COM (Carotid occlusion model)

TEG (Thromboelastography)

Safety Pharmacology

Thrombogenicity/ Wessler Test in rabbits

Rixubis was not more thrombogenic than commercial rFIX

General safety pharmacology in macaques

No adverse effect on thecardiovascular or respiratory system

WCBP, Jan. 30, 2014 19

Nonclinical Animal Studies – Results Summary /2

Study Results

Pharmacokinetics PK in mice Similar results were obtained

with Rixubis and commercial rFIX

PK in rats

PK in macaques

Single dose toxicity mice NOAEL: 7500 IU/kgEscalating dose and pilot 1-month repeated dose toxicity study in macaques

NOAEL: 750 IU/kg


Safety profiles of Rixubis and commercial rFIX are co mparable

Toxicology 1-month repeated dose toxicity rats NOAEL: 750 IU/kg

1-month repeated dose toxicity in macaques

NOAEL: 750 IU/kg

Local tolerance rabbitWell tolerated at clinical application route

Immunology Comparative immunogenicity in miceSimilar results were obtainedwith Rixubis and commercial rFIX

WCBP, Jan. 30, 2014 20

In vivo thrombogenicity testing - Wessler test

Item

FIXpre-

activation(%)

Nominal Dose

(IU/kg)Individual Scores

MeanScore

Rixubis Lot 1 0.01 750 0.5 0.5 0.5 0 0.5 0 0.3

Rixubis Lot 2 0.01 750 0 0 0 0 0.5 0 0.08

Rixubis Lot 3 0.01 750 0 0 0 0 0 0 0


Commercial pdFIX 0.03 750 0 0 0.5 0 0.5 0.5 0.25

Commercial rFIX 0.11 750 0 2 0 0 2 0.5 0.75 Rixubis Lot 3+ spiked FIXa 0.11 750 0.5 0.5 0.5 0.5 0.5 0 0.4

� No thrombogenic potential was observed with Rixubis

� The calculated mean score for the commercial rFIX wa s slightly higher

� BAX 326 spiked with FIXa slightly increased the scor eWCBP, Jan. 30, 2014 21

Summary - Nonclinical Animal Studies

• General safety pharmacology studies revealed no adv erse effect.

• Rixubis was not more thrombogenic than commercial rFI X in a rabbit stasis model.

• Toxicity profile similar to that of commercial rFIX (NOAEL of 7500 U/kg in mice).

• No differences in the immunogenicity of Baxter‘s rFIX and


• No differences in the immunogenicity of Baxter‘s rFIX and commercial rFIX in mice.

• No antibody development against CHO proteins.

• PK of rFIX activity in mice, rats, and macaques cons istent between rFIX and commercial rFIX.

• Rixubis was similarly effective at equivalent doses of commercial rFIX.

− Efficacy demonstrated in FIX ko mice using several m odels

WCBP, Jan. 30, 2014 22

Clinical TrialsPh 1/3 Pivotal (n = 60 prophylaxis/15-20 OD)PK (PK crossover with commercial rFIX and repeat-PK),hemostatic efficacy, safety, immunogenicity over 50 EDs to RIXUBIS or 6 months, whichever occurs last, in PTPs ≥ 12 years

Ph 3 Surgery (about 30 major and minor surgeriesin ~ n = 20-30)

Peri- and postoperative hemostatic efficacy and safetyStart: after PK parameters of 16 subjects (descriptive statistics) and hemostatic efficacy data of ≥ 10 bleeds in ≥ 10

RIXUBIS Clinical Development Program

Completed

Interim CSR / extension


statistics) and hemostatic efficacy data of ≥ 10 bleeds in ≥ 10 subjects available and reviewed by DSMB

Ph 2/3 Pediatric (n = 24)PK, hemostatic efficacy, safety, immunogenicity in PTPs < 12 yearsStart: after ≥ 10 subjects completed pivotal and data reviêwedby DSMB

Ph 3 Continuation (n = 100 adult/pediatrics)Long-term hemostatic efficacy, safety, immunogenicity and IRin PTPs 2 – 70 years of age

Ongoing

*EMA/CHMP/BPWP/144522/2009: Guideline on clinical investigation of recombinant and human plasma-derived factor IX products

Completed

WCBP, Jan. 30, 2014 23

PROPRIETARY - DO NOT COPY OR DISTRIBUTE - Baxter Healthcare Corp.WCBP, Jan. 30, 2014 24

RIXUBIS Ph 1/3 Pivotal Clinical Study: Summary

Pharmacokinetics:

� Mean initial IR 0.7 across both age cohorts and consistent over time

� Mean half-life 25.31 ± 3.13 h

Hemostatic Efficacy:

� Median ABR 2 (0.0 – 10.8), mainly due to injury-related bleeds

� 39.1% of subjects (9/23) had „zero bleeds“

� 88.5% of treated bleeds (23/26) treated with 1 or 2 infusions, 57.7% required 1


� 88.5% of treated bleeds (23/26) treated with 1 or 2 infusions, 57.7% required 1 infusion

� Hemostatic efficacy rating ‘excellent’ or ‘good’ in 96.2% (25/26) of all treated BEs

Safety:

� Rixubis was safe and well tolerated in all 23 treated subjects

� No inhibitory or treatment related positive binding anti-FIX antibodies

� No antibodies to CHO proteins

� No thrombotic events or severe allergic reactions

� No (serious) adverse reactions related to Rixubis

RIXUBIS Summary of all clinical data

RIXUBIS was efficacious and safe in pediatric and adult patients with severe and moderately severe hemophilia B in

� Treatment and prevention of bleeding episodes

� Routine prophylaxis

� Perioperative management

Based on:

� Phase 1/3 pivotal study in 73 subjects (completed)


� Phase 1/3 pivotal study in 73 subjects (completed)

� Phase 2/3 pediatric study in 23 subjects (completed)

� Phase 3 surgery study with 14 subjects (interim data, study ongoing)

� Integrated safety summary with 99 unique subjects including data of all 4 RIXUBIS studies with a total of 14,018 infusions of RIXUBIS and covering the following age ranges (data-cut 14 June 2013):

− ≥ 16 years: n = 73− 12 - < 16 years: n = 3− 6 - < 12 years: n = 12− < 6 years: n = 11

WCBP, Jan. 30, 2014 26

Rixubis: Baxter’s rFIX Program

Summary� Development of a recombinant FIX molecule for treatment and

prevention of bleeding in patients with hemophilia B

� Expression in CHO cells

� Plasma-albumin free manufacturing process

� Pre-clinical studies established that Rixubis has a lower FIXa content compared to a commercial rFIX product


compared to a commercial rFIX product

� A pivotal global phase 1/3 clinical trial proceeds to evaluate the pharmacokinetics, efficacy, safety and immunogenicity of Rixubis

� Biologicals License Application (BLA) approved by FDA in June 2013

� MAA filed 30 Oct 2013 – European Union (EMA)

WCBP, Jan. 30, 2014 27

BAX 326: Baxter’s rFIX Program


“As the first recombinant coagulation factor IX indi cated specifically for routine prophylaxis to prevent ble eding, Rixubisbecomes a new weapon in our arsenal to protect Hemo philia B patients ,” said Karen Midthun, M.D., director of the FDA’s Center for Biologics Evaluation and Research. “This approval provides patients and physicians with an alternative treatment option to prevent or reduce the frequency of bleeding episodes .”

WCBP, Jan. 30, 2014 28

Acknowledgment

The Product Development and Preclinical Team @ Baxt er:

J. Windyga, Institute of Hematology and Transfusion Medicine, Warsaw, Poland

T. Lissitchkov, Specialized Hematological Hospital “Joan Pavel”, Sofia, Bulgaria

O. Stasyshyn, Institute of Blood Pathology and Transfusion Medicine of the Academy of Medical Sciences of Ukraine”, Lviv, Ukraine

V. Mamonov, Hematological Research Center, Moscow, Russia

L. Rusen, Prof. Dr. C. T. Nicolau National Institute for Transfusional Hematology, Bucharest, Romania


B. E. Abbuehl, W.-Y. Wong, M.-S. Oh, M. Chapman, B. G. Pavlova, G. Wuerth,B. Valenta

B. Dietrich, S. Kubik, W. Auer, W. Höllriegl, A. Schiviz, B. Reipert, F. Horling, M. Wolfsegger, E.-M. Muchitsch

H. Rottensteiner, G. Schrenk, E. Böhm, M. Reiter, M. Kaliwoda, K. Varadi, H. Gritsch, P. Matthiessen, A. Mitterer, M. Hasslacher, M. Graninger, M. Loeflund, H.-P. Schwarz, F. Scheiflinger

The Product Development and Preclinical Team @ Baxt er:

& the whole R&D, Manufacturing, Quality and Regulatory Affairs team of Baxter BioScience

WCBP, Jan. 30, 2014 29

BACK-UP


FIXa issue on assay and recovery in patients

• Pharmacokinetic studies in hemophilia B have found in vivo recovery of FIX to be uniformly lower than the factor VIII recovery in hemophilia A.

• Recovery of FIX antigen was significantly greater than the recovery of FIX activity

– Liebman HA et al., Kinetics of factor IX activity differ from that of factor IX antigen in patients with haemophilia B receiving high-purity factor IX replacement. Haemophilia.1999 May;5(3):174-80

• The recovery following rFIX infusion (expressed as FIX activity increase in U/dL per IU FIX concentrate/kg body weight infused) was significantly lower than that following the last plasma-derived factor IX (pdFIX)


– Poon MC, et al., Recombinant factor IX recovery and inhibitor safety: a Canadian post-licensure surveillance study. Thromb Haemost. 2002 Mar;87(3):431-5.

• Is the lower recovery a result from rapid binding to high-affinity receptors on platelets and endothelium?

• Methods discrepancy with rFIX: Does chromogenic/clotting discrepancy indicate presence of activated FIX in some FIX products?

• Are FIX products correctly labeled because FIX activity might reflect the sum of FIX and (smaller amounts of FIXa) also contained in the products?

WCBP, Jan. 30, 2014 31

The effect of increasing FIXa content on FIX clotting levels (FIX:C)

Pickering and Gray, 2007 (Poster for Geneva ISTH Co ngress)

• One-stage assay is sensitive to activated FIX.

• Factor IXa at 0.4 IU/1000 IU FIX or above produced a significantly higher potency measurement when assayed by the one-stage clotting method.

Time (hrs)% increase in FIX:C after the addition of FIXa (IU/ml/100 0 IU FIX)

0.2 0.4 1.0 5.0

0 5 ± 5.3 8 ± 1.6* 20 ± 2.1** 29 ± 1.5**


0.5 5 ± 4.1 8 ± 2.4* 4 ± 2.8** 27 ± 1.3**

1.0 5 ± 3.8 9 ± 2.0* 26 ± 2.4** 27 ± 3.4**

2.0 5 ± 3.5 9 ± 3.3* 25 ± 2.7** 26 ± 2.0**

3.0 4 ± 3.1 8 ± 0.5* 20 ± 1.2** 27 ± 1.4*** = p value >0.05 and ** = p value <0.005

At 0 hour, 0.2, 0.4 and 1.0 IU/FIXa/ 1000 IU FIX increased the FIX:C activity of the concentrate by 5 ± 5.3, 8 ± 1.6 and 20 ± 2.1 %, respectively.

Three hours incubation did not return the FIX:C to a level found in the unspiked sample and the activities were found to have increased by 4 ± 3.1, 8 ± 0.5 and 20 ± 1.2%.

WCBP, Jan. 30, 2014 32

FIXa assay issue: Conclusions

� “These results indicate that FIXa can affect the mea surements of FIX clotting activity in therapeutic FIX concentrat es”

� “A FIXa level above 0.4 IU/1000 IU FIX in a therapeu tic product may lead to an apparently higher potency measuremen t when assayed by the one-stage clotting method.”

(Pickering and Gray, 2007)


� Is the presence of FIXa in commercial FIX products (particularly rFIX) the reason for the lower than expected recovery in hemophilia B patients?

WCBP, Jan. 30, 2014 33

RIXUBIS labeling strategy

� Potency of RIXUBIS is measured and assigned with a 1 -stage clotting assay (as requested for pd FIX by EP monograph 2.7.11. Assay of human coagulation factor IX)

� The in-house secondary standard (RIXUBIS standard) i s calibrated against the current international standa rd for FIX concentrates (4th International Standard for FIX WH O standard: WHO 07/182)


standard: WHO 07/182)

� The type of aPTT reagent used prevents from overesti mation of FIX activity and thus lowers the risk of underdo sing of hemophilia B patients

� RIXUBIS contains much less FIXa than commercial pd FI X and rFIX products

WCBP, Jan. 30, 2014 34

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