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Biochemical, Functional, Pharmacological and Toxicological Characterization of
RIXUBIS: A Novel Recombinant Human Factor IX Product
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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
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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
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� 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
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– 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
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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
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• 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
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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)
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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
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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
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• 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
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� 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
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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
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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++
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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
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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)
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� 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)
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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
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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
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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
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� 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
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• 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
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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
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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
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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
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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
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• 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
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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
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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
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� 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)
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� 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
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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
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“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
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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
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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)
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– 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**
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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)
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� 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)
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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