December 4 2015 Developed through a collaboration between Moderator 2 Maria Elisa Mancuso MD PhD Haematologist Angelo Bianchi Bonomi Hemophilia and Thrombosis Center Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico ID: 481863
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Slide1
Current Trends in the Management of Hemophilia
December 4, 2015
Developed through a
collaboration between:Slide2
Moderator2
Maria Elisa Mancuso, MD, PhD
Haematologist, Angelo Bianchi Bonomi Hemophilia and Thrombosis CenterFondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoDepartment of Pathophysiology and Transplantation
University of MilanMilan, Italy
To submit questions, please text them to 609-400-1695Slide3
Panelists3
Margaret V. Ragni, MD, MPH
Professor of MedicineDivision of Hematology/OncologyDirector
Hemophilia Center of Western PennsylvaniaUniversity of PittsburghPittsburgh, Pennsylvania
Craig M. Kessler, MDProfessor of Medicine and PathologyDirector, Division of CoagulationHemophilia and Thrombosis Comprehensive Care CenterGeorgetown University Medical CenterWashington, DCJohannes Oldenburg, MD, PhDProfessorInstitute of Experimental Haematology and Transfusion MedicineUniversity of BonnBonn, Germany
To submit questions, please text them to 609-400-1695Slide4
Directions
Submitting QuestionsTo submit questions to the panel, please email my.question.is1@gmail.com
OR text 609-400-1695Audience members can submit a question to the faculty at any time during the program. We may not be able to answer all due to time constraints.
Answering the Poll Questions With the Worldwide KeypadTo use the keypad, simply press the number that corresponds with the option you wish to choose.There is no enter button.
If you make a mistake, you can revote at any time during the polling period.At the end of the event please leave the keypads on your chair.4Slide5
Introduction
Maria Elisa Mancuso, MD, PhD
Haematologist,
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Department of Pathophysiology and Transplantation
University of Milan
Milan, Italy
Developed through a
collaboration between:Slide6
Learning Objectives
Identify key data concerning advances in prophylaxis and the use of extended half-life factor replacement for hemophilia A and BEvaluate key clinical issues associated with advances in hemophilia care, including monitoring and genotyping
Determine best practice management strategies through the presentation and discussion of cases6To submit questions, please text them to 609-400-1695Slide7
EHL ProductsHow Far Are We?
EHL products promise a paradigm shift in treatment
Fewer infusions, longer and higher protection, increased adherence, and improved QoLTreatment individualization seems to be the key: not a standard regimen for allTreatment tailoring according to patient characteristics
7To submit questions, please text them to 609-400-1695Slide8
Margaret V. Ragni, MD, MPH
Overview of approved EHL productsImpact of EHL on prophylaxis
Longer half-life vs higher trough levelsManagement of the active adolescent8
EHL and ProphylaxisMoving From the Clinic to the Real WorldTo submit questions, please text them to 609-400-1695Slide9
Monitoring New Products
Rationale for monitoring: when and whoAdapt activity to half-life and vice versa
What is important for healthcare providersWhat is important for patientsAvailable assays and their interpretation9
To submit questions, please text them to 609-400-1695Slide10
Craig M. Kessler, MD
Rationale for monitoringConcept of extended half-life
Challenges to monitoringAvailable assaysDifferent monitoring for different patients10
Monitoring the Standard and New ProductsConundrums of Clinical Care
To submit questions, please text them to 609-400-1695Slide11
The Impact of Genes and Genetics
Hemophilia is a congenital disorder due to genetic mutationsGenotyping as a driver for interpreting clinical phenotype
Exploring the impact of genotype-phenotype on clinical practice and patient managementGenotyping for all?The role of genetic counseling
11To submit questions, please text them to 609-400-1695Slide12
Johannes Oldenburg, MD, PhD
What do we know about genotype-phenotype relationshipWhat can we do with genotyping?
Who is a candidate?The role of genetic counseling12
Genotyping and PhenotypingScientific and Practical ImplicationsTo submit questions, please text them to 609-400-1695Slide13
EHLs and Prophylaxis
Moving From the Clinic to the Real World
Margaret V. Ragni, MD, MPH
Professor of Medicine
Division of Hematology/OncologyDirectorHemophilia Center of Western PennsylvaniaUniversity of PittsburghPittsburgh, PennsylvaniaDeveloped through acollaboration between:Slide14
14
First case of hemophilia in US
1803
First whole blood transfusion
1840Queen Victoria -- hemophilia1843Deficiency of factor VIII, IX1930s
Plasma
1936
Cryoprecipitate
1964
Clotting factor: VII, IX, PCC
1960-80s
FIX,
FVIII genes cloned
1982-84
Liver transplant: cure
1985
Recombinant factor VIII, IX, VIIa
1992-99
Extended Half-Life VIII, IX
2010-15
Queen Victoria’s Family
Treatment Timeline
To submit questions, please text them to 609-400-1695Slide15
Introduction
Exciting time in clot factor management:Extended half-life proteins for hemophilia
Paradigm shift in treatment:Fewer infusionsLonger protection from bleedsImproved quality of lifeReduced immunogenicity
15To submit questions, please text them to 609-400-1695Slide16
Overview
FDA-approved EHL productsrFVIIIFc: Recombinant factor VIII-FC fusion protein
rFIXFc: Recombinant factor IX-Fc fusion proteinPEG-rFVIII: pegylated, full-length recombinant factor VIII Phase 3 pivotal studies
Mahlangu J, et al: rFVIIIFc fusionaPowell JS, et al: rFIXFc fusion
bCollins PW, et al: glycoPEGylated factor IX (N9-GP)c Konkle BA, et al: PEG-rFVIIIdSafety, efficacy, and pharmacokineticsImplementation in clinical settingCase discussion16a. Mahlangu J, et al. Blood
. 2014;123:317-325; b.
Powell JS, et al. N Engl J Med
. 2013;369:2313-2323;
c
. Collins PW, et al.
Blood
. 2014;124:3880-3886; d. Konkle BA, et al.
Blood
. 2015;126:1078-1085.Slide17
The Hemophilias
Defect Deficient, defective FVIII, FIXGenetics
X-linked DisorderClinicalBleeds into joint, musclesSeverity
Mild (> 5%) traumaticModerate (1-5%) traumaticSevere (< 1%) spontaneous, traumaticMorbidity
Spontaneous joint bleedsGoalPrevent bleeds by maintaining > 1% Half-LifeFVIII: 8-12 h; FIX: 12-24 h DosingFVIII: 3/wk; FIX: 2/wk17Prince AlexeiTo submit questions, please text them to 609-400-1695Slide18
Factor Level and Bleed RiskProphylaxis: FVIII, IX dosing to prevent spontaneous bleeds
18
Risk:
Spontaneous bleeds increase as time < 1% increases
Goal: Maintain factor > 1% to prevent spontaneous bleeds
Collins PW, et al.
J Thromb Haemost
.
2009;7:413-420.
Predicted Bleeds per Year
Time With Factor VIII < 1 IU dL
-1
, h/wk
-1Slide19
Prophylaxis Landmark Study
Randomized Trial -- Hemophilia A age < 30 mo (N = 65)Aim --
To determine if prophylaxis (3,4/wk) prevents joint disease19
Prophylaxis
(N = 32)Standard Therapy(N = 33)P ValueNo joint damage (MRI), %
93
55
.002
No joint damage (X-ray), %
96
81
.10
Median no.
joint bleeds, no. patients/y
.20
4.35
< .001
Inhibitor formation, %
6.2
0
.24
Life-threatening
bleeds, %
0
9
.24
CVAD infections, %
91
76
.19
Conclusion:
Prophylaxis prevents joint damage and bleeds
Manco-Johnson MJ, et al.
N Engl J Med
. 2007;357:535-544.
To submit questions, please text them to 609-400-1695Slide20
Problems With ProphylaxisProphylaxis
Reduces joint bleedsa
Reduces joint damage by MRIStandard of care for severe hemophiliaProblemsRequires frequent injections: FVIII 3/wk; FIX 2/wkInvasive, costly: 50% of adults avoid prophylaxis
bPorts, access: most children receive ~1/wk dosec20
a. Manco-Johnson MJ, et al.
N Engl J Med
. 2007;357:535-544; b. Walsh CE, Valentino LA.
Haemophilia
. 2009;15:1014-1021;
c
. Ragni MV, et al.
Haemophilia
. 2012;18:63-68.Slide21
EHL FVIII and FIX ProteinsFc-IgG fusion proteins
rFIXFca
rFVIIIFcbAlbumin-fusion proteinsrFIX-FPcPegylated/glycoPEGylated proteinsN9-GP
dN8-GPeBAY 94-9027fPEG-rFVIII
g21a. Powell JS, et al. N Engl J Med. 2013;369:2313-2323; b. Mahlangu J, et al. Blood. 2014;123:317-325; c. Santagostino E, et al. ISTH 2015. Abstract OR347; d. Collins PW, et al. Blood. 2014;124:3880-3886; e. Tiede A, et al. J Thromb Haemost. 2013;11:670-678; f. Coyle TE, et al. J Thromb Haemost. 2014;12:488-496; g. Konkle BA, et al. Blood. 2015;126:1078-1085.Slide22
EHL Proteins22
Protein
Phase
Dose
(IU/kg)SubjectsABRResponse
Inhibitor
Half-life
Recombinant
FVIII EHL Proteins
rFVIIIFc
a
III
25-50
2/wk
N = 165
2.9
97.8%
0.0%
1.5-fold
(19
h)
N8-GP
b
III
50
q 4d
N = 175
1.3
95.5%
0.0%
1.5-fold
(18.3 h)
BAY 94-9027
c
III
25-60
1-2/wk
N
= 132
1.5
--
0.0%
1.4-fold
(18.7 h)
PEG-rFVIII
III
45
2/wk
N = 101
1.9
95.9%
0.0%
1.4-1.5-fold
Recombinant FIX EHL Proteins
rFIXFc
e
III
50-100
q 7-10d
N = 61
2.0
97.3%
0.0%
2.5-fold
(82 h)
rFIX-FP
f
III
50-75
q 7-14d
N = 63
--
98.6%
0.0%
> 5.0-fold
(105 h)
N9-GP
g
III
40
q wk
N = 29
1.0
100.0%
0.0%
2.5-fold
(93 h)
a.
Mahlangu J, et al.
Blood
. 2014;123:317-325; b.
Giangrande P, et al.
J
Thromb
Haemost
.
2015;13. Abstract OR212
; c.
Boggio LN, et al.
Blood.
2014;124. Abstract 1526
; d. Konkle BA, et al.
Blood
. 2015;126:1078-1085; e.
Powell JS, et al.
N Engl J Med
. 2013;369:2313-2323;
f
. Santagostino E, et al. ISTH 2015. Abstract OR347; g. Collins PW, et al.
Blood
. 2014;124:3880-3886. Slide23
EHLs: Clinical Trials Update
Phase 3 Clinical TrialsSafe, well tolerated
Improved t½, recovery; delayed clearanceNo inhibitor developmentNo allergic reactionsNo thrombosis
Efficacy comparable to rFVIII, rFIXSafety comparable to rFVIII, rFIX 23
To submit questions, please text them to 609-400-1695Slide24
EHL Dosing24
Republished with permission of the American Society of Hematology from
Mahlangu J, et al. Blood. 2014;123:317-325; permission conveyed through Copyright Clearance Center, Inc.; From Powell JS, et al.
N Engl J Med. 2013;369:2313-2323. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
SHL: 25-25-50 U/kg TIW rFVIIIEHL: 25/65 U/kg BIW rFVIIIFcSHL: 75-100 U/kg BIW rFIXEHL: 75-100 U/kg 1/wk rFIXFc3%1%Slide25
EHL: Potential Implications
Longer duration factor level > 1% factorLess frequent infusions
Fewer ports, ED visitsFewer interruptions of school, workImproved QoL25
To submit questions, please text them to 609-400-1695Slide26
EHL Improves Half-life, AUC
A FVIII level > 1% was sustained in ~50% of adults receiving rFVIIIFc 50 U/kg q5d in phase 2 trial
Yet they had continued protection against bleeds Prolonged AUC (time spent > 1%) prevents bleeds26
Republished with permission of the American Society of Hematology from Mahlangu J, et al. Blood. 2014;123:317-325; permission conveyed through Copyright Clearance Center, Inc.Slide27
AUC: SHL vs EHL27
Mahdi AJ, et al.
Br J Haematol. 2015;169:768-776.
Upper Panel:
SHL
Lower Panel:
EHL
For a once-weekly EHL protein to achieve a similar trough to an alternate-day SHL protein, the peak will need to be higher, with a longer time spent below a "critical level" and fewer peaks during the week
SHL = standard half-life; EHL = extended half-life
To submit questions, please text them to 609-400-1695Slide28
FVIII Trough and Prophylaxis
Prophylaxis StudyDose to achieve FVIII ≥ 1% differs by patient
Thus, individualized dosing may be more effectivePK-Guided Prophylaxis Study in 34 severe hemophilia A patientsIndividual dose to achieve trough 1% VIII determined
Individual trough to prevent bleeds determinedIndividual PK and bleeds for optimal prophylaxis modeled
Median FVIII at Bleed (N = 34)Joint Bleeds: 3.43 U/dL (0-42)Other Bleeds: 2.87 U/dL (0-11) Spontaneous: 2.71 U/dL (0-26)28Spotts G, et al. Blood. 2014;14. Abstract 689.To submit questions, please text them to 609-400-1695Slide29
FVIII Trough and Prophylaxis29
Spotts G, et al.
Blood. 2014;14. Abstract 689.Trough, %
Number
Bleed-Free, %≥ 115/3444
≥ 3
20/34
59
≥ 5
26/34
76
≥ 10
29/34
85
≥ 15
32/34
94
≥ 20
33/34
97
≥ 25
33/34
97
≥ 30
34/34
100
Minimally Effective Trough Target Trial
Findings:
76% predicted to be bleed-free at VIII
≥ 5%; and 94% at > 15%
Conclusion:
Individualized PK provides personalized prophylaxis regimen
To submit questions, please text them to 609-400-1695Slide30
Bleed type, frequency
Will EHLs delay onset and reduce type and frequency of bleed? Prophylaxis
Will EHLs simplify, encourage; at what dose and what trough?Chronic joint diseaseWill EHLs slow onset of joint disease, severity, surgery? Inhibitor formation
Will EHLs reduce inhibitor frequency, titer, or shorten ITI?30
What Is the Real-World Impact of EHLs?To submit questions, please text them to 609-400-1695Slide31
Prophylaxis, bleeds, joint disease
To demonstrate reduced ABR, infusion, time < 1%, improved joint preservation and lifestyleProspective data collection: PINK
LINK, QoL, PK, Cost-Effect Studies Inhibitor formation, toleranceTo demonstrate reduced immunogenicity, shorter and simpler immune tolerance induction
Prospective data collection: INHIBIT Study, HIRE Study31
Impact of Implementing EHLsTo submit questions, please text them to 609-400-1695Slide32
At HCWP, since 2014 FDA licensure: N=73 switched to EHL
32
Hemophilia A(N = 52)
Hemophilia B(N = 21)
Switched to rFVIIIFcSwitched to rFIXFcPTPs (2 doses/wk)< 1 y (N = 4) < 18 y (N = 33) rFVIIIFc ITI (N = 3)
PTPs
(1 dose/7-10/d)
Ragni
, M. unpublished data.
Impact of EHL: Local Experience
To submit questions, please text them to 609-400-1695Slide33
Prophylaxis
Initiate at 1st bleed once weeklyBreakthrough bleeds
Escalate to twice weeklyInhibitor prone-children Dose once weekly before bleedInhibitor patients
Initiate ITI as alternate day therapyPersonalized Rx Use trough to adjust dose to
> 1% Growth spurt Monitor q 3-6 months in children, adolescents Ongoing bleeds Discuss treatment duration, frequencySports Assess troughs and dose frequency 33 Impact of EHL: ConsiderationsTo submit questions, please text them to 609-400-1695Slide34
What Is Optimal Therapy?"Quotable Quotes" for consideration
The optimal trough is ~1% EHLs are for severe patients only
EHLs are for prophylaxis patients only EHLs should not be used in infants EHLs are not for inhibitor patients34
To submit questions, please text them to 609-400-1695Slide35
What Is Optimal Therapy?“Quotable Quotes” for consideration:
The optimal trough is ~1%EHLs are for severe patients only
EHLs are for prophylaxis patients only EHLs should not be used in infantsEHLs are not for inhibitor patients35
NOT NECESSARILY
NOT NECESSARILYNOT NECESSARILY
NOT NECESSARILYNOT NECESSARILY
To submit questions, please text them to 609-400-1695Slide36
EHL and Inhibitor FormationWhat Is the Evidence?
Fc contains Tregs that suppress immune responsea
Ig antibodies coupled to haptens induce Ag-specific tolerancebIn hem A mice, weekly rFVIIIFc reduces inhibitors (vs rFVIII)b EHL activate
, expand T regulatory epitopes, reduce immunogenicityFc Fusion proteinsc,d
Albumin Fc proteinse Pegylated proteinsf,gInhibitor formation: lower titer, more rapid toleranceh36a. Rath T, et al. Crit Rev Biotechnol. 2015;35:235-254; b. Lei TC, Scott DW. Blood. 2005;105:4865-4870; c. Borel Y. Immunol Rev. 1980;50:71-104. d. De Groot AS, et al. Blood. 2008;112:3303-3311; e. Basto AP, et al. Mol Immunol
. 2015;64:36-45; f. Chapman AP. Adv Drug Deliv Rev
. 2002;54:531-545. g. Hershfield MS. In Poly(ethylene glycol): chemistry and biological applications. 134-44. h. Malec LM, et al. ASH 2015. Abstract 3531.Slide37
Patient Management Issues
Is clinical or laboratory monitoring necessary to manage patients using long-lasting products?Is PK needed to determine optimal dose?
Are breakthrough bleeds sufficient monitoring?When should the prophylaxis dose be increased, decreased?37
To submit questions, please text them to 609-400-1695Slide38
Clinical Case: Presentation
Adolescent active in sports on prophylaxis15-year-old with moderately severe hemophilia B
Basketball practice twice/wk, game weekendsCurrent rFIX prophylaxis: 1-2/wk at nightRecent hip bleed, and recurrent ankle bleeds Growth spurt, next visit in 6 months
38To submit questions, please text them to 609-400-1695Slide39
How would you manage this patient’s prophylaxis?Remain on his regimen
Increase frequency of the current rFIX regimenSwitch to EHL every 7 days Switch to EHL every 10 days
39Clinical Case: QuestionsSlide40
Clinical Case: QuestionsWe decided to switch the patient to an EHL.
What starting dose would you use?75 U/kg once weekly
75 U/kg every 10 days100 U/kg once weekly100 U/kg every 10 days40Slide41
Clinical Case: Management
Adolescent active in sports on prophylaxis15-year-old with moderately severe hemophilia B
Basketball practice twice/wk, game weekendsCurrent rFIX prophylaxis: 1-2/wk at nightRecent hip bleed, and recurrent ankle bleeds Growth spurt, next visit in 6 months
41
75 U/kg/wk100 U/kg/wkPeak
1.01
--
U/mL
Trough
0.01
0.02
U/mL
Begun on rFIXFc 75 U/kg/wk:
Breakthrough BleedsSlide42
Conclusion: Personalized Approach
Sports
Invincibility with responsibility Transition issuesSelf-infusion, adjusted to practice, games One size does not fit all
Get peaks, troughsGrowth spurtGet frequent weights!
Infants/childrenOnce-weekly EHL prophy may be optimalRealistic expectationsAssess adherence, arthropathyAdherenceMay not improve with EHLChronic arthropathyMay not improve with EHL42To submit questions, please text them to 609-400-1695Slide43
Monitoring the Standard and New Factor Replacement Products
Conundrums of Clinical Care
Craig M. Kessler, MD
Professor of Medicine
and PathologyDirector, Division of CoagulationHemophilia and Thrombosis Comprehensive Care CenterGeorgetown University Medical CenterWashington, DCDeveloped through acollaboration between:Slide44
Presentation Overview
Rationale for monitoring: Understanding PKChallenges to monitoring
Available assaysCase study44
To submit questions, please text them to 609-400-1695Slide45
Hemophilia Clinical Trial Pipeline45
Hemophilia With Inhibitors
New Recombinants
BAX817 –
rFVIIaTransgenic rhFVIIaLonger-actingOBI-1 – rpFVIIICB813d – rVIIa analogueCSL689 – rVIIa:albumin fusionrVIIa:CTPHemophilia ALonger-actingrFVIII:Fc*BAY94-9027 – PEGylated rFVIIIBAY855 – PEGylated rFVIII*
CSL627 – SingleChain rFVIIINew Recombinants
simoctogog alfa – rFVIIIoctocog alfa sucrose plasma protein-free– rFVIII
GreenGene F - rFVIII
Hemophilia B
New Recombinants
IB1001 – rFIX
BAX326 – rFIX
*
Longer-acting
rFIX:Fc
*
CSL654 – rFIX:albumin fusion
Cross-Segment
Longer-acting
MC710 – pdFVIIa + pdFX
ACE910 – SC bispecific Ab
siRNA vs Antithrombin
* = ApprovedSlide46
Patients with mild/moderate hemophilia (ie, residual factor levels ≥ 1%) bleed less frequently and have less arthropathy
> 1% selected for existing economics and treatment protocol burden
Venous access and frequency of dosing 2-3X/wk for FVIIIAnimal models show that every single bleed matters and can cause irreversible damage when it occurs in the brain, solid organs, or joints1% trough level is too low to prevent all bleeds, particularly with active lifestyles or those with established joint damage
"FVIII/FIX levels of 1% limit the ability for full social integration equivalent to someone without a bleeding disorder. It is wholly insufficient to accommodate major or accidental trauma causing bleeding. The fear of traumatic injury remains a constant." 46
Skinner MW.
Haemophilia
. 2012;18:3-5.
Premise of Prophylaxis Therapy in Hemophilia
To submit questions, please text them to 609-400-1695Slide47
Peak range
May help prevent activity-related bleeds
a,bArea under the curveMay help prevent subclinical bleeding
aTrough
May help prevent spontaneous bleedinga,cUnderstanding the Curve47
Area under the curve
Peak following infusion
Trough
Time
Percent Factor Level
Infusion
Peak range
a. Collins PW, et al.
Haemophilia
. 2011;17:2-10; b. Collins PW.
Haemophilia
. 2012;18:131-135; c.
Collins PW, et al.
J Thromb Haemost
. 2009;7:413-420.Slide48
NHF has rated certain activities based on their perceived risk
48
Anderson A, et al.
Playing It Safe: Bleeding Disorders, Sports and Exercise. 2005.
1Safe1.5
Safe to Moderate risk
2
Moderate risk
2.5
Moderate to Dangerous risk
3
Dangerous
Risk Associated With Activity Is Highly Variable
To submit questions, please text them to 609-400-1695Slide49
Increased activity level is associated with an increased propensity to bleed
More factor is required to reduce the level of risk to the same as category 1There is still a high risk of bleeding at 100% factor level
49
Broderick CR, et al.
JAMA
. 2012;308:1452-1459. Copyright © 2012 American Medical Association. All rights reserved.
Category 2 vs Category 1 Activities Are Associated With Increased Risk of BleedingSlide50
Category 3 activity is associated with the highest propensity to bleed
Even more factor is required to reduce the level of risk to the same as category 1 There is still a risk of bleeding at 100% factor level
50
Broderick CR, et al.
JAMA
. 2012;308:1452-1459. Copyright © 2012 American Medical Association. All rights reserved.
Category 3 Activities Associated With
Highest
Risk of BleedingSlide51
Most patients experienced between 0-2 bleeds per year
Bleeding rate did not vary by the week of the year
Most bleeds occurred within 1 h of activity51
Bleed Window
Broderick CR, et al.
JAMA
. 2012;308:1452-1459. Copyright © 2012 American Medical Association. All rights reserved.
Data Highlight Transient Nature of Bleed RiskSlide52
Increased potential for collisions is associated with an increase in the risk of bleeding
Increasing factor levels can decrease the risk of bleeds
1% increase in factor = 2% decrease in riskMost bleeds associated with physical activity are apparent within an hourSuggests the need to have highest factor levels during the time of highest risk
52
Broderick CR, et al.
JAMA
. 2012;308:1452-1459.
Key Takeaway Lessons From Broderick 2012
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US Joint Outcome Study53
Manco-Johnson MJ, et al.
N Engl J Med
. 2007;357:535-544.
Episodic
No routine infusions
Treatment of Acute Joint Bleed
40 U/kg immediately
20 U/kg at 24 & 72 h
20 U/kg alternate days until complete resolution of
pain and normal physical exam, up to 4 weeks
Prophylaxis
rFVIII 25 U/kg alternate days
Exit: Joint Outcome on
MRI & X-Ray at Age 6 y
Age < 30 months
FVIII ≤ 2%; no inhibitors
≤ 2 joint hemorrhages
Randomize
Study ProtocolSlide54
Primary Outcome54
Manco-Johnson MJ, et al.
N Engl J Med
. 2007;357:535-544.
Median number of joint bleeds
Prophylaxis vs Episodic arm:
0.2 vs 4.35/y
Prophylaxis → 83% relative risk reduction
Proportion of
Children With No Cartilage/Bone Changes
on MRI in the
6 Index Joints
at
Study Exit
20
0
80
100
Episodic -- 55%
Prophylaxis -- 93%
40
60
Number of Children, %
To submit questions, please text them to 609-400-1695Slide55
55
From Manco-Johnson M, et al. N
Engl
J Med. 2007;357:535-44. Copyright © 2007 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
MRI Score
10
9
8
7
6
5
4
1
0
0
5
10
15
20
Number of Clinically Evident Index-Joint Hemorrhages
2
3
25
Some joints with no hemorrhages had high MRI scores
Damaged
joints
Some joints with >10 hemorrhages had no bone/cartilage damage
Subclinical Bleeds by Joint Score in All PatientsSlide56
In a separate study:
Patients with hemophilia A or B (n=26) received prophylaxisJoints were asymptomatic
5/26 patients had a worsening of MRI findings without experiencing a joint bleedHigher MRI scores were correlated with higher rates of clinically asymptomatic ankle joints over a 10-year periodEarly morphologic changes in clinically asymptomatic ankles can be detected using MRI, despite adequate prophylaxis
56
Olivieri M, et al.
Haemophilia
. 2012;18:369-374.
Identification and Long-term Observation of Early Joint Damage by MRI
To submit questions, please text them to 609-400-1695Slide57
Correlation between the number of clinically evident hemarthroses and joint failure defined by MRI is weak, leading the investigators to suggest that:
"…chronic microhemorrhages into the joints or subchondral bone in young boys with hemophilia causes deterioration of joints without clinical evidence of hemarthroses and that prophylaxis prevents this subclinical process."
What is the effect on other body structures? Brain, kidney, etc57
Manco-Johnson MJ, et al.
N Engl J Med
. 2007;357:535-544.
Key Finding of the US Joint Outcome Study
To submit questions, please text them to 609-400-1695Slide58
A low factor level may not provide sufficient protection during activities
No correlation was found between bleeding frequency and trough FVIII levels (prospective randomized ESPRIT study)a
Patients may require a higher factor level during activitiesA personalized approach allows the physician to tailor patients’ regimens to their individual lifestyle
58
a. Gringeri A, et al.
J Thromb Haemost.
2011;9:700-710
.
A Personalized Approach May Benefit Active Individuals
With
Hemophilia
To submit questions, please text them to 609-400-1695Slide59
Half-life extended rFVIII/rFIX products could facilitate maintenance of desired trough levels during prophylaxis
Some patients may need higher trough levels because of frequent bleeding, presence of target joints, or higher physical activity
Pharmacokinetic profiles may be as individual as lifestyles AgeGenotypes
Clearance mechanismsVWF activity levelsThrombophilia factors
FVIII/FIX activities of at least 15-30% would allow for more "carefree" or "more normal" lifestyles; no monitoring would be necessary; no joint bleeds would be expectedBut at what cost to the individual and to society?59How Can We Reasonably Start to Achieve Higher Trough Levels?Slide60
PK responses to various clotting factor concentrates and the doses administered are patient dependent with inter-individual variance
Dosage of clotting factor replacement required to reach any predetermined plasma level can be optimized for each individual patient according to PK responses
Comparing PK characteristics between new and currently available concentrates is a mandatory regulatory prerequisite to establish bioequivalence before licensing60Pharmacokinetic Studies Why Perform Them?
To submit questions, please text them to 609-400-1695Slide61
Cumbersome and demanding (particularly in children)
Require long washout Crossover with existing licensed product
3 different lots for regulatory purposes and patients concerned about switching10 sampling points on the decay curveMay not reflect real-life conditions such as bleeding, surgery, or exercise
61Pharmacokinetic Studies Why NOT Perform Them?
To submit questions, please text them to 609-400-1695Slide62
Cmax of loading dose for on-demand treatment and for prompt pain relief
In vivo recovery is not a useful predictor for dose optimization for prophylaxisa
Half-life, AUC, and trough for maintenance therapy by repeated bolus administration or continuous infusion Which PK parameter takes into account dose, half-life, AUC, and trough expressing the total exposure of patient to the concentrate?Clearance, because it is the dose/AUC ratio
62
a. Björkman S, et al.
Haemophilia
. 2007;13:2-8.
C
max
Elimination Half-life
AUC
Trough
Which Is the Most Important PK Parameter to
Evaluate
the Efficacy of Replacement Therapy?
To submit questions, please text them to 609-400-1695Slide63
Individual PK can vary by agea
and withinb the patients themselvesIn pediatric and adult studies, t
1/2 has been shown to range from 6 to 25 hours for recombinant FVIIIc,d63
a. Turnheim K.
Exp Gerontol
. 2003;38:843-853; b. Collins PW, et al.
J Thromb Haemost
. 2010;8:269-275; c. Tarantino MD, et al.
Haemophilia
. 2004;10:428-437; d. Blanchette VS, et al.
J Thromb Haemost
. 2008;6:1319-1326.
Postinfusion
Time, h
Individual PK Can Influence When the Individual
Is
at RiskSlide64
The Cmax increased proportionally to the dose, but it was comparable between equal doses of rFVIII and rFVIIIFc
The total exposure (AUCINF
) also increased proportionally to the dose AUCINF of rFVIIIFc was 1.48- and 1.56-fold greater than that of rVIII at 25 IU/kg (P = .002) and 65 IU/kg (P < .001), respectively64
Republished with permission of the American Society of Hematology, from Powell JS, et al.
Blood
. 2012;119:3031-3037; permission conveyed through Copyright Clearance Center, Inc.
Time After Start of Infusion, h
Time After Start of Infusion, h
Plasma FVII Activity, IU/
dL
Plasma FVII Activity, IU/
dL
PK Profiles in Patients With Low Doses
and
High DosesSlide65
As the level of VWF increased, the CL of rFVIIIFc and of rFVIII decreased
As the level of VWF increased, the t1/2 of rFVIIIFc and of rFVIII increased
Fc moiety of rFVIIIFc does not alter the role of VWF in protecting FVIII from clearance65
VWF Antigen, %
VWF Antigen, %T1/2, hCL, mL/h/kgR2= 0.5415P = .0012R2= 0.5492P
= .0016
R2= 0.6403P
= .0003
R
2
= 0.7923
P
< .0001
Republished with permission of the American Society of Hematology, from Powell JS, et al.
Blood
. 2012;119:3031-3037; permission conveyed through Copyright Clearance Center, Inc.
VWF Ag Levels Influence CL and t1/2 of FVIII Activity
After
Infusion of
rFVIII
or
rFVIIIFc
Slide66
Important Conclusions
Adult terminal t1/2 approx 82 h, but initial decay is much faster
Error bars reflect individual variabilityIn the published trial, interval adjusted to keep trough > 1% in this study armThe slope varies on a log scale
66
From Powell JS, et al.
N
Engl
J Med
. 2013;369:2313-2323. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Duration of Factor IX Activity With Recombinant
Factor IX and rFIXFc at a Dose of 50 IU/kg
1 w = 168 h
Time Course of FIX Activity With Standard and
EHL
Factor ProteinsSlide67
67
Republished with permission of the American Society of Hematology, from
Negrier
C, et al.
Blood
. 2011;118:2695-2701; permission conveyed through Copyright Clearance Center, Inc..
The mean t
1/2
of N9-GP was 93 h which was approximately 5 times longer compared with the patients' previous FIX product (
P
< .001)
Time, h
FIX Activity, U/mL
Example of N9-GP vs Standard Factor IX ActivitySlide68
Facilitation of PK Monitoring
EMA, WHO, WFH recommend a PK study for every patient who starts a new clotting factor concentrate in order to optimize the patient-specific treatment regimens, taking into account inter-subject variability in drug dispositiona,b
If 10- or 12-point PK is too demanding, reduced 4- or 5-point timing may be used without losing significant informationcPK population models (for FVIII products): results from 3 clinical trials used Bayesian analysis for individual parameters (eg, age, BW, activity score, joint score, etc) Critical time points: 1 h and 9-12 h
68
a. Berntorp E, et al.
Haemophilia
. 2003;9:1-4; b. Shapiro AD, et al.
Haemophilia
. 2005;11:571-582; c. Morfini M, et al.
Haemophilia
. 2015;21:204-209
.Slide69
Requires large population Children and adults differ
Product specificRequires validation: UK and Canadian studies (NCT02528968 and NCT02061072) are under way to collect published and unpublished PK data on all products
Web application: 2-3 samples/patient; no washout used; 18 patientsaBased on physical activity, joint score, and PK parameters, through level chosen and most appropriate dosage for each patient calculated
69
a. Bello IF, et al. ASH 2015. Abstract 3534
.
Facilitation of PK Monitoring (cont)
To submit questions, please text them to 609-400-1695Slide70
The assay method definitely matters
Single stage (PTT-based assays) performance depends on the activating substance; preferred worldwide due to simplicity, automation, and cost control
Kaolin Silica Ellagic acid
27 APTT reagents, 16 FVIII-deficient plasmas; 15 ref plasmas commercially available, making a potential combination of 6480 different APTT assaysaChromogenic assay (probably more uniform)
Risk is at least twofold If the assay underreports true level, we might overtreat If the assay/drug combination doesn’t reflect 60 years of PTT history, we might be fooling ourselves to aim for 1% or any arbitrary levelShould industry create central labs? This will allow interlab comparisons 70
a. UK NEQAS for Blood Coagulation: Survey 203, Version 1. 2014.
Assays
Lab Differences
To submit questions, please text them to 609-400-1695Slide71
Product
Chromogenic/OSCA
Comments
B-Domain Truncated rFVIII (NovoEight)
~ 1Why different from ReFacto? Only slight difference in B-domain linker; tendency of OSCA to underestimate values at high levels and to overestimate values at low levels (NovoEight gp)25-100% variation with different OCSA reagents
Chromogenic testing only
B-domain deleted rFVIIIFc
1.27
OSCA slightly overestimated activity at low levels; no specific APTT reagent discrepancies
B-domain deleted rFVIII, pegylated --
(Bay94-9027)
Some silica OSCAs (little or no activity measured)
With ellagic acid OSCA saw analyser and reagent differences. Rectified by product standard; Chromogenic assay accurate
Pegylated
full-length
rFVIII
~1
All but 2 APTT reagents would be in range
Human-cl rhFVIII
~1
FVIII deficient plasma for APTT needs to have VWF
Sc rFVIII with truncated B-domain and covalent linkage between heavy and light chain
Discrepant between chromogenic and one-stage (more in line with ReFacto)
Use chromogenic assay
71
EMA. Workshop Report. 2014.
Characterization of New FVIII Products
Activity
Assay Assessment
To submit questions, please text them to 609-400-1695Slide72
Product
Chromogenic/OSCA
Comments
glycopegylated rFIX
OSCA with SynthAFax – correlates with chromogenic assaysPegylation affects activity in 1-stage assay, APTT reagent dependent; Chromogenic correlates with non-clinical/clinical efficacyrFIX-FcOSCA with ellagic acid reagent; underestimate with silica and kaolin
Chromogenic kits see lot to lot differences in 1 of kits; See variability in field study of post-infusion testing of spiked samples (0.05-0.8 IU/mL) with OSCA
rFIX –Albumin (rIX-FP)
~1
One-stage clotting assay used
Full-length rFIX
good agreement between one-stage and the 2 chromogenic assays
one-stage clotting activity of a rFIX product is dependent on the APTT reagent when the 4th IS for FIX concentrates is used as the reference. Chose silica type
72
EMA. Workshop Report. 2014.
Characterization of New FIX Products
Activity Assay Assessment
To submit questions, please text them to 609-400-1695Slide73
Measuring rFVIIIFc in the Lab73
Sommer JM, et al.
Haemophilia
. 2014;20:294-300.
To submit questions, please text them to 609-400-1695Slide74
74
Sommer JM, et al.
Haemophilia
. 2014;20:294-300.
Label Activity, IU mL
-1
Mean
Ratio CS
(n = 11 labs)/OS (n = 30 labs)
Mean CS/OS Ratio at Individual Labs
(n =
11*)
Range of CS/OS Ratios at Individual Labs
(n =
11*)
0.80
1.12
1.12
0.81-1.78
0.20
1.02
1.07
0.48-1.61
0.05
0.86
1.00
0.58-1.60
rFVIII
Label Activity, IU mL
-1
Mean
Ratio CS
(n = 11 labs)/OS (n = 30 labs)
Mean CS/OS Ratio at Individual Labs
(n =
11*)
Range of CS/OS Ratios at Individual Labs
(n =
11*)
0.87
1.26
1.27
0.87-2.18
0.22
1.26
1.37
0.59-2.63
0.054
1.04
1.24
0.65-2.08
rFVIIIFc
*Eleven of 30 participating laboratories performed both the one-stage and chromogenic substrate assays.
rFVIIIFc Chromogenic vs One-Stage Assays
To submit questions, please text them to 609-400-1695Slide75
32-year-old man with severe hemophilia B
He is undergoing on-demand treatment
He has 12 bleeds per year with mild arthropathy developing in his shoulderHe has to stock shelves in his warehouse job at the end of every month75
Clinical Case
PresentationTo submit questions, please text them to 609-400-1695Slide76
76
Time
Percent Factor Level
Infusion
For this activity, where on the curve would you want his factor level to be?
A
B
A
B
Clinical Case
QuestionsSlide77
77
How would you achieve this goal?On-demand at the end of the month
ProphylaxisPK testing to determine when to treatClinical Case
QuestionsSlide78
78
What product would you use? Standard half-life product
Extended half-life productClinical Case QuestionsSlide79
Discussion79
Individualized prophylaxis requires PK data and lifestyle considerations, age, etc
Each of the new products will continue to confound how we monitor factor activity levels for each new product in a number of patientsWe can overcome these issues by "overtreating" and always maintaining trough levels > 15%
The original economics of maintaining a 1-3% trough level may not be realistic as pts become more active Chromogenic assays may be the way to go, cost not withstanding; HTCs will need both assay techniques
To submit questions, please text them to 609-400-1695Slide80
Genotyping and Phenotyping: Scientific and Practical Implications
Johannes Oldenburg, MD, PhD
Professor
Institute of Experimental Haematology and Transfusion Medicine
University of Bonn
Bonn, Germany
Developed through a
collaboration between:Slide81
Why Mutation Analysis?
Genetic counselingGenotype -- Phenotype information
Degree of severity Inhibitor riska,bSeverity of bleeding, clinical coursec,d,e
Assay discrepanciesf,g81
a. Oldenburg J, Pavlova A. Haemophilia. 2006;12:15-22; b. Gouw SC, et al. Blood. 2012;119:2922-2934; c. Santagostino E, et al. J Thromb Haemost. 2010;8:737-743; d. Carcao MD, et al. Blood. 2013;121:3946-3952, S1; e. Pavlova A, Oldenburg J. Semin Thromb Hemost. 2013;39:702-710; f. Oldenburg J, Pavlova A. Hamostaseologie. 2010;30:207-211; g. Trossaërt M, et al. J Thromb Haemost. 2011;9:524-530.Slide82
82
26 exons
186 kb
FVIII-gene
Exon
26
14
22
1
cDNA
7 kb
Mature protein
NH
2
COOH
2332 aa
300 kDa
A1
A2
B
A3
C1
C2
Activated
protein
A1
A2
A3
C1
C2
Me
2+
Factor VIII
From Gene to Protein
To submit questions, please text them to 609-400-1695Slide83
Mutation Profile in Hemophilia A83
Severe
phenotype
Severe and
nonsevere
phenotype
Mutation Type
Absolute
(n = 850)
Relative, %
Intron 22 Inversion
302
35.7
Intron 1 Inversion
8
0.9
Stop Mutation
79
9.3
Small del/ins
86
10.2
Large Deletion
25
3.0
Splice Site
22
2.6
Missense Mutation
323
38.2
Oldenburg J, et al.
Haemophilia
.
2006;12
Suppl
6:15-22.
To submit questions, please text them to 609-400-1695Slide84
84
Mechanism of the Intron 22 Inversion
Factor VIII
Factor VIII To submit questions, please text them to 609-400-1695Slide85
DNA extraction: high molecular weight genomic DNA (needed for intron 22 inversion analysis)
PCR amplification of fragments Inversion 22 inversion testing Intron 1 inversion is analyzed by PCR
Sequencing exons and flanking intronic regions (33 fragments) MLPA-testing (duplication screening in all samples with no mutation found)Time2 wk in the routine setting
Can speed it up to 2-3 d85
F8 Gene Analysis Stepwise ApproachTo submit questions, please text them to 609-400-1695Slide86
Testing Strategy86
Hemophilia A
Intron 1/22 inversions
Positive
Result
Sequencing the
F8
gene
Negative
Large
duplications
Positive
Result
Negative
Hemophilia B
Sequencing the
F9
gene
Result
Large
duplications
Positive
NegativeSlide87
Hemophilia Genotype/Phenotype87
Pavlova A, et al.
Semin Thromb Hemost. 2013;39:702-710.© Georg Thieme Verlag KG.
Environmental Factors
Hemophilia PhenotypeGeneticFactorsPatient DependentBehaviorBody habitus
First joint bleed
Non-patient Dependent
FVIII:C Lab Assays
Treatment
Factor VIII/IX Genotype
Co-inherited Genetic Variables
Severe
Nonsevere
Small del/ins in A stretch of FVIII
Non-conserved splice-site mutations
Missense mutations
Missense mutations with discrepancy between FVIII:C assays
FV Leiden
Thrombophilic gene mutations
Polymorphisms in FVII
Platelets function
Polymorphisms in inflammatory,
immunoregulatory
cytokines genesSlide88
88
Very large number of different gene defects
Majority of mutations are unique to the kindred
Intron 1/22 Inversions
Nonsense
Splice-site mutations
Small del/ins
Large deletions
Severe hemophilia
Missense mutations
Mild/moderate hemophilia
Sometimes: Severe hemophilia
The protein is formed but is functionally less active/inactive
No protein is formed
Genotype/Phenotype
Degree of SeveritySlide89
Characteristics of Patients With Severe Hemophilia Who Are Mild Bleeders
89
Santagostino E, et al. J Thromb Haemost. 2010;8:737-743.
Cases, Mild Bleeders
(n = 22)All Controls(n = 50)Median age, y (IQR)32 (27-43)
38 (30-44)
Hemophilia B, no (%)
7
(32)
4 (8)
Median age at first bleed,
mo
(IQR)
42 (12-75)
12 (12-24)
Median age at first joint bleed,
mo
(IQR)
84 (36-108)
24 (21-48)
Median number of bleeds/y (IQR)
0 (0-1)
20 (9.5-31.5)
Median factor consumption, IU kg
-1
y
-1
(IQR)
60 (37-158)
1957
(862-2238)
Median orthopedic joint score (range)
3 (0-7)
15 (9-24)
Median
Pettersson
score (range)
18 (9-25)
35 (25-46)
Median FVIII antigen, IU dL
-1
(IQR)
1.4 (< 0.5-3.5)
< 0.5 (< 0.5-0.7)
Median FIX antigen, IU dL
-1
(IQR)
9.9 (0.8-148)
< 0.5 (< 0.5-0.8)
Median ETP in PRP, n
m
x min (IQR)
850 (476-1145)
460 (137-830)
Null mutations, no. (%)
2/20 (10)
28/48 (58)
PTG20210A, no. (%)
1/21 (5)
2 (4)
FV
Leiden, no. (%)
0
3 (6)Slide90
Mutation Type and Inhibitor Prevalence 90
0
Prevalence of Inhibitors
100
7550
25
Schwaab R, et al.
Thromb Haemost.
1995;74:1402-1406;
Oldenburg J, Pavlova A.
Haemophilia
. 2006;12:15-22
.
Large
Deletions
41%
Nonsense
31%
Small
Deletions
16%
Intron 22/1
Inversions
21%/17%
Missense
5%
Splice site
3%
Single
Domain
25%
Multi
Domain
88%
Light
chain
40%
Heavy
chain
17%
Non A-Run
21%
A-Run
3%
C1-C2
10%
Non C1-C2
3%
Slide91
91
Eckhardt CL, et al.
Blood.
2013;122:1954-1962.
Heavy ChainLight ChainDistribution of F8 Missense Mutations Associated
With Inhibitor DevelopmentTo submit questions, please text them to 609-400-1695Slide92
Genotype/PhenotypeInhibitor Formation
92
High risk
NON-NULL MUTATIONSMissense mutations -- synthesis of an endogenous but functionally abnormal protein
Low riskNULL MUTATIONS Severe rearrangements in the F8 gene preclude the synthesis of the protein
To submit questions, please text them to 609-400-1695Slide93
Mutation Profile in Hemophilia B93
Giannelli F,
et al.
Nucleic Acids Res
. 1998;26:265-268.To submit questions, please text them to 609-400-1695Slide94
Hemophilia A: 25-30%Hemophilia B: 3-5
%Hemophilia A: 80% null mutation, 20% non-null mutations
Hemophilia B: 20% null mutations, 80% non-null mutationsThe proportion of null mutations (meaning absence of endogenous protein) determines the risk of inhibitor formation.
94Oldenburg J, Pavlova A.
Haemophilia. 2006;12:15-22. Gouw SC, et al. Blood. 2012;119:2922-2934.Epidemiology: Incidence InhibitorsHemophilia A vs Hemophilia BSlide95
The "Good" vs "Bad" Risk Patient
Factors Contributing to Low RiskGenetic Background
Negative family historyNon-severe hemophiliaWhite origin
Missense mutationIL10 134 negativeTNF alpha A2 negative
CTLA4-318 T positiveEnvironmentalEarly prophylaxisAbsence of danger signalsType of concentrate95
Factors Contributing to High Risk
Genetic Background
Positive family history
Severe hemophilia
African origin
Null mutation
IL10 134 positive
TNF alpha A2 positive
CTLA4-318 T negative
Environmental
Early event-based treatment
Intensive treatment
Continuous infusion
Danger signals
Type of concentrateSlide96
96
2.
Individualizing therapy regimen
1.
Determining the a priori risk of inhibitor formation (F8 gene analysis)Low inhibitor risk:"Classical therapy" depending on the bleeding Prophylaxis follows symptoms of bleeding
High inhibitor risk:
"
Early prophylaxis
"
low-dose FVIII exposure, before onset of bleeding, avoiding
"
danger
"
signals
Prophylaxis at age 9-10 months, once-weekly 250 IU
Kurnik K, et al.
Haemophilia.
2010;16:256-262.
Perspective
Individualization of Therapy Regimens
To submit questions, please text them to 609-400-1695Slide97
Genotype/Phenotype Assay Discrepancies
97
Discrepancies 1/3 of cases with nonsevere hemophilia
or
FVIII:C one-stage > FVIII:C chromogenic
FVIII:C one-stage < FVIII:C chromogenic
NO consensus to which method most accurately represents the FVIII cofactor function in vivo and gives clinically relevant FVIII:C levels
Poulsen AL, et al.
Haemophilia.
2009;15:285-289.Slide98
Assay Discrepancy
Assay discrepancy is related to the geography of the point mutationIn the intersection between A-domains
FVIII:C chromogenic is lower than the one-stage assay. In some instances the phenotype may shift to moderate hemophilia A For example, at thrombin cleavage sites, converse assay discrepancy is foundFVIII:C chromogenic is near normal while the factor VIII:C by one-stage technique corresponds to mild hemophilia
98To submit questions, please text them to 609-400-1695Slide99
Assay DiscrepanciesChromogenic vs One-Stage Ratio
99
Factor
Chromogenic/One-Stage Ratio
Causes of DiscrepancyMissense mutations in F8Localized in the A1-A2-A3 domain interfaces
≤ 0.5
These mutations are associated with reduced stability of the
FVIIIa
heterodimer
Effect is minimized
in the one-stage assay and the prolonged incubation time of the first step of the chromogenic assay favors a higher rate of A2 dissociation leading to reduced FVIII activity
Located close to or within thrombin cleavage
sites, or FIX- or VWF-binding sites
≥ 2
These mutations affect thrombin activation or FVIII binding to
FIXa
or VWF
The one-stage assay is sensitive
to alterations in thrombin binding or cleavage of FVIII whereas the chromogenic assay is not
Peyvandi F, et al.
J Thromb Haemost
. In press.Slide100
Mutations are localized in the A1-A2-A3 domain interfaces
100
Pipe SW,
et al.
Blood. 2001;97:685-691; Yadegari H, et al. Haematologica. 2013;98:1315-1323.
Literature
Bonn
Chromogenic Assay > One Stage AssaySlide101
Issues of Discrepant FVIII:C Assays101
Setting the cutoff level to define discrepancy
Which assay to use for defining degree of severity and for monitoring treatment?Understanding the mechanisms of discrepancy?Is there a relationship to the assay discrepancies in Bdel rFVIII concentrates/potency issue with one-stage/chromogenic assay?
To submit questions, please text them to 609-400-1695Slide102
New Products ChallengeAssays
ProblemsOne stage vs chromogenic
Potency determination and patient monitoringOptionsUse of chromogenic assayOne stage: use of ellagic acid-based APTT reagentsConcentrate specific reference standards
Conversion factorsGo with a product compatible for the local assay setup
102To submit questions, please text them to 609-400-1695Slide103
QuestionWhich mutation type indicates a low risk of inhibitor formation?
Nonsense mutationLarge deletionMissense mutation
Intron 22 Inversion103Slide104
Summary104
Genotyping has become standard in hemophilia A and B
Genotyping is nowadays mainly driven by the phenotype information less by genetic counselingGenotype is informing about Degree of severity, bleeding frequency
Risk of inhibitor formationFVIII assay discrepanciesGenetics may further be determinants for half-life, subsequent individual dosing, and manifestation of joint arthropathySlide105
Question and Answer Session Submitting Questions
To submit questions to the panel, please email my.question.is1@gmail.com OR
Text 609-400-1695ORUtilize the microphones in the center aisle105Slide106
CME CreditTo receive CME credit:
Complete the evaluation online at www.medscape.org/townhall/current-trends-in-hemophilia The URL will be accessible until December 18, 2015
106
Developed through a
collaboration between: