and Immunogenicity Peyman Eshghi Prof of Pediatric Hematology ampOncology Pediatric Congenital Hematologic Disorders Research Center Mofid Children Hospital Shahid Beheshti University of Medical sciences ID: 917686
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Slide1
Slide2Switching between coagulation factors
and Immunogenicity
Peyman Eshghi
Prof. of Pediatric Hematology &Oncology
Pediatric Congenital Hematologic Disorders Research Center
Mofid
Children Hospital
Shahid Beheshti University of Medical sciences
Tehran,12-10-1397
Slide3What is recombinant CFCs and their classification?
Why recombinant therapy in haemophilia?
What is the risk of inhibitor development with recombinant products?
How should we switch from
pdFC
to
rFC
?
Slide4Slide5Slide6B domain does not seem to have any function with respect to FVIII clotting activity
3
Truncated B domain
6
HC, heavy chain
; LC, light chain
Thim L et al. Haemophilia 2010;16:349
‒
59
Ezban M et al. Euro J Haematol 2014;93:369
‒76Toole JJ et al. Proc Natl Acad Sci 1986;83:5939‒42
C2
C1
A3
A2
A1
a1
a2
a3
A2
A1
a1
a2
C2
C1
A3
a3
Full length FVIII
Truncated B domain
1
372
740
1648
2020
2173
2332
1
372
741–750
1638–1648
2020
2173
2332
750
1637
HC (1–740)
B domain (741–1648)
LC (1649–2332)
HC (1–740)
LC (1649–2332)
B
B
Slide7Extensive purification process to yield a
homogeneous product
Developed to obtain a highly purified product and to minimize risk of viral contamination
1
Detergent inactivation
Helps inactivate and eliminate
enveloped viruses
Also serves to concentrate the product
2
Immunoaffinity
chromatography
Selects intact molecules
3
Anion-exchange chromatography
Separates molecules by their charge
5
Gel filtration
Utilizes size
to
remove
FVIII
multimers
and
other contaminants
to yield a highly homogeneous product
4
Nanofiltration
4
20-nm double filter has been shown to remove
small
nonenveloped
viruses based on size exclusion
7
WFH guidelines: gold standard in viral
safety
Slide88
Recombinate
(CHO)
Full Length
rFVIII
Xyntha
BDD
rFVIII
(CHO)
Kogenate
-FSFull Length rFVIII (BHK)AdvateFull Length rFVIII (CHO)Nuwiq
BDD
rFVIII (HEK)
EloctateBDD rFVIII
fused to Fc (HEK)
turoctocog
alfaBDD rFVIII (CHO)
ReFacto
AF
BDD
rFVIII
(CHO)
Approved rFVIII products
Slide9What is recombinant CFCs and their classification?
Why recombinant therapy in haemophilia?
What is the risk of inhibitor development with recombinant products?
How should we switch from
pdFC
to
rFC
?
Slide10Global shortage of safe Plasma
compared to increased CF request and
consumption regardless of strict donor
selection,PCR,NAT
test,etc
.
Safety with regard to blood-borne
pathogens:
non-enveloped
viruses (eg, B19V and PARV4),perions,etcPurity :minimize non clotting-factor protein exposureScalability and reproducibility of the manufacturing processAllows for molecular engineering to create improvementsLonger acting, fewer infusionsMany protraction principles theoretically mitigate immunogenicityAlternative routes of administrationWhy recombinant therapy in haemophilia?
Slide11HCV and HIV transmission successfully reduced, but safety concerns remain
1
:
Plasma-derived products may contain infectious
non-enveloped viruses
(
eg
, B19V and PARV4)
2,3
:
Not all inactivated by heat methods1Not affected by solvent/detergent procedures1Available viral-inactivation methods unable to inactivate prions1Modern manufacturing processes may reduce contamination but transmission risk remains3,4Ongoing vigilance and monitoring of both people with haemophilia and clotting factor products essential5Ongoing concerns for contamination of factor concentrate
1.
Srivastava A
et al.
Haemophilia
.
2013;19(1):1-47.
Wu CG
et al.
Transfusion
.
2005;45(6):1003-1010.Fryer JF
et al. Vox Sang. 2007;93(4):341-347.Schneider B et al. Haemophilia. 2008;14(5):978-986.
Norja
P et al. Br J Haematol.
2012;159(4):385-393.
Slide12Increasing product purity and viral safety results
in lower manufacturing yields and higher costs
Slide13Slide14Slide15Slide16What is recombinant CFCs and their classification?
Why recombinant therapy in haemophilia?
What is the risk of inhibitor development with recombinant products?
How should we switch from
pdFC
to
rFC
?
Slide17Type
of concentrate
Plasma-
derived
Recombinant
Age
at
treatment
onset
Treatment
regimen
Dosage
Frequency
Prophylactic
vs on-demand
Intensity
of
treatment
Danger
signals
Bacterial
/
viral
infectionVaccinationSurgery
Antenatal
exposure to maternal FVIII
Patient-related
Severity of haemophilia
F8 gene mutation
Family history of inhibitors
black ethnic origin
Polymorphisms of immune-response genes (IL-10, CTLA4, TNFA, and FCGR)
Inhibitor
Risk factors for inhibitor development
Slide18UNTIL THE YEAR 2016 AND SIPPET:
MULTIPLE OBSERVATIONAL STUDIES
Contradictory outcomes of studies and systematic reviews
Different designs
Heterogenous
population (MTPs)
Postmarketing
studies
not including high-risk children
Slide192004
Slide20Risk of inhibitor development does not vary with FVIII concentrate used
CANAL Study (
Gouw
, 2007)
1
Recombinant FVIII (
rFVIII
) products not associated with higher risk of inhibitor development than plasma-derived (PD) products
RODIN Study (
Gouw
, 2013)2Risk of inhibitor development with PD products similar to rFVIII productsStudies of treatment-associated inhibitor risk
Exposure days: 24-hour period during which a dose of concentrate has been administered
Gouw et al. Blood 2007; 109(11):4693–4697
Gouw et al. New England Journal of Medicine 2013;368:231–239
SIPPET Project. 2013. Available at: www.sippet.org
Slide21RODIN Study
Global Medical Affairs Dialogue Meeting
21
Slide22Objectives
To assess whether the type of FVIII product (recombinant vs. plasma-derived) and switching among products were associated with inhibitor development
Methods & Materials
Observational ,multicenter, prospective , non-controlled, non-randomized study
Consecutive,
previously untreated patients
(N=574) with severe haemophilia A
Data collected on all clotting-factor administration ≤75 exposure days or until the development of inhibitory antibodies
Study Overview
22
Date
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Factor VIII Products and Inhibitor Development in Severe Haemophilia A
Slide23Methods: Assessment of Incidence/Risk
Assessment of Incidence/Risk
Switching Among Products
Risk was assessed in children who were receiving a plasma-derived and then switched to a recombinant product
23
Presentation title
Date
Plasma-derived vs. recombinant
von Willebrand factor (vWF)*
No vWF
<0.01 IU vWF/IU FVIII
≥0.01 IU vWF/IU FVIII
Product types
Plasma-derived
1
st
, full-length
2
nd
, B-domain-deleted
2
nd
full-length
3
rd
, full-length
*
Kogenate (Bayer Healthcare) and Refactor AF (Pfizer) were not evaluated due to small number of patients on therapy
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Slide24Patient characteristics
Recombinant
[no. (%)]
Plasma-
Derived
(N=88)
All Types
(N=574)
3rd, Full-Length
(N=157)
2nd, Full-Length
(N=183)
1st, Full-Length
(N=59)
2nd, B-Domain-
Deleted
(N=77)
Family history
-
ve
for inhibitors
64 (40.8)
50 (27.3)
21 (35.6)
21 (27.3)
24 (27.3)
187 (32.6)
+ for inhibitors
22 (14.0)
16 (8.7)
11 (18.6)
14 (18.2)
20 (22.7)
83 (14.5)
Mutation
High-risk
95 (60.5)
100 (54.6)
35 (59.3)
37 (48.1)
56 (63.6)
331 (57.7)
Low-risk
45 (28.7)
60 (32.8)
18 (30.5)
20 (26.0)
28 (31.8)
172 (30.0)
24
Presentation title
Date
*Median age listed in years
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Slide25Risk of Inhibitor Development (1)
Product
Days
*
Any Inhibitor
Development
Unadjusted
Hazard Ratio
Adjusted
Hazard Ratio
Ratio
P Value
Ratio
P Value
Recombinant
25,661
1.00
NA**
1.00
NA**
Plasma-derived
4,018
1.14
(0.75-1.72)
0.54
0.96
(0.62-1.49)
0.87
25
Date
* Number of exposure days
**NA denotes not applicable
Factor VIII Products and Inhibitor Development in Severe Haemophilia A
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Slide26Risk of Inhibitor Development (2)
Product
Days*
Any Inhibitor
Development
Unadjusted
Hazard Ratio
Adjusted
Hazard Ratio
Ratio
P Value
Ratio
P Value
Recombinant
(generation, length)
3
rd
,
full
9,297
1.00
NA**
1.00
NA**
2
nd
, full
9,143
1.37
(0.93-2.01)
0.11
1.60
(1.08-2.37)
0.02
1
st
, full
2,464
1.12
(0.61-2.04)
0.72
0.99
(0.53-1.83)
2
nd
, B-domain deleted
4,491
1.00
(0.60-1.65)
0.99
1.01
(0.60-
1.70)
0.97
Plasma-derived
4,018
1.31
(0.81-2.11)
0.27
1.16
(0.70-1.92)
0.56
26
Date
* Number of exposure days
**NA denotes not applicable
Factor VIII Products and Inhibitor Development in Severe Haemophilia A
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Slide27Adjusted Relative Risk of Inhibitor Development
27
Date
Adjusted Relative Risk
(95% CI)
3
rd
Full
1
2
3
●
●
●
●
●
●
●
2
nd
Full
1
st
Full
2
nd
B-Domain-Deleted
All Plasma-Derived
All Recombinant
Plasma-Derived
N=574
Factor VIII Products and Inhibitor Development in Severe Haemophilia A
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Risk of Inhibitor Development
Plasma-derived and recombinant products carried a similar risk
Second-generation were associated with a significantly higher risk than third-generation full-length products
Findings are in line with CANAL study
2
Slide28Recombinant and plasma-derived FVIII
products conferred similar risks of inhibitor development
B-domain modified products
were not associated with increased risk of inhibitor development
Switching
among products was not associated with risk of inhibitor development
2,3
Take-home messages from the RODIN study
28
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Iorio A et al. Blood. 2012; 120:720–7.
Hay C. Presented at WFH Congress Paris, 10 July 2012.
Slide29INTRINSIC LIMITATIONS OF OBSERVATIONAL STUDIES
Confounding by indication
, i.e., the choice of product class, is made on the basis of
treaters
’ perception of inhibitor risk (family history of inhibitors, null gene mutations)
Very heterogeneous
enrolment criteria
(truly severe/moderately severe, truly previously untreated/minimally treated with FVIII concentrates)
Heterogeneous
sample sizes and designs
(retrospective, prospective, case series, inception cohorts) Poor reliability of inhibitor data from multiple participating centers (different testing intervals, poor assay standardization particularly for low-titer inhibitor)
Slide30EXPERT OPINIONS
“The issue of comparative inhibitor safety is best addressed by a prospective, randomized controlled clinical trial….”
Aledort L. J
Thromb
Haemost
2011;9:413
“Only prospective, well designed clinical trials will provide a definite answer… ”
Berntorp & Shapiro. The Lancet 2012;379:144
Slide31The SIPPET study
The first investigator-initiated, international, multicenter, prospective, controlled, randomized, open-label clinical trial on inhibitor frequency in
303 PUPs from
42 hemophilia
centres
in 14 countries
when exposed to plasma-derived FVIII products with von
Willebrand
factor or to recombinant FVIII
products
Slide32Study protocol
STUDY DESIGN
Inclusion criteria
male, age <6 years
severe hemophilia A (FVIII:C < 1%)
negative inhibitor measurement at enrolment
no or minimal treatment (< 5 ED) exposure to blood products
Treatment allocation
randomized to either a single pdFVIII containing VWF or rFVIII
Follow up
50 ED, or 3 years, or until inhibitor development
Treatment regimen
at the discretion of local physicians
INHIBITOR DEFINITIONS
Positivity
≥ 0.4 BU/mL
High-titer
≥ 5 BU
Transient
spontaneously disappearing within 6 months
INHIBITOR DETERMINATION
Sampling time
every 3-5 ED within the first 20 ED, then every 10 ED or every 3 months and every two weeks during prophylaxis
Q
:“An inhibitor
titer
of
0.6 BU/mL is to be taken as clinically significant”
2
A :
By
modified Nijmegen significant
titer
is
≥
0.4 BU/ml
PUP
Slide3342 hemophilia
centres
in 14 countries
in
4 continents
Patients enrollment
251
Patients
analyzed
125
pdFVIII
126
rFVIII
303
PUPs with severe HA screened
Slide34Slide35All
High-
titre
SIPPET results
Incidence of inhibitors:
37.3%
in rFVIII
vs
23.2%
in pd-FVIII
HR:Hazard
Ratio
Slide36Majority of patients from India (33%), Egypt (31%) and Iran (12%)
Fewer patients from developed countries
eg
US (7%) and EU (6%)
A sensitive analysis looking at HR results
every time that a given country is left out shows no change
1. Results are not country-driven
Slide37Compares two types/classes of products, not two specific
products 84
% of patients assigned to
rFVIII
received 1
st
and 2
nd
generation products
and 16% received available 3rd generation at that time (did not include turoctocog alfa; Eloctate and Nuwiq)A sensitive analysis looking at HR results every time that a given recombinant product is left out shows no change
2. Results are not recombinant product-driven
Slide38The highest rate of inhibitor development is in the first 10 EDs with a rate for rFVIII that started earlier, lasted longer and peaked higher
ALL INHIBITORS
HIGH-TITRE INHIBITORS
(
Peyvandi et al.
J
Thromb
Haemost
2017,
doi
: 10.1111/jth.13888)
Timing and severity of inhibitor development
:
a SIPPET subanalysis
Slide39Slide40Genetic risk stratification:
a SIPPET
subanalysis
Patients were classified at:
High risk
when they carried a null mutation
Low risk
when they carried another o no causative variant
Rosendaal FR et al. Blood 2017; 130:1757-1759
Slide41Genetic risk stratification:
Kaplan-Meier survival curves
Low risk
for patients with low genetic risk and treated with
pdFVIII
Intermediate risk
for patients with a high genetic risk and treated with
pdFVIII
High risk
for patients treated with
rFVIII
regardless their genetic profile
Rosendaal FR et al. Blood 2017; 130:1757-1759
Slide42Take home message from SIPPET study:
Previous Untreated Patients (PUP) treated with
rFVIII
have higher risk to develop inhibitors than those treated with
pdFVIII
containing VWF
It occurs mostly before 30
Eds
The highest rate of inhibitor development is in the first 10 EDs with a rate for
rFVIII
that started earlier, lasted longer and peaked higherIt happened with all classes of rFVIIIs which were available and used in the study Has not warned against rFVIII usage or switching in PTP
These findings lead to better understand the mechanisms of the immunogenicity of various FVIII preparations
Slide43Misunderstandings
from both groups of studies
RODIN & CANAL
There is
NO RISK
to start
rFVIII
in PUPs
Switching from
pdFVIII to rFVIII is safe in ANY CLINICAL CONDITIONS (surgery, intensive treatment , post-ITI,
etc)SIPPETDo not use recombinent CFS IN CHILDRENDO NOT SWITCH from pdFVIII to rFVIIIDo starting rFVIII in lOW RISK instead of HIGH RISK PUPs (regarding to their mutations or family history of inhibitor)
Slide44In MCCCH (our
ceneter in TEHRAN)68 patient with hemophilia(PWH) less than 15 Y old on regular prophylaxis:
48 /68 are on
rFVIII
:
9/48 were PUPs who were enrolled in SIPPET
37/48 switched from
pdFVIII
to rFVIII
20/68 are on pdFVIII
Iranaian Society of Thrombosis & Hemostasis wrote an official letter to MOH to resolve misunderstandings from the study and guide how to satate switching from pdFVIII to rFVIIIAND IT IS APPLIED IN IRAN
Slide45Development of inhibitors is rare in PTPs
1,2
Low but definite risk remains throughout the patient’s life
2
Reported incidence of 2.5–5.5 per 1000 treatment years
3
Few risk factors for inhibitor development in PTPs identified
4
Data from EUHASS showed no significant difference in inhibitor incidence between
pdFVIII
and rFVIII products5Baseline risk of inhibitors is low in PTPs45
EUHASS, European Haemophilia Safety Surveillance; FVIII, Factor VIII; pdFVIII, plasma-derived FVIII; PTPs, previously treated patients
1. Fischer K et al. Thromb Haemost 2015;113(5):968-75; 2. Coppola A et al. Semin Thrombosis DOI
http://dx.doi.org/10.1055/s-0036-1581102
; 3. Hay CRM, et al. Haemophilia 2015;21(2):219–226; 4.
Xi M et al. J Thromb Haemost 2013;11(9):1655–1662; 5.
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9
As a mostly conservative scenario :
We can start with
pdFVIII
in PUPs and after 30-50
Eds switch to rFVIII to warranty the most safety margin for our patients
SIPPET-2: the aim of this study is to assess whether switching from the use of plasma-derived FVIII containing VWF to the use of a recombinant FVIII product after the period of higher risk for inhibitor occurrence (first 50 EDs) is safe, without the occurrence of a new peak of inhibitor development.
Slide46What is recombinant CFCs and their classification?
Why recombinant therapy in haemophilia?
What is the risk of inhibitor development with recombinant products?
How should we switch from
pdFC
to
rFC
?
Slide47Rationale for switching
Product-specific considerations
Improved safety (real or perceived)
1,2
Less risk of infection
1,2
Less inhibitor risk
1
Fewer side-effects (e.g. allergic reactions)
1,2Newer generation of product1,2
Volume of final product3Mixing and administration device1,2Storage advantage1,2Longer half-life1,2Other considerationsPrice1,2National contracting1,2 Shortage or termination of product supply3Patient/family preference1,2Participation in a clinical trial/research study1,2
“It is extremely rare, if not impossible, for adult [people with haemophilia] in most countries worldwide to have used the same concentrate throughout their lives”
1
Iorio et al. Blood 2012;120(4):720-727
Santagostino
E, et al.
Eur
J
Haematol
2015;94(4):284-9
Slide48Common treatment switches
48
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9
Plasma-derived product
Recombinant product
Recombinant product
Recombinant product*
*Including extended half-life products
Slide49Overview of rFVIII product switches:
national switches
Country
Study type (follow up)
N patients (% severe haemophilia A)
History
of inhibitors, n (%)
Product switched
from
Product switched to
Exposure to new product
Inhibitor
incidence at baseline,
n (%)
Inhibitor
incidence post-switch, n (%)
Ireland
1
Retrospective (20 months)
94 (89.4%)
17 (18%)
rFVIII-CHO (mainly
ReFacto
®
)
Kogenate
®
(
rFVIII-BHK)
20–100 EDs: 26%;
>100 EDs: 54%
1 (1.2)
1 (1.1)
de novo
3 (3.2) recurrent
Ireland
2,3
Retrospective
(30 months)
113 (89.4)
17 (15)
Kogenate
®
(74%);
Helixate
®
(23%)
Advate
®
85% had >100 EDs
2 (1.7)
1 (0.9)
de novo
UK
(UKHCDO registry)
3,4
Prospective
516 (100%) switchers
682 non-switchers (controls)
0
Advate
®
(82%)
Kogenate
®
/
Helixate
®
18%)
ReFacto
-AF
®
_
0
Switchers: 4 (0.75)
de novo
Non-switchers: 1 (0.1)
de novo
Cohort studies show a generally low incidence of new inhibitors when unselected groups are switched to new products.
Slide50Overview of rFVIII product switches:
national switches
50
Country
Study type (follow up)
N patients (% severe haemophilia A)
History
of inhibitors, n (%)
Product switched
from
Product switched to
Inhibitor
incidence at baseline,
n (%)
Inhibitor
incidence post-switch, n (%)
Canada (AHCDC surveillance programme)
1
Prospective
814
64 (7.9)
pdFVIII
Kogenate
®
35 (4.3)
10 (3.0)
*
de novo
7 (2.1)
*
recurrent
Canada (AHCDC surveillance programme)
2,3
Prospective
(24 months)
274 (72.3)
24 (8.8)
Kogenate
®
Kogenate FS
®
2 (1.4)
**
2 (1.4) recurrent
*
Out of a total of 339 patients with 2 years follow up;
**
In subjects completing the full surveillance protocol of 24 months
AHCDC, Association of Hemophilia Clinic Directors of Canada; pdFVIII, plasma-derived factor VIII
1.
Giles AR et al. Transfusion Science 1998; 19(2): 139–148; 2.
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9; 3. Rubinger M et al. Haemophilia 2008;14:281–286;
Cohort studies show a generally low incidence of new inhibitors when unselected groups are switched to new products.
Slide51Inhibitor incidence in an Italian cohort study
51
PTP, previously treated patient; rFVIII, recombinant FVIII
Gringeri A et al. Brit J Haematology 2004; 126:398–404
Parameter
Details
Study type
Prospective/retrospective cohort study
Participants
PTPs with severe haemophilia A
Study inclusion years
Retrospective: 1999
–2001
Total
cohort
Prospective:
N=25
R
etrospective:
N=94
Product switch
ReFacto
®
Inhibitor development
History of inhibitors,
n %
0
Inhibitor
development, n (%)
Prospective:
1 (4%)
Retrospective: 1 (1.4%)
Low incidence of inhibitor development following switching to rFVIII
Slide52Slide53Modified
*
DELPHI process in 2011 aimed to reach consensus on statements/topics relating to product switching (N=12)
Investigating perceived barriers to switching: HCPs
53
ED, exposure days; HCP, healthcare professional;
*
Structured group communication involving a kick-off face-to-face meeting presenting the topic followed by multiple sequential rounds of question and answer sessions
Matino D, et al. Haemophilia 2014;20:200–206
Consensus statement
Consensus, % respondents
‘There is
no clear signal of an increase in inhibitor development
when switching to and from the currently available recombinant factor concentrates.’
90
‘It is considered beneficial, whenever possible, to
keep patients on the same product for the first 50 ED
…
should the reason for switching be an important one, it has to be considered that no evidence exists against switching during this time.’
92
‘
Careful observation for inhibitors will be required
when introducing the new FVIII molecules.’
92
Slide54Consideration on inhibitor development with switching FCs
usually occur in the first 50 EDs (PUP)
Intensive treatment/surgery may influence
Simultaneous infection or inflammation process may trigger
Patients with family history of inhibitors may have higher risk
Patients with a previous history of inhibitors may be at risk of inhibitor recurrence
Including those with successful ITI
Recommendation for switching FCs
Apply in PTPs
DO NOT switch when patients have:
Intensive treatmentSurgery Simultaneous infection or inflammation processFamily history of inhibitorprevious history of inhibitors
Slide55Physicians should discuss different FVIII products with patients before the need for switching arises
Monitor switched patients for inhibitor development
1
Test for inhibitors:
Before switching
2,3
At regular intervals after switching
2,3
After intensive treatment/surgery
2Physicians are obliged to prospectively monitor safety and efficacy of new products4All switching patients should be enrolled into registry studies3
Srivastava et al. Haemophilia 2013 Jan;19(1):e1-47
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9
Iorio et al. Blood 2012; 120: 720-727Keeling et al. Haemophilia 2008;14:671–684
Guidelines and expert opinion
55
Slide56Thank you for your attention
Time for your question