2. Switching 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,

3. What 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?

5. There are three generations of recombinant factors1-3
First-generation recombinant products
Manufactured using animal- and human-derived proteins in the cell culture stage of production
Included pasteurised human albumin in the formulation process to stabilise the final product
Second-generation recombinant products
Animal- and human-derived proteins used in the cell culture stage of production
No albumin in the final product
Third-generation recombinant products
Latest development in clotting factor technology
No additional (exogenous) human- or animal-derived protein in the cell culture process, purification or final formulation
First-generation rFVIII molecules were grown in culture medium that contained mammalian proteins to support growth, however these proteins may introduce viruses, prions or other pathogens.
Second-generation rFVIII molecules were produced in serum-free cultures, and third-generation molecules are produced in the absence of any animal-derived raw materials.
References
Advate SPC. Baxter AG. Vienna, Austria
Franchini M, Lippi G. Recombinant factor VIII concentrates. Seminars in Thrombosis and Hemostasis. 2010a;36: p
National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders Available at: Accessed April 5, p13
For further information, refer to Training Module 3, section IB

6. 6
Truncated B domain
B domain does not seem to have any function with respect to FVIII clotting activity3 C2 C1 A3 A2 A1 a1 a2 a3
Full length FVIII
Truncated B domain 1
372
740
1648
2020
2173
2332
741–750
1638–1648
750
1637
HC (1–740)
B domain (741–1648)
LC (1649–2332) B
Key messages
The turoctocog alfa molecule consists of a heavy chain of 88 kDa including a 21 amino-acid residue truncated B domain and a light chain of 79 kDa
There are several reasons for using a B-domain truncated molecule:
The B-domain does not seem to have any function with respect to clotting activity
The expression of full-length FVIII in mammalian cell lines is considerably more difficult than B-domain-truncated variants
The purification and characterization of a full-length FVIII molecule containing 19 potential N-glycosylation sites in the B domain would also be considerably more complex than a B-domain-truncated molecule
Additional information
The upper figure shows the structure of the full-length FVIII molecule, consisting in 2332 aa residues
The lower part of the figure illustrates the structure of turoctocog alfa where the amino acid sequence of the Heavy Chain and Light Chain are identical to the corresponding sequences of full-length FVIII
The 908 aa residue from the B-domain has been replaced by a 21 aa residue truncated B-domain linker sequence: this represents 10 aa from the N-terminal of the B-domain, linked to 11 aa residues from the C-terminal of the B-domain
If questioned about whether the rFVIII molecule includes a B-domain
turoctocog alfa is a B-domain truncated molecule
No available rFVIII product is truly full length or truly B-domain-deleted. All modern FVIII products, including turoctocog alfa from Novo Nordisk, will be B-domain truncated/deleted, as the product is more homogeneous and easier to produce and characterise
Reference
Thim L et al. Haemophila 2010;16:349–59
Please note: These slides are for internal use only. External use will require approval from senior management and the purchase of all necessary copyright permissions for figures.
HC, heavy chain; LC, light chain
Thim L et al. Haemophilia 2010;16:349‒59
Ezban M et al. Euro J Haematol 2014;93:369‒76
Toole JJ et al. Proc Natl Acad Sci 1986;83:5939‒42

7. Extensive 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 5
Gel filtration
Utilizes size to remove FVIII multimers and other contaminants to yield a highly homogeneous product 2
Immunoaffinity chromatography
Selects intact molecules 3
Anion-exchange chromatography
Separates molecules by their charge 4
Nanofiltration4
20-nm double filter has been shown to remove small nonenveloped viruses based on size exclusion
Notes1-3
Novoeight® uses an extensive 5-step purification process, including a detergent inactivation and concentration step, an immunoaffinity chromatography step, anion-exchange chromatography, nanofiltration, and finally, a gel filtration step
This purification process was developed to obtain a highly purified product and to minimize the risk of viral contamination
The detergent inactivation step is designed to eliminate any potential viral contaminants, but also serves to concentrate the molecule:WFH guidelines: gold standard in viral safety4
The immunoaffinity chromatography step selects intact molecules
The anion-exchange chromatography step separates molecules based on charge
The 20-nm double nanofiltration step has been shown to remove small nonenveloped viruses based on size exclusion4WFH guidelines: option of choice when considering non-enveloped viruses4
The gel filtration step (size exclusion step) separates the remaining protein by size, removing multimers of the Novoeight® molecule
This purification process yields a homogeneous product
References
Novoeight® Prescribing Information. Plainsboro, NJ: Novo Nordisk Inc.; 2014.
Thim L, Vandahl B, Karlsson J, et al. Purification and characterization of a new recombinant factor VIII (N8). Haemophilia. 2010;16(2):
Morfini M. Innovative approach for improved rFVIII concentrate. Eur J Haematol. 2014;93(5):
Data on file at Novo Nordisk Inc. November 30, 2012.
WFH guidelines: gold standard in viral safety

8. Approved rFVIII products
1992
1999
2000
2003
2008
2013
2014
turoctocog
alfa
BDD rFVIII (CHO)
Eloctate
BDD rFVIII
fused to Fc (HEK)
ReFacto AF BDD rFVIII (CHO)
Advate
Full Length rFVIII (CHO)
Recombinate (CHO)
Full Length rFVIII
Regulatory authorities have approved several different rFVIII products for the treatment of haemophilia A.
Advate. Prescribing information.
Kogenate FS.
Refacto AF.
Xyntha. Prescribing information.
Nuwiq. Healthcare Professionals Website
Eloctate. Prescribing information.
For further information, refer to Training Module 6a, B.
Kogenate-FS
Full Length rFVIII (BHK)
Xyntha
BDD rFVIII (CHO)
Nuwiq
BDD rFVIII (HEK)

9. What 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?

10. Why recombinant therapy in haemophilia?
Global 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,etc
Purity :minimize non clotting-factor protein exposure
Scalability and reproducibility of the manufacturing process
Allows for molecular engineering to create improvements
Longer acting, fewer infusions
Many protraction principles theoretically mitigate immunogenicity
Alternative routes of administration

11. Ongoing concerns for contamination of factor concentrate
HCV and HIV transmission successfully reduced, but safety concerns remain1 :
Plasma-derived products may contain infectious non-enveloped viruses (eg, B19V and PARV4)2,3 :
Not all inactivated by heat methods1
Not affected by solvent/detergent procedures1
Available viral-inactivation methods unable to inactivate prions1
Modern manufacturing processes may reduce contamination but transmission risk remains3,4
Ongoing vigilance and monitoring of both people with haemophilia and clotting factor products essential5
KEY SLIDE
While modern manufacturing processes may reduce contamination of blood products with parvoviruses, the risk of transmission remains1,2; ongoing vigilance and monitoring of both people with hemophilia and clotting factor products is therefore essential3
References
Schneider B, Fryer JF, Oldenburg J, Brackmann HH, Baylis SA, Eis-Hübinger AM. Frequency of contamination of coagulation factor concentrates with novel human parvovirus PARV4. Haemophilia. 2008;14(5):
Norja P, Lassila R, Makris M. Parvovirus transmission by blood products - a cause for concern? Br J Haematol. 2012;159(4):
Fryer JF, Hubbard AR, Baylis SA. Human parvovirus PARV4 in clotting factor VIII concentrates. Vox Sang. 2007;93(4):
Srivastava A et al. Haemophilia. 2013;19(1):1-47.
Wu CG et al. Transfusion. 2005;45(6):
Fryer JF et al. Vox Sang. 2007;93(4):
Schneider B et al. Haemophilia. 2008;14(5):
Norja P et al. Br J Haematol. 2012;159(4): 1.

12. Increasing product purity and viral safety results in lower manufacturing yields and higher costs

13. Diagnosed Haemophilia A
Patient With Hemophilia A
(App. 389,000)
Diagnosed Haemophilia A
(App. 150,000)
Around half of the diagnosed patients receive treatment with Factor VIII worldwide

16. What 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?

17. Risk factors for inhibitor development
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)
Type of concentrate
Plasma-derived
Recombinant
Inhibitor
Age at treatment onset
Treatment regimen
Dosage
Frequency
Prophylactic vs on-demand
Intensity of
treatment
Danger
signals
Bacterial/viral infection
Vaccination
Surgery
Antenatal exposure to maternal FVIII

18. UNTIL 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

19. 2004

20. Studies of treatment-associated inhibitor risk
Risk 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)2
Risk of inhibitor development with PD products similar to rFVIII products
Although it has been suggested that the risk of inhibitor formation can vary with the type of FVIII concentrate used for treatment (i.e. recombinant vs. plasma derived), this concern has been shown to be unfounded in a number of studies
CANAL Study
Retrospective, multicentre study to determine the effect of product choice on risk of inhibitor development in 316 previously untreated patients (PUPs) with severe haemophilia A
26% patients developed clinically relevant inhibitors, 80% of which were high titre
Neither use of recombinant FVIII nor switching between products was associated with a higher risk of inhibitor development
RODIN study2
Prospective study of product choice/switching and inhibitor development in 574 PUPs with severe haemophilia A
32% patients developed clinically relevant inhibitors, 65% high-titre
Neither switching among brands of FVIII products nor switching from plasma-derived to recombinant products increased risk of inhibitor development
SIPPET Study3
Ongoing randomised clinical trials assessing risk of inhibitor development with different FVIII products
Estimated completion date of November, 2014
References
Gouw SC, van der Bom JG, Auerswald G, et al. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood. 2007;109(11):4693–4697
Gouw SC, van der Bom JG, Ljung R, et al. Factor VIII products and inhibitor development in severe hemophilia A. New England Journal of Medicine. 2013;368:231–239
SIPPET Project Available at:
Definitions
Exposure days: 24-hour period during which a dose of concentrate has been administered
For further information, please see Section II C of the Turoctocog Alfa Training Modules: Module 2: Congenital Haemophilia
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 Available at:

21. Global Medical Affairs Dialogue Meeting
RODIN Study
Global Medical Affairs Dialogue Meeting

22. Study Overview Objectives
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
The objective of this study was to assess whether recombinant FVIII (rFVIII) products and switching among products was associated with inhibitor development in consecutive, previously untreated children (N=574) with severe haemophilia A (FVIII activity <0.01 IU/ml) born between 2000 and The type of recombinant product and the content of von Willebrand Factor (vWF) was also assessed for inhibitor development. Children with the presence of inhibitory antibodies were excluded from this study. Data was collected on all clotting-factor administration for up to 75 exposure days or until the development of inhibitory antibodies. After 75 days, inhibitor development becomes rare (approximately 2-5 cases per 1000 patient-years).
Factor VIII Products and Inhibitor Development in Severe Haemophilia A
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Date

23. Methods: 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
Plasma-derived vs. recombinant
No vWF
<0.01 IU vWF/IU FVIII
≥0.01 IU vWF/IU FVIII
von Willebrand factor (vWF)*
Product types
Incidence of inhibitor development was assessed according to the type of product used. First, inhibitor risk was compared between plasma-derived VIII and all recombinant products. Second, the risk associated with the content of vWF (0 IU vWF/IU FVIII, <0.01 and ≥0.01) was assessed. Recombinant products do not contain vWF. Examples of products that contain <0.01 IU vWF/IU FVIII are monoclonal antibody-purified plasma-derived products. Examples of products that contain ≥0.01 IU vWF/IU FVIII are other types of plasma-derived products. Third, inhibitor incidence among plasma-derived, first-generation full-length recombinant, second-generation B-domain-deleted recombinant, and second- and third-generation full-length recombinant products was assessed. First-generation rFVIII molecules were grown in culture medium that contained mammalian proteins to support growth, however these proteins may introduce viruses, prions or other pathogens. Second-generation rFVIII molecules are produced in serum-free cultures but still contain albumin as stabilizer. Third-generation molecules are produced in the absence of any animal-derived raw materials.
The investigators evaluated the risk of inhibitor development in children who were receiving a plasma-derived product and who were then switched to a recombinant product, as compared with those who only received a plasma-derived product. Association between switching among various types of rVIII products and inhibitor development was also assessed.
Plasma-derived
1st, full-length
2nd, B-domain-deleted
2nd full-length
3rd, 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.
Date
Presentation title

24. Patient 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)
*Median age listed in years
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Date
Presentation title

25. Risk of Inhibitor Development (1)
Product
Days*
Any Inhibitor Development
Unadjusted
Hazard Ratio
Adjusted
Ratio
P Value
Recombinant
25,661
1.00
NA**
Plasma-derived
4,018
1.14
( )
0.54
0.96
( )
0.87
This table presents the risk of inhibitor development among patients receiving either recombinant (all types) or plasma-derived FVIII (all types). Hazard ratios were adjusted for race or ethnic group; age at first exposure to factor VIII; reason for first treatment; interval between exposure days; dose of FVIII; FVIII genotype; and status with respect to family history of haemophilia and inhibitors, history of switching among product brands, peak treatment episodes of either at least 3 consecutive days or at least 5 consecutive days, history of major surgery, and regular prophylaxis. Hazard ratios were adjusted for race or ethnic group; age at first exposure to factor VIII; reason for first treatment; interval between exposure days; dose of FVIII; FVIII genotype; and status with respect to family history of haemophilia and inhibitors, history of switching among product brands, peak treatment episodes of either at least 3 consecutive days or at least 5 consecutive days, history of major surgery, and regular prophylaxis.
* Number of exposure days
**NA denotes not applicable
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Date
Factor VIII Products and Inhibitor Development in Severe Haemophilia A

26. Risk of Inhibitor Development (2)
Product
Days*
Any Inhibitor Development
Unadjusted
Hazard Ratio
Adjusted
Ratio
P Value
Recombinant (generation, length)
3rd, full
9,297
1.00
NA**
2nd, full
9,143
1.37
( )
0.11
1.60
( )
0.02
1st, full
2,464
1.12
( )
0.72
0.99
( )
2nd, B-domain deleted
4,491
( )
1.01
( )
0.97
Plasma-derived
4,018
1.31
( )
0.27
1.16
( )
0.56
This table presents the risk of inhibitor development among patients receiving different recombinant product types vs. plasma-derived products. A first-generation full-length recombinant product, Kogenate (Bayer Healthcare), and a third-generation B-domain–deleted recombinant product, Refacto AF (Wyeth), were used only in 10 and 3 patients on 103 and 163 exposure days, respectively, so the effect of these products on inhibitor development was not studied. The only first-generation full-length product in this category was Recombinate (Baxter BioScience). Hazard ratios were calculated as described previously.
* Number of exposure days
**NA denotes not applicable
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Date
Factor VIII Products and Inhibitor Development in Severe Haemophilia A

27. Adjusted Relative Risk of Inhibitor Development
(95% CI)
3rd Full 3
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 2 ● ●
Findings are in line with CANAL study2 ● ● ● ● 1 ●
The data presented here is the adjusted relative risk for previously untreated children with severe haemophilia A (N=574). As absolute risk varies according to cumulative number of exposure days, pooled logistic regression with the cumulative number of exposure days as the time variable was used to account for varying risk. In comparing all recombinant products and all plasma-derived products (left), the reference group was the recombinant products. In comparison of specific products (right), the reference group was the third-generation full-length recombinant products. The only first-generation full-length recombinant product evaluated was Recombinate (Baxter BioScience). The I bars indicate 95% CI.
All Recombinant
All Plasma-Derived
2nd Full
1st Full
Plasma-Derived
2nd B-Domain-Deleted
N=574
Gouw SC et al. N Engl J Med. 2013; 368:231–9.
Date
Factor VIII Products and Inhibitor Development in Severe Haemophilia A

28. Take-home messages from the RODIN study
Recombinant 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
Switching among products was not associated with risk of inhibitor development, which is in line with previously conducted meta-analysis and UK switch data.2,3 Very importantly, B-domain modified recombinant products were not associated with increased risk of inhibitor development. However, the findings related to second-generation full-length product will require further studies to be clarified/confirmed, as there is no straightforward explanation for this observation.
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.

29. The 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

31. SIPPET results
Incidence of inhibitors: 37.3% in rFVIII vs 23.2% in pd-FVIII
All
In survival analysis, the hazard ratio (HR) is the ratio of the hazard rates corresponding to the conditions described by two levels of an explanatory variable. For example, in a drug study, the treated population may die at twice the rate per unit time as the control population. The hazard ratio would be 2, indicating higher hazard of death from the treatment. Or in another study, men receiving the same treatment may suffer a certain complication ten times more frequently per unit time than women, giving a hazard ratio of 10.
Hazard ratios differ from relative risks and odds ratios in that RRs and ORs are cumulative over an entire study, using a defined endpoint, while HRs represent instantaneous risk over the study time period, or some subset thereof. Hazard ratios suffer somewhat less from selection bias with respect to the endpoints chosen and can indicate risks that happen before the endpoint
High-titre
HR:Hazard Ratio

32. 1. Results are not country-driven
Majority 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

33. 2. Results are not recombinant product-driven
Compares two types/classes of products, not two specific products 84% of patients assigned to rFVIII received 1st and 2nd 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

34. Timing and severity of inhibitor development: a SIPPET subanalysis
The 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: /jth.13888)

36. Genetic 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:

37. Genetic 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:

38. Take 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 higher
It 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

39. Misunderstandings from both groups of studies
RODIN & CANAL
SIPPET
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)
Do not use recombinent CFS IN CHILDREN
DO NOT SWITCH from pdFVIII to rFVIII
Do starting rFVIII in lOW RISK instead of HIGH RISK PUPs (regarding to their mutations or family history of inhibitor)

40. In 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 rFVIII
AND IT IS APPLIED IN IRAN

41. What 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?

42. Rationale for switching
Product-specific considerations
Improved safety (real or perceived)1,2
Less risk of infection1,2
Less inhibitor risk1
Fewer side-effects (e.g. allergic reactions)1,2
Newer generation of product1,2
Volume of final product3
Mixing and administration device1,2
Storage advantage1,2
Longer half-life1,2
Other considerations
Price1,2
National contracting1,2
Shortage or termination of product supply3
Patient/family preference1,2
Participation 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
Reference
Iorio et al. Blood 2012;120(4):
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9
Iorio et al. Blood 2012;120(4):
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9

43. Common treatment switches
Plasma-derived product
Recombinant product
Recombinant product
Recombinant product*
Key message:
Common switches are:
From a plasma-derived to recombinant product
From one recombinant product to another
References:
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9
*Including extended half-life products
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9

44. Overview 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 (%)
Ireland1
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
Ireland2,3
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)
Advate® (82%) Kogenate®/ Helixate® 18%)
 ReFacto-AF® _
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.
Key message:
Cohort studies show a generally low incidence of new inhibitors when unselected groups are switched to new products.
Abbreviations:
ED, exposure day; rFVIII-CHO, recombinant factor VIII produced in Chinese hamster ovary cells; rFVIII-BHK, recombinant factor VIII produced in baby hamster kidney cells; UKHCDO, United Kingdom Haemophilia Centre Doctors Organisation
Reference
Singleton E et al. Thromb Haemost 2007; 98: 1188–1192
Bacon C et al. Haemophilia 2011; 17: 407–411
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9
Hay CRM, et al. Haemophilia 2015;21(2):219–226

45. Overview 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
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 FS®
2 (1.4)**
2 (1.4) recurrent
Cohort studies show a generally low incidence of new inhibitors when unselected groups are switched to new products.
Key message:
Cohort studies show a generally low incidence of new inhibitors when unselected groups are switched to new products.
Reference
Giles AR et al. Transfusion Science 1998; 19(2): 139–148
Santagostino E, et al. Eur J Haematol 2015;94(4):284-9
Rubinger M et al. Haemophilia 2008;14:281–286
*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;

46. Inhibitor incidence in an Italian cohort study
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 Retrospective: N=94
Product switch
ReFacto®
Inhibitor development
History of inhibitors, n %
Inhibitor development, n (%)
Prospective: 1 (4%)
Retrospective: 1 (1.4%)
Low incidence of inhibitor development following switching to rFVIII
Key message:
An Italian study reported a low incidence of inhibitor following switching to rFVIII products
Previous products were a mix of pdFVIII and rFVIII
References:
Gringeri A et al. Brit J Haematology 2004; 126:398–404
PTP, previously treated patient; rFVIII, recombinant FVIII Gringeri A et al. Brit J Haematology 2004; 126:398–404

48. Investigating perceived barriers to switching: HCPs
Modified* DELPHI process in 2011 aimed to reach consensus on statements/topics relating to product switching (N=12)
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.’
Key message:
A modified DELPHI process with 12 HCPs showed consensus on various statements relating to product switching
92% believed that ‘there is no clear signal of an increase in inhibitor development when switching to and from the currently available recombinant factor concentrates.’
References:
Matino D, et al. Haemophilia 2014;20:200–206
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

49. DO NOT switch when patients have:
Recommendation for switching FCs
Consideration 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
Apply in PTPs
DO NOT switch when patients have:
Intensive treatment
Surgery
Simultaneous infection or inflammation process
Family history of inhibitor
previous history of inhibitors

50. Guidelines and expert opinion
Physicians should discuss different FVIII products with patients before the need for switching arises
Monitor switched patients for inhibitor development1
Test for inhibitors:
Before switching2,3
At regular intervals after switching2,3
After intensive treatment/surgery2
Physicians are obliged to prospectively monitor safety and efficacy of new products4
All switching patients should be enrolled into registry studies3
Key message:
Guidelines and expert opinion recommend that switching patients be monitored for inhibitor development.
References
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:
Keeling et al. Haemophilia 2008;14:671–684
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:
Keeling et al. Haemophilia 2008;14:671–684

51. Thank you for your attention Time for your question