2. Extended Half Life and Conventional Clotting Factors for Hemophilia
Glenn Pierce MD PhD
WFH Board of Directors
La Jolla, California USA
World Federation of Hemophilia (WFH)
Indonesian Hemophilia Society (IHS)
Symposium on Hemophilia Care
Sanur, Bali, Indonesia
23 April 2017

3. Evolution of modern hemophilia treatment
Investigational therapies (2015–)
► Gene therapy
► Novel agents
Therapeutic Value
Protein engineering era
EHL clotting factors (2014–)
► Prolonged half-life (FVIII/FIX)
Recombinant clotting factors FVIII, FIX, FVIIa (1990s)
Recombinant era
Plasma-derived clotting factors (1969)
► Widespread viral contamination
Evolution of Products
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4. Why Were Extended Half Life Products Developed?
Conventional plasma-derived and recombinant clotting factors have short half lives
Most prophylaxis regimens don’t prevent crippling arthritis, they delay it
Frequent intravenous infusions required to control bleeding
Extended half life FVIII and FIX decrease the frequency and burden of treatment
Mazepa et al Blood Mar 16. pii: blood [Epub ahead of print]; Dunn AL The long and short of it: using the new factor products ASH Education 2015;
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5. Extended Half-Life Products Extend the Time Between Infusions
Half life: amount of time it takes for 50% of drug to be eliminated
Half-lives are averages of a population
Individuals can have half-lives that are average, or at the extremes of the population
Half life dictates how frequently clotting factor must be administered to protect from bleeding
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6. How to Create Extended Half-Life Products?
2 Primary Methods
Fusion- Protein Engineering
FIX-albumin (Idelvion)
FVIII-Fc (Eloctate) and FIX-Fc (Alprolix), a portion of IgG
Both albumin and IgG remain in the circulation for weeks
Neonatal Fc receptor (FcRn) recycles Fc/Alb fusion proteins
8+ Fc proteins have been FDA approved with a good safety profile
IgG-Fc is responsible for tolerance induction and placental transfer
Pegylation- Manufacturing Process
PEG, a petroleum derivative, slows degradation when attached to protein
Site specific- BAY via Cysteine mutation
Sugars attached to clotting factor- N8-GP, N9-GP
Random-BAX855 (Adynovate)
Multiple Pegylated proteins have been FDA approved
Chamow S and Ashkenazi A Trends Biotechnol 1996; Dumont JA et al. BioDrugs. 2006;20: ; Rath T et al Crit Rev Biotechnol, Early Online: 1–20
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7. Neonatal Fc Receptor Recycling Pathway
Figure 3. FcRn recycling pathway.29 IgG and Fc fusion proteins are taken up from circulation into cells by nonspecific pinocytosis and/or endocytosis mechanisms.49 As the endosomes become acidic, the Fc domain of IgG or Fc fusion proteins binds to FcRn. Once the endosome fuses back at the cell surface, Fc dissociates from FcRn at neutral pH and IgG and Fc fusion proteins are released back into the circulation.49 In contrast, circulating proteins that do not interact with FcRn are trafficked to endosomal and lysosomal degradation pathways.29,50 Ultimately, Fc degrades naturally and does not accumulate in the body.51 Despite its name, the expression of human FcRn is stable throughout life.52 Reprinted with permission from Roopenian and Akilesh.29
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:
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8. Eloctate (rFVIIIFc) and Alprolix (rFIXFc)
How are they similar to conventional recombinant and plasma-derived Factor VIIII and IX concentrates?
How are they different?
Half life
Dosing frequency
Dose (rFIXFc)
Optimal usage?
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9. PIVOTAL STUDY RESULTS Blood. 2014;123(3):317-325
Regulatory approvals in multiple geographies: US, Canada, Japan, Australia, EU
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10. Extended Half Life clotting factors
Prolongation of the half-life
Reduction of the number of injections required for treatment and prophylaxis
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11. Dosage and Administration: Eloctate (rFVIIIFc) Dosing Guidelines
ELOCTATE, Antihemophilic Factor (Recombinant), Fc Fusion Protein, is a recombinant DNA derived, antihemophilic factor indicated in adults and children with Hemophilia A
Similar to other FVIIIs
Calculation of the required dose of Factor VIII based on empirical finding- 1 IU Factor VIII/kg raises plasma Factor VIII level 2 IU/dL. In vivo peak increase in Factor VIII level expressed as IU/dL (or % of normal) estimated using : Estimated Increment of Factor VIII (IU/dL or % of normal) = [Total Dose (IU)/kg] x 2 (IU/dL per IU/kg) The dose to achieve a desired in vivo peak increase in Factor VIII level may be calculated using the following formula: Dose (IU) = body weight (kg) x Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)
The label notes that one IU of ELOCTATE per kg body weight increases the circulating level of Factor 8 by 2 IU/dL and provides two formulas: One calculating the expected in vivo peak given a certain dose, and another to identify the dose required to reach a desired factor 8 rise
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12. Dosage and Administration: Alprolix (rFIXFc) Dosing Guidelines
ALPROLIX, Coagulation Factor IX (Recombinant), Fc Fusion Protein, is a recombinant DNA derived, coagulation Factor IX concentrate indicated in adults and children with hemophilia B
1 IU ALPROLIX/kg increases circulating Factor IX 1% [IU/dL]. Estimate required dose or expected in vivo peak increase in Factor IX level expressed as IU/dL (or % of normal) using the following formulas:
IU/dL (or % of normal) =
[Total Dose (IU)/Body Weight (kg)] x Recovery (IU/dL per IU/kg) OR
 Dose (IU) =
Body Weight (kg) x Desired Factor IX Rise (IU/dL or %)
x Reciprocal of Recovery (IU/kg per IU/dL)
Dose adjustment may be necessary in pediatric patients under 12 years of
For patients 12 years of age or older, dose adjustment is not usually required.
Similar
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13. How do extended half-life products change treatment in hemophilia?
Acute bleeding
Surgery
Prophylaxis
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14. Dosing regimens for Acute Bleeding events
Efficacy comparable to standard coagulation factors:
impact of EHL rFVIII is less remarkable than EHL rFIX products
Type of bleeding
Dosage
Frequency of dosing (hours)
rFVIII Standard
rFVIII EHL
Minor/Moderate
20-40 IU/kg
20-30 IU/kg
12 to 24
24 to 48
Major (Life threatening hemorrhages)
40-50 IU/kg
8 to 24
Doses similar, frequency differs
Type of bleeding
Dosage
Frequency of dosing (hours)
rFIX Standard
rFIX EHL
Minor/Moderate
30-60 IU/kg
12 to 24 48
Major (Life threatening hemorrhages)
60-80 IU/kg
IU/kg
24 for the first 3 days, then every 48 hours
US Product inserts, Eloctate and Alprolix
Mahlangu et al Blood 2014
Powell et al N Engl J Med 2013
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15. Routine prophylaxis rFVIII extended half-life
Standard
EHL
Low dose
prophylaxis with EHL#
Recommended dose
20-40 IU/kg
25-65 IU/kg
10-20 IU/kg
Frequency
2 days
3-5 days
4-7 days
Doses similar, frequency differs
#No data available for the EHL yet
Eloctate product insert
Mahlangu et al Blood 2014
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16. Routine prophylaxis rFIX extended half-life
Standard
EHL
Low dose
prophylaxis with EHL#
Recommended dose
50 IU/kg
100 IU/kg
10-20 IU/kg
Frequency
3-4 days
7 days
10-14 days
7-10 days
Doses similar, frequency differs,
overall dose less
#No data available for the EHL yet
Alprolix product insert
Powell et al NEJM 2013
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17. Efficacy - rFIX extended half-life
These protein engineered drugs simplify prophylactic regimens
Conventional products  2 infusions/week
rFIX Extended half-life  1 infusion/1-2 weeks
Reduction in injection frequency  50-75%
Monday
Thursday
Sunday
Critical level
Conventional products  3-4 infusions/week
rFIX Extended half-life  1-2 infusion/week
Reduction in injection frequency  33-66%
Extended protection from bleeding
Improving adherence and burden of therapy
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18. Surgery rFVIII extended half-life
The rFVIII extended half-life products may offer small impact on dosing frequency during the first 48 hours
The daily dose adopted with rFVIII-Fc is similar to that of standard rFVIII
rFVIII requires median total dose of IU/kg (day of surgery)
rFVIII-Fc requires median total dose of IU/kg (day of surgery)
As with conventional FVIII use peri-surgery, dose and frequency should be based upon measured FVIII activity levels
(Mahlangu JN et al. Thromb Haemost 2016; 116:
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19. Surgery rFVIII extended half-life
Initial dose similar, frequency differs
(Highlights of prescribing information to use standard rFVIII)
(Highlights of prescribing information to use Eloctate, rFVIII-Fc)
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20. Surgery rFIX extended half-life
rFIX extended half-life products enable marked reduction in dosing frequency for major surgical procedures
Daily dose rFIX-Fc less than standard rFIX
rFIX median dose 154 IU/kg (day of surgery)
rFIX-Fc median dose IU/kg (day of surgery)
After 3 days, dosing intervals may be extended
Dose and frequency should be based upon measured FIX activity levels
(Powell JS et al. Br J Haematol. 2015;168:124–34.; Ragni MV et al. J Haemophilia 2002; 8: 91–7)
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21. Surgery rFIX extended half-life
Initial dose similar, frequency differs
(Highlights of prescribing information to use standard rFIX)
(Highlights of prescribing information to use Alprolix, rFIX-Fc)
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22. Warnings and Precautions
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, possible with ELOCTATE and ALPROLIX. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.
Neutralizing Antibodies
Formation of neutralizing antibodies (inhibitors) to Factor VIII or Factor IX can occur following administration of ELOCTATE or ALPROLIX. If the plasma Factor level fails to increase as expected or if bleeding is not controlled after Factor administration, suspect the presence of an inhibitor (neutralizing antibody).
Monitoring Laboratory Tests:
Factor VIII results can be obtained with all instruments and reagents.
Factor IX results can be affected by the type of aPTT reagent used. Measurement with a one-stage clotting assay using a kaolin-based aPTT reagent will likely result in an underestimation of activity level. Ellagic acid and silica reagents are ok.
Class Effects
The Warnings and Precautions section of the label states that hypersensitivity reactions, including anaphylaxis, are possible with ELOCTATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. The label states to immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.
Furthermore, formation of neutralizing antibodies – inhibitors - to Factor 8 can occur following administration of ELOCTATE. The label states to monitor all patients for the development of Factor 8 inhibitors by appropriate clinical observations and laboratory tests. If the plasma Factor 8 level fails to increase as expected or if bleeding is not controlled after ELOCTATE administration, the label indicates that one should suspect the presence of an inhibitor.
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23. Use in Specific Populations Pediatric Use
Pharmacokinetic studies in children show shorter half-life and lower recovery of Factor VIII and Factor IX compared to adults. Because clearance has been shown to be significantly higher in the younger, pediatric population (2 to 5 years of age), higher and/or more frequent dosing based on body weight may be needed.
Dosing needs similar, frequency differs
The label states that pharmacokinetic studies in children have demonstrated a shorter half-life and lower recovery of Factor 8 compared to adults. Because clearance has been shown to be significantly higher in the younger, pediatric population, specifically those 2 to 5 years of age, higher and/or more frequent dosing based on body weight may be needed.
Safety and efficacy studies have been performed in 56 previously treated, pediatric patients less than 18 years of age who received at least one dose of ELOCTATE as part of routine prophylaxis, on-demand treatment of bleeding episodes, or perioperative management.
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24. In Summary
Extended half life FVIII and FIX products have been approved for treatment and prevention of bleeding in Hemophilia A and B, respectively. These products contain an active Factor VIII or Factor IX molecule
EHL are similar to conventional FVIII and FIX products
Doses required to treat major and minor bleeding episodes and surgery
Assays to measure FVIII and FIX activity (with exceptions)*
EHL are different from conventional FVIII and FIX products
Prolonged dosing intervals for prophylaxis, acute treatment, and surgery
Second dose to treat bleeding may not be required
Next generation research: better protection and greater decrease in treatment burden, including gene therapy
*Eloctate- no assay issues
Alprolix- do not use kaolin to initiate One Stage assay
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25. Immune Tolerance Induction Not in Product Label
Eloctate
Anecdotal case reports of rapid induction of tolerance using Eloctate
Groomes et a., Reduction of Factor VIII Inhibitor Titers During Immune Tolerance Induction With Recombinant Factor VIII-Fc Fusion Protein, Pediatr Blood Cancer 2016 DOI /pbc
Malec, Ragni, et al., ASH patients who received IU/kg of rFVIIIFc for ITI therapy every other day or thrice weekly and achieved inhibitor level less than 0.6 B.U in 12 weeks
Alprolix
Extreme caution is warranted due to risk of anaphylaxis and/or nephrotic syndrome- class effect
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26. Thank You
Glenn Pierce MD PhD

27. Alprolix and Eloctate Bibliography-1
Peters RT, Low SC, Kamphaus GD, Dumont JA, Amari JV, Lu Q, Zarbis-Papastoitsis G, Reidy TJ, Merricks EP, Nichols TC, Bitonti AJ. Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood, 2010, 11;115: Shapiro AD, MV Ragni, LA Valentino, NS. Key, NC Josephson, JS. Powell, G Cheng, AR Thompson, J Goyal, KL Tubridy, RT. Peters, JA. Dumont, D Euwart, L Li, B Hallen, P Gozzi,1 AJ Bitonti, H Jiang, A Luk, GF Pierce, Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients Blood, 2012, 119: Dumont JA, T Liu, SC Low, X Zhang, G Kamphaus, P Sakorafas, C Fraley, D Drager, T Reidy, J McCue, HG Franck, EP Merricks, T Nichols, AJ Bitonti, GF Pierce, H Jiang. Prolonged Activity of a Recombinant Factor VIII-Fc Fusion Protein In Hemophilia A Mice And Dogs Blood, 2012, 119: Powell JS, NC Josephson, DQuon3, MV Ragni, G Cheng5, E Li, H Jiang, L Li, JA Dumont, J Goyal, X Zhang, J Sommer, J McCue, M Barbetti, A Luk, GF Pierce Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients Blood, 2012, 119: Peters RT, G Toby, Q Lu, T Liu, JD Kulman, SC Low, AJ Bitonti, GF Pierce. Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. Thromb Haemost, 2013, 11: Powell JS, J Pasi, MV Ragni, MC Ozelo, L Valentino, JN Mahlangu, NC Josephson, D Perry, MJ Manco-Johnson, S Apte, RI Baker, GC Chan, N Novitzky, RS Wong, S Krassova, G Allen, H Jiang, A Innes, S Li, LM Cristiano, J Goyal, JM Sommer, JA Dumont, K Nugent, G Vigliani, A Brennan, A Luk, GF Pierce, on behalf of the B-LONG investigators. Phase 3 study of recombinant factor IX Fc in hemophilia B. N Engl J Med, 2013, 369: Mahlangu J, J Powell, M Ragni, P Chowdary, N Josephson, I Pabinger, H Hanabusa, N Gupta, R Kulkarni, P Fogarty, D Perry, A Shapiro, J Pasi, S Apte, I Nesterov, H Jiang, S Li, S Neelakantan, LM Cristiano, J Goyal, J Sommer, JA Dumont, N Dodd, K Nugent, G Vigliani, A Luk, A Brennan, GF Pierce, on behalf of the A-LONG investigators. Phase 3 study of recombinant factor VIII Fc in hemophilia A. Blood, 2014, 123: Sommer JM, N Moore, B McGuffie-Valentine, S Bardan, Y Buyue, GD Kamphaus, BA Konkle, GF Pierce. Comparative field study evaluating the activity of recombinant Factor VIII-Fc fusion protein (rFVIIIFc) in plasma samples at clinical haemostasis laboratories. Haemophilia, 2014, 20: McCue J, D Osborne, J Dumont, R Peters1, B Mei1, GF Pierce, K Kobayashi, D Euwart. Validation of the manufacturing process used to produce long- lasting recombinant factor IX Fc fusion protein. Haemophilia 2014; 20:e327-e335. Sommer JM, Y Buyue* S Bardan, RT Peters, H Jiang, GD Kamphaus, E Gray, GF Pierce. Comparative field study: impact of laboratory assay variability on the assessment of recombinant factor IX Fc fusion protein (rFIXFc) activity. Thromb Haemost 2014; 112: Shapiro A, Ragni M, Kulkarni R, Oldenburg J, Srivastava A, Quon D, Pasi J, Hanabusa H, Pabinger I, Mahlangu J, Fogarty P, Lillicrap D, Kulke S, Potts J, Neelakantan S, Nestorov I, Li S, Dumont J, Jiang H, Brennan A, Pierce GF. Dosing Recombinant Factor VIII Fc Fusion Protein: Relationship of Extended Dosing Interval to Prior Treatment Regimen and Baseline von Willebrand Factor Level. J Thromb Haemost, 2014; 12: Powell J, A Shapiro, M Ragni, C Negrier, J Windyga, M Ozelo, J Pasi, R Baker, J Potts, S Li, B Mei, GF Pierce, B Robinson. Switching to recombinant factor IX Fc fusion protein prophylaxis results in fewer infusions, decreased FIX consumption, and lower bleeding rates. Brit J Haematol, 2015; 168:
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28. Alprolix and Eloctate Bibliography-2
Powell J, S Apte, H Chambost, C Hermans, S Jackson, N Josephson, J Mahlangu, M Ozelo, K Peerlinck, J Pasi, D Perry, M Ragni, X Wang, H Jiang, S Li, LM Christiano, A Innes, K Nugent, A Brennan, A Luk, G Allen, GF Pierce, B Robinson. Long-Lasting Recombinant Factor IX Fc Fusion (rFIXFc) for Perioperative Management of Subjects with Haemophilia B in the Phase 3 B-LONG Study. Brit J Haematol, 2015; 168: G Young, J Mahlangu, R Kulkarni, B Nolan, R Liesner, J Pasi, C Barnes, S Neelakantan‡, G Gambino, LM Cristiano, GF. Pierce, G Allen, for the Kids A-LONG Investigators. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost, 2015; 13: Nolan B, J Mahlangu, D Perry, G Young, R Liesner, B Konkle, S Rangarajan, S Brown, H Hanabusa, KJ Pasi, I Pabinger, S Jackson, LM Cristiano, X Li, GF Pierce, G Allen. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A. 2015, Haemophilia doi: /hae McCue J, Ri Kshirsagar, K Selvitelli, B Mei, R Peters, GF Pierce, J Dumont, S Raso, H Reichert. Manufacturing process used to produce longer lasting recombinant factor VIII Fc fusion protein, Biologicals 2015; 43: Dumont J, KS Loveday, DR Light, GF Pierce, H Jiang. Evaluation of the Toxicology, Pharmacokinetics, and Local Tolerance of Recombinant Factor IX Fc Fusion Protein in Animals. Thromb Res 2015; 136: Hanabusa H, M Shima, K Nogami, T Matsushita, K Fukutake, M Taki, M Sekai, Y Dong, S Neelakantan, LM. Cristiano, GF. Pierce, B Mei. Evaluation of the Safety, Pharmacokinetics, and Efficacy of Recombinant Factor VIII Fc Fusion Protein in Japanese Subjects With Severe Haemophilia A: Analysis from the A-LONG Study. Haemophilia In press. M Shima, K Fukutake, H Hanabusa, T Matsushita, M Taki, M Sakai, T Hirakata, Y Dong, S Li, LM Cristiano, GF Pierce, B Mei. Japanese Subject Subpopulation Analysis of B-LONG: A Phase 3 Study of Long-Acting Recombinant Factor IX Fc Fusion Protein. Japanese J Thromb Haemost. Toby GG, T Liu, Buyue Y, X Zhang, AJ Bitonti, GF Pierce, J Sommer, H Jiang, RT Peters. Recombinant factor IX-Fc maintains full procoagulant properties and exhibits prolonged efficacy in hemophilia B mice. 2015, PLOS One, Submitted. Krishnamoorthy S, T Liu, D Drager, S Patarroyo-White, E Seth-Chhabra, R Peters, N Josephson, D Lillicrap, R Blumberg, GF Pierce, H Jiang. Tolerance Induced by Recombinant Factor VIII Fc (rFVIIIFc) Fusion Protein in Hemophilia A Mice. Submitted Wyrwich KW, S Krishnan, P Auguste, J-LL Poon, R von Maltzahn, R Yu, GF Pierce, B Mei, J Mahlangu, S von Mackensen. Health-Related Quality of Life Changes with Treatment of Longer Acting Clotting Factors: Haem-A-QoL Scores in the A­LONG and B-LONG Clinical Studies of Recombinant Factor VIII and IX Fc Fusion Proteins. Submitted. Dumont, J, KS Loveday, DR Light, GF Pierce, H Jiang. Evaluation of the Toxicology and Pharmacokinetics of Recombinant Factor VIII Fc Fusion Protein in Animals Submitted Thromb Res. AD Shapiro, JN Mahlangu, D Perry, J Pasi, DV Quon, P Chowdary, E Tsao, S Li, A Innes, GF Pierce, GA Allen, B Robinson. Treatment of Bleeding Episodes With Recombinant Factor VIII Fc Fusion Protein in Subjects With Severe Hemophilia A in the Phase 3 A-LONG Study. Submitted K Fischer, R Kulkarni, B Nolan, J Mahlangu, S Rangarajan, G Gambino, L Diao, A Ramirez-Santiago, GF Pierce, G Allen. Recombinant Factor IX Fc Fusion Protein in Children with Hemophilia B. Submitted. J Pasi, M Ozelo, J Mahlangu, M Ragni, D Perry, E Tsao, S Li, A Innes, G Pierce, B Mei, B Robinson. Treatment of Bleeding Episodes in Subjects With Hemophilia B Using Recombinant Factor IX Fc Fusion Protein in the Phase 3 B-LONG Study. Submitted Rath T, K Baker, JA Dumont, RT Peters, H Jiang, S-W Qiao, WI Lencer, GF Pierce, RS Blumberg. Fc-fusion proteins and FcRn: structural insights for longer lasting and more effective therapeutics. Crit Rev Biotechnol Jun;35(2):
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29. Structure of Fc Fusions
1 FVIII/FIX:2 Fc S S S S S S A1 A2 A3 C1 C2 Fc
Eloctate Fc
metal ion-mediated non-covalent bond
glycosylated asparagine
disulfide bridge
free cysteine S
sulfated tyrosine g g g g g g
PRO
GLA H
EGF-B
EGF-A
ACT PEP
CATALYTIC Fc
PRE g g g g g g b S P Fc
N-glycosylation
Interchain disulfide bond g
Gamma carboxylated
glutamic acid S
Tyrosine sulfation P
Serine phosphorylation
O-glycosylation b
b-hydroxylation
Alprolix
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30. 12: Clinical Pharmacology 12.1: Mechanism of Action
ELOCTATE is a recombinant fusion protein that temporarily replaces the missing Coagulation Factor VIII needed for effective hemostasis. ELOCTATE contains the Fc region of human immunoglobulin G1 (IgG1), which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation and prolonging their plasma half-life.
The Mechanism of Action section states that ELOCTATE is a recombinant fusion protein that temporarily replaces the missing Coagulation Factor 8 needed for effective hemostasis.
ELOCTATE contains the Fc region of human immunoglobulin G1, which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation and prolonging their plasma half-life.
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31. Global study including 17 countries Enrolling centers: 50
A-LONG B-LONG
Global study including 17 countries
Enrolling centers: 50
Overall 93.5% of subjects completed study
55 subjects had ≥50 EDs
Global study including 19 countries
Enrolling centers: 60
Overall, 92.7% of subjects completed study
At end of study, 111 subjects completed ≥50 EDs
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32. How is rFVIIIFc Produced?
Different
B-domain deleted (BDD)-rFVIIIFc produced by recombinant DNA technology from a human embryonic kidney (HEK) cell line, which has been extensively characterized. HEK cell line expresses BDD-rFVIIIFc into defined, cell culture medium containing no materials derived from animal or human sources. BDD-rFVIIIFc purified using a series of chromatography steps, including affinity capture with a recombinant, single chain antibody fragment produced in a yeast expression system. No human or animal derived proteins are used in the purification or formulation processes. The production process also incorporates two dedicated viral clearance steps - detergent treatment step for inactivation and 15 nm filtration step for removal of viruses.
Similar
BDD-rFVIIIFc is produced by recombinant DNA technology from a human embryonic kidney (HEK) cell line, which has been extensively characterized. The HEK cell line expresses BDD-rFVIIIFc into a defined, cell culture medium that does not contain any proteins derived from animal or human sources.
→ BDD-rFVIIIFc is purified using a series of chromatography steps, including affinity capture with a recombinant, single chain antibody fragment produced in a yeast expression system.
→ No human or animal derived proteins are used in the purification or formulation processes.
→ The production process also incorporates two dedicated viral clearance steps - a detergent treatment step for inactivation and a 15 nm filtration step for removal of viruses.
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33. Dosage and Administration: Routine Prophylaxis
Different
Recommended starting regimen: 50 IU/kg of ELOCTATE administered every 4 days Regimen may be adjusted based on patient response: IU/kg at 3-5 day intervals More frequent or higher doses up to 80 IU/kg may be required in children less than 6 years of age.
For routine prophylaxis the recommended starting regimen is 50 IU/kg of ELOCTATE administered every 4 days.
→The regimen may be adjusted based on patient response with dosing in the range of 25 to 65 IU/kg at 3 to 5 day intervals.
More frequent or higher doses up to 80 IU/kg may be required in children less than 6 years of age.
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34. Clinical Pharmacology Pharmacokinetics
PK of ELOCTATE (rFVIIIFc) was evaluated in 28 subjects following 10 minute intravenous infusion of single 50 IU/kg dose. PK profile obtained at week 14, after repeated dosing, was comparable with the PK profile obtained after the first dose. PK data demonstrate that ELOCTATE has a prolonged circulating half-life. Conventional FVIII half life is ~12 hr in adults
Table 4: Pharmacokinetic Parameters* (arithmetic mean, 95% CI)
PK Parameters
rFVIIIFc (95% CI) N = 28
Cmax (IU/dL)
109 (102, 116)
Terminal half-life (h)
19.7 (17.4, 22.0)
CL (mL/h/kg)
2.06 (1.78, 2.34)
Vss (mL/kg)
49.5 (46.9, 52.2)
Incremental Recovery (IU/dL per IU/kg)
2.26 (2.13, 2.40)
Time to 1% (days)
5.10 (4.54, 5.66)
Different
The pharmacokinetics of ELOCTATE were evaluated in 28 subjects following a 10 minute intravenous infusion of a single dose of 50 IU/kg. The PK parameters in table 4 were based on plasma 8 activity measured by the one-stage clotting assay. The PK profile obtained at week 14, after repeated dosing, was comparable with the PK profile obtained after the first dose. The PK data demonstrate that ELOCTATE™ has a prolonged circulating half-life
Section 12.3 goes on to detail the pharmacokinetic parameters—expressed as the arithmetic mean—in Table 4 of Section 12. For those of you familiar with the primary manuscript of the A-LONG paper, you may recall that the half-life was listed as 19.0 hours; whereas Table 4 gives the half-life as 19.7 hours. It is important to understand the difference between these two values. The half-life listed in the label was calculated based on the arithmetic mean, whereas the half-life in the primary manuscript was expressed as a geometric mean. Geometric means are more conservative than arithmetic means. Industry standard for labeling uses arithmetic means.
(note to programmer: add in time for the viewer to read the table).
*Based on a 50 IU/kg dose; Abbreviations: CI = confidence interval; Cmax = maximum observed activity; CL = clearance; Vss = body weight adjusted volume of distribution at steady-state; Time to 1% = time after dose when FVIII activity has declined to 1 IU/dL above baseline.
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35. Clinical Pharmacology Pharmacokinetics Table 5: Comparison of PK Parameters of ELOCTATE by Age
Pediatric Study
Phase 3 Study
2 to 5 years
N = 10
6 to 11 years
N = 27
12 to 17 years
N = 11
IR (IU/dL per IU/kg)
1.89 (1.75, 2.03)
2.44 (2.02, 2.85)
1.85 (1.58, 2.12)
t½ (h)
12.0 (9.55, 14.4)
14.6 (11.5, 17.7)
16.4 (14.1, 18.6)
CL (mL/h/kg)
3.88 (2.91, 4.49)
2.70 (2.30, 3.09)
2.66 (2.34, 2.98)
Vss (mL/kg)
58.7 (54.7, 62.6)
49.9 (44.5, 55.3)
60.3 (53.3, 67.3)
Table 5 of Section 12.3 outlines the PK parameters for patients 2 to 5 years, 6 to 11 years and 12 to 17 years of age. Again, note that these PK parameters are expressed as the arithmetic mean.
(note to programmer: add in time for the viewer to read the table).
Table 5 presents the PK parameters calculated from the pediatric data of 48 subjects, less than 18 years of age after receiving a single 50 IU/kg dose.
1PK parameters are presented in arithmetic mean (95% CI); Abbreviations: CI = confidence interval IR=incremental recovery;1/2 = elimination half-life; CL = clearance; Vss = volume of distribution at steady-state
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36. Bleeding Episode Etiology Individualized Prophylaxis
Clinical Studies Table 7: Median (IQR)1 Annualized Bleed Rate by ELOCTATE Treatment Arm
Bleeding Episode Etiology
Individualized Prophylaxis
(N=117)
Weekly
Prophylaxis
(N=23)
Episodic
(On-Demand)
Overall ABR
1.60
(0.00, 4.69)
3.59
(1.86, 8.36)
33.57
(21.14, 48.69)
Spontaneous ABR
0.00
(0.00, 2.03)
1.93
(0.00, 4.78)
20.24
(12.21, 36.81)
Joint ABR
(0.00, 3.11)
(0.00, 7.62)
22.76
(15.07, 39.02)
Table 7 of the clinical studies section of the label lists the median annualized bleeding rate by treatment arm. 117 patients had an overall median ABR of 1.6 in the individualized prophylaxis arm. 23 subjects had an overall median ABR of 3.59 in the fixed-weekly prophylaxis arm and 23 subjects had an overall median ABR of in the episodic arm.
Spontaneous annualized bleeding rates were 0 in the individualized arm, 1.93 in the fixed-weekly arm and in the episodic arm.
1Median (interquartile range, 25th and 75th percentiles).
Pierce/WFH

37. 6: Adverse Reactions 6.2: Immunogenicity
Clinical trial subjects were monitored for neutralizing antibodies to Factor VIII. No subjects developed confirmed, neutralizing antibodies to Factor VIII. One 25 year old subject had a transient, positive, neutralizing antibody of 0.73 BU at week 14, which was not confirmed upon repeat testing 18 days later and thereafter. The detection of antibodies that are reactive to Factor VIII is highly dependent on many factors, including: the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease.
Immunogenicity is described in section Subjects in the phase 3 clinical trials were monitored for neutralizing antibodies to Factor VIII. No subjects developed confirmed, neutralizing antibodies to Factor VIII. One 25 year old subject had a transient, positive, neutralizing antibody of 0.73 BU at week 14, which was not confirmed upon repeat testing 18 days later and thereafter.
The label notes that the detection of antibodies that are reactive to Factor 8 is highly dependent on many factors, including: the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease
Pierce/WFH

38. Dosage and Administration Routine Prophylaxis Alprolix
The recommended starting regimens are either:
50 IU/kg once weekly
OR:
100 IU/kg every 10 days
Adjust dosing regimen based on individual response.  
Different
Pierce/WFH

39. Pharmacokinetics: ALPROLIX Adults
PK data demonstrate that ALPROLIX has prolonged circulating half-life.
Table 4: Pharmacokinetic Parameters (Arithmetic Mean, CV)
PK Parameters
rFIXFc (50 IU/kg)
(N = 22)
Cmax (IU/dL)
(68.3%)
CL (mL/kg/h)
(28.4%)
Vss (mL/kg)
(28.2%)
Terminal T1/2 (h)
(37.2%)
IR (IU/dL per IU/kg)
(58.7%)
Time to 1% FIX activity (d)
(23.8%)
Different
PK parameters are presented in arithmetic mean (CV%)
Abbreviations: IR = incremental recovery; T1/2 = elimination half-life; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state, Time to 1% FIX activity = estimated time in days after dose when FIX activity has declined to approximately 1 IU/dL above baseline
Pierce/WFH

40. Pharmacokinetics Table 5: Comparison of Pharmacokinetic Parameters of rFIXFc by Age Category
PK parameter1
2 to 5 years
(N = 5)
6 to 11 years
(N = 13)
12 to 17 years
(N = 11)
IR (IU/dL per IU/kg)
(15.7%)
(29.2%)
(36.4%)
T½ (h)
(32.1%)
(23.1%)
(19.1%)
CL (mL/h/kg)
4.406 (16.8%)
(25.1%)
(25.6%)
Vss (mL/kg)
(19.2%)
(28.5%)
(24.9%)
Different
1PK parameters are presented in arithmetic mean (CV%)
Abbreviations: IR = incremental recovery; T ½= elimination half-life; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state
Pierce/WFH

41. Pharmacokinetics: ALPROLIX Adults
100 IU/kg dose
ALPROLIX™
Pharmacokinetics
Cmax, IU/dL
99.89 (20.1%)
Clearance, mL/kg/h
2.65 (21.7%)
Time to 1% FIX activity, days
15.8 (21.3%)
n=27
Different
Pierce/WFH

42. Similar Clinical Studies 2.95 1.38 17.69
Table 7: Median Annualized Bleeding Rate by Treatment Arm
Bleeding Episode Etiology
Prophylaxis Fixed Weekly Interval (N=61)
Prophylaxis Individualized Interval (N=26)
Episodic (On Demand) (N=27)
Overall ABR
(IQR)*
2.95
(1.01, 4.35)
1.38
(0.00, 3.43)
17.69
(10.77, 23.24)
Spontaneous ABR (IQR)*
1.04
(0.00, 2.19)
0.88
(0.00, 2.30)
11.78
(2.62, 19.78)
* IQR=interquartile range
Five subjects (2 in prophylaxis fixed weekly interval arm, 3 in prophylaxis individualized interval arm) did not have sufficient data to be included in the efficacy analysis.
Pierce/WFH

43. Pediatric Use
Safety, efficacy and pharmacokinetics of rFIXFc in children with haemophilia B: Results of the Kids B-LONG study
International Society on Thrombosis and Haemostasis - 25th Congress
June 20-15, 2015
Toronto
Kathelijn Fischer1, Roshni Kulkarni2, Beatrice Nolan3, Johnny Mahlangu4, Savita Rangarajan5, Giulia Gambino6, Lei Diao6, Alejandra Ramirez-Santiago6, Glenn F. Pierce6, Geoffrey Allen6
Pierce/WFH

44. rFVIIIFc (Eloctate) and rFIXFc (Alprolix) Dosing Regimens
Pierce/WFH

45. Long Term Safety
Pierce/WFH

46. Surgery Using Eloctate and Alprolix
Brit J Haematol, 2015; 168:
Surgery Using Eloctate and Alprolix
Pierce/WFH

47. Pierce/WFH

48. Thromb Haemost 2014; 112: 932–940
Pierce/WFH