View
222
Download
0
Category
Preview:
Citation preview
Personalized hemophilia treatment
Abdulkareem Almomen, MD, FRCPC, Professor of Medicine-Hematology,
King Saud University & Blood and Cancer Center, Riyadh
Jeddah, 24 February 2018
CONFIDENTIAL; DO NOT DISTRIBUTE
• Nonfactor replacement therapies for hemophilia
• Anti-tissue factor pathway inhibitor [Anti-TFPI]; OW/SC
• RNA interference agent against antithrombin; OW/SC
• Gene Therapy
Gene therapy has the potential to lessen disease severity from a severe phenotype to a moderate or mild phenotype through continuous production of factor VIII or IX after one administration of a gene vector, especially since a small rise in circulating coagulant proteins to at least 1% of normal levels can substantially ameliorate the bleeding phenotype.
Future Therapies
3
Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet. 2016;388(10040):187-197
Gene Therapy
• Gene therapy has the potential to lessen disease severity from a severe phenotype to a moderate or mild phenotype through continuous production of factor VIII or IX after one administration of a gene vector, especially since a small rise in circulating coagulant proteins to at least 1% of normal levels can substantially ameliorate the bleeding phenotype.
What Is Gene Therapy?
• Gene therapy is1-2:
– A strategy used to replace or repair a dysfunctional gene
– Most applicable to diseases caused by a single gene mutation
– An approach to improve symptoms or potentially cure a disease
– Administered ex vivo or in vivo, depending on the vector
• The vector (vehicle based on the capsid of a nonreplicating virus) delivers the desired gene to a particular “target”3
1. Kumar SR, et al. Mol Ther Methods Clin Dev. 2016;3:16034. 2. Thomas CE, et al. Nat Rev Genet. 2003;4(5):346-358. 3. Mingozzi F, et al. Blood.
2013;122(1):23-36.
Gene Therapy
Gene delivery vehicle or carrier
Gene that works
Cell
Nucleus
Added Gene
Genetic Material (Chromosomes)
Gene therapy aims to give a gene that works correctly to a person who needs it.
Gene Therapy
• A cell contains genetic material within its nucleus made up of genes in chromosomes
• These genes provide instructions to the cell and help it make proteins (like clotting factor)
• When genes are missing or incorrect, it is difficult for the cell to work correctly
Cell
Nucleus
Genetic Material (Chromosomes)
Background
• Proper factor VIII dosage requirement for hemophilia patients varies significantly due multifactorial influence including individual pharmacokinetics (PK), age, blood group, gender, type of factor used and type of test.
• Therefore PK has to be performed for each patient according to each clotting factor and has to be repeated at certain intervals
Effect of blood groups on FVIII& VWF O vs non- O (A,B,AB)
0
20
40
60
80
100
120
Group o Group A,B,AB
FVIII:C VWF:Ag
Effect of age on: FVIII:C, VWF: Ag, VWF:CBA, VWF:Rcof, and ADAMTS13
0%
20%
40%
60%
80%
100%
120%
140%
160%
Age <40 y Age: 50 y Age > 50 y
FVIII:C VWF:Ag ADAMTS13
Effect of age on clearance and T1/2 of FVIII
0
2
4
6
8
10
12
14
16
FVIII T1/2 (H)1 5 10 20 30 40 50 60 70
Variation of FVIII T ½ (H)
0
2
4
6
8
10
12
14
16
18
20
FVIII T 1/2 (h)
FVIII pd (14)
R.FIII(16)
BDD FVIII (11)
EHL FVIII (19)
Data are from different studies with different patients cohorts
Pharmacokinetic blood sampling
• Adults:(11 samples) at zero, 15 min, 30 min, 1 hour, 3, 6, 9 hours, 24, 28, 32 hours, 48 hours
• Children: (5 samples) 30 min., 1, 9 hours, 24 hours, 48 hours
New Methods !!!
New methods with less (2) blood samples
• Many methods are being developed as a software that requires only 2 blood samples within 48 hours after infusion.
• Each method is specific for each product
Variation of FIX T ½ (H)
0
10
20
30
40
50
60
70
80
90
100
FIX T1/2 (H)
pdFIX (16.5)
r.FIX (17.5)
EHL.FIX (86)
Data are from different studies with different patients cohorts
Frequency Impact?
EHLs every 7-10 days
SHLs once weekly data
!!!
Effect of laboratory tests
• Pre-analytical,
• Test performance,
• Type of test : PTT or chromogenic
• Specific tests
In summary
• Factor VIII & IX recovery, clearance and half-life are influenced by many factors including blood group, age, body weight, ethnicity, type of factor and type of testing.
• Population model PK is not suitable for individual patients,
• PK has to be performed for each patient individually, for each clotting factor concentrate and to be repeated at least once every 10 years, so that, adequate, cost effective dose and frequency can be calculated accurately for each patient
Recommended