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Personalized hemophilia treatment - hematology-sa.orghematology-sa.org/.../2018/03/Personalized-Hemophilia-  · PDF fileCONFIDENTIAL; DO NOT DISTRIBUTE •Nonfactor replacement therapies

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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

Evolution of Hemophilia Therapies:

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

Anti-tissue factor pathway inhibitor [Anti-TFPI];

Anti-tissue factor pathway inhibitor [Anti-TFPI];

RNA interference agent against antithrombin

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 target3

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

Population based PK model (cannot be )

FVIII clearance obtained from 100 (10-65 y, 10 samples) and 52 children (1-5 y, 4 samples)

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

Effect of age on VWF: Ag

Effect of age on ADAMTS13

Effect of age on: FVIII:C, VWF: Ag, VWF:CBA, VWF:Rcof, and ADAMTS13

0%

20%

40%

60%

80%

100%

120%

140%

160%

Age 50 y

FVIII:C VWF:Ag ADAMTS13

Effect of age on clearance and T1/2 of FVIII

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

Effect of weight & BMI on in-vivo recovery of FVIII

Variation of FVIII T (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 (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

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