New Treatment New Treatment Modalities; Modalities; Recombinant Factor Recombinant Factor VIII Products – VIII Products – “Factor VIII after “Factor VIII after 2008” 2008” (More Choices) (More Choices) Gita V. Massey, MD Gita V. Massey, MD June 20, 2009 June 20, 2009
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New Treatment Modalities; Recombinant Factor VIII Products – “Factor VIII after 2008” (More Choices) Gita V. Massey, MD June 20, 2009.
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New Treatment Modalities;New Treatment Modalities;Recombinant Factor VIII Recombinant Factor VIII Products – “Factor VIII Products – “Factor VIII
after 2008”after 2008”(More Choices)(More Choices)
Gita V. Massey, MDGita V. Massey, MD
June 20, 2009June 20, 2009
The Goals of Safe TherapyThe Goals of Safe Therapy Promote adequate Promote adequate
hemostasis with minimal hemostasis with minimal side effectsside effects
Prevent transmission of Prevent transmission of viral and “other” viral and “other” pathogenspathogens
Decrease thrombogenicity Decrease thrombogenicity of concentrates used to of concentrates used to treat Factor IX deficiencytreat Factor IX deficiency
Promote hemostasis in the Promote hemostasis in the presence of inhibitors presence of inhibitors (and minimize inhibitor (and minimize inhibitor formation?)formation?)
Cost and ease of useCost and ease of use
Safety from Pathogen Safety from Pathogen TransmissionTransmission
Where are we coming from?Where are we coming from?Donor SelectionDonor Selection
Recovered plasma from volunteer Recovered plasma from volunteer donorsdonors
Questioning about infectious risksQuestioning about infectious risksSource plasma from apheresis Source plasma from apheresis
donorsdonors
Where are we coming from?Where are we coming from?Plasma ScreeningPlasma Screening
1940’s – syphilis1940’s – syphilis1972 – hepatitis B surface antigen1972 – hepatitis B surface antigen1985 – HIV antibody1985 – HIV antibody1987 – ALT 1987 – ALT (surrogate marker for (surrogate marker for
hepatitis)hepatitis)1990 – Hepatitis C antibody1990 – Hepatitis C antibodyNow – “NAT” Now – “NAT” (nucleic acid testing)(nucleic acid testing) HAV, HAV,
HBV, HCV, HIV, B-19HBV, HCV, HIV, B-19
Where are we coming from?Where are we coming from?Viral InactivationViral Inactivation
Heat treatmentHeat treatment Late 1970’s, early 1980’s -“pasteurization” and “dry”Late 1970’s, early 1980’s -“pasteurization” and “dry” Not effective for hepatitis, B-19Not effective for hepatitis, B-19 Fear of increased inhibitors with denatured proteinFear of increased inhibitors with denatured protein
Solvent DetergentSolvent Detergent 19851985 Dissolving lipid envelopes of virusesDissolving lipid envelopes of viruses Not effective against HAV and B-19Not effective against HAV and B-19
Increased PurificationIncreased Purification Specific activity (increase amount of desired protein)Specific activity (increase amount of desired protein) 1980’s – immuno-affinity purification (monoclonal 1980’s – immuno-affinity purification (monoclonal
antibodies)antibodies) High purity does not equal high safetyHigh purity does not equal high safety
REMEMBERREMEMBER CDC maintains CDC maintains
surveillance over viral surveillance over viral infections transmitted by infections transmitted by plasma productsplasma products
Last HIV transmissions Last HIV transmissions from a USA concentrate from a USA concentrate were in 1987 were in 1987
No viral-inactivated No viral-inactivated concentrate made from concentrate made from HIV-Ab screened plasma HIV-Ab screened plasma has transmitted HIVhas transmitted HIV
No transmission of No transmission of hepatitis by modern hepatitis by modern concentrates has been concentrates has been observedobserved
We have arrived!We have arrived!The Recombinant ProductsThe Recombinant Products
1990’s1990’s Human genes Human genes
transfected into nuclei transfected into nuclei of hamster cellsof hamster cells
Cells replicate and Cells replicate and express factor in express factor in culture mediumculture medium
Factor is extracted Factor is extracted from culture medium from culture medium by chromatographyby chromatography
Factor stabilized – Factor stabilized – albumin or sugarsalbumin or sugars
Recombinant ProductsRecombinant Products
AdvantagesAdvantages Less viral Less viral
contaminationcontamination Production of Production of
“designer” “designer” moleculesmolecules
DisadvantagesDisadvantages Discordance of Discordance of
labelled units (labelled units (in in vitrovitro) vs. recovery ) vs. recovery in patients (in patients (in vivoin vivo))
Laboratory assay Laboratory assay methodsmethods
Cannot absolutely Cannot absolutely exclude pathogenic exclude pathogenic viruses in hamster viruses in hamster cell culturescell cultures
The Product GenerationsThe Product Generations
First GenerationFirst Generation Media enriched with human or animal plasma proteins for initial cell Media enriched with human or animal plasma proteins for initial cell
cultureculture Albumin in final formulationAlbumin in final formulation
Second GenerationSecond Generation Sucrose substituted for albumin in final formulationSucrose substituted for albumin in final formulation
Third GenerationThird Generation No human or animal plasma proteins in purification or final formulationNo human or animal plasma proteins in purification or final formulation
perception of risk is perception of risk is serious and validserious and valid
Newly-diagnosed Newly-diagnosed patients and patients and patients who have patients who have only used only used recombinant factors recombinant factors in the pastin the past
The Other Recombinant The Other Recombinant FactorsFactors
BenefixBenefix Factor IX deficiencyFactor IX deficiency Similar production Similar production
to factor VIII to factor VIII productsproducts
Problems with Problems with calculated dose calculated dose matching recovered matching recovered dosedose
NovoSevenRTNovoSevenRT Used for Factor VII Used for Factor VII
Similar production to Similar production to factor VIII productsfactor VIII products
Problems include Problems include cost, very short half-cost, very short half-life, antibodies, and life, antibodies, and possible possible thrombogenicitythrombogenicity
The Global PictureThe Global Picture
80% of estimated 80% of estimated 400,000 people 400,000 people with hemophilia with hemophilia receive no receive no treatmenttreatment
The Future – Where are we The Future – Where are we Going?Going?
bioengineered for bioengineered for improved therapeutics improved therapeutics – the “designer – the “designer molecules”molecules” Improve biosynthesis Improve biosynthesis
and secretionand secretion Prolong half-life – Prolong half-life –