new treatment modalities; recombinant factor viii products – “factor viii after 2008” (more...

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

Donor selectionDonor selection Plasma screeningPlasma screening Viral inactivationViral inactivation Recombinant productsRecombinant products

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

The ProductsThe Products

Recombinate (Baxter – 1Recombinate (Baxter – 1stst generation) generation)HelixateFS/KogenateFS (Bayer/ZLB HelixateFS/KogenateFS (Bayer/ZLB

Behring – 2Behring – 2ndnd generation) generation)ReFacto (Wyeth – 2ReFacto (Wyeth – 2ndnd generation) * generation) *Advate (Baxter – 3Advate (Baxter – 3rdrd generation) generation)Xyntha (Wyeth – 3Xyntha (Wyeth – 3rdrd generation) generation)

*ReFacto will not be available after 5/31/09*ReFacto will not be available after 5/31/09

Production of FactorsProduction of FactorsRECOMBINRECOMBINATEATE

KOGENATE KOGENATE FSFS

HELIXATE HELIXATE FSFS

REFACTOREFACTO(*ReFacto will not (*ReFacto will not be available after be available after 5/31/09)5/31/09)

ADVATEADVATE XYNTHAXYNTHA

CELL LINE CELL LINE FOR FOR EXPRESSIONEXPRESSION

CHOCHO BHKBHK CHOCHO CHOCHO CHOCHO

FVIII FVIII MOLECULEMOLECULE

Full-Full-lengthlength


B-B-domain domain deleteddeleted


B-B-domain domain deleteddeleted

STABILIZERSTABILIZER Human Human

albumialbuminn

SucroseSucrose SucroseSucrose TrehalosTrehalosee

MannitolMannitol

SucroseSucrose

PolysorbPolysorbate 80ate 80

PLASMAPLASMA

ALBUMIN-ALBUMIN-FREEFREE

METHODMETHOD

NoNo NoNo NoNo YesYes YesYes

VIRUSVIRUS

INACTIVATIINACTIVATION/ON/

PURIFICATIOPURIFICATIONN

IA, IEIA, IE IA, IE, IA, IE, SDSD

ultrafiltrultrafiltrationation

IA, IE, IA, IE, SDSD

nanofiltrnanofiltrationation


ultrafiltrultrafiltrationation


nanofiltrnanofiltrationation

Clinical Efficacy of FactorsClinical Efficacy of FactorsRECOMBINARECOMBINATETE

KOGENATE KOGENATE FSFS

HELIXATE FSHELIXATE FS

REFACTO REFACTO (*ReFacto will not (*ReFacto will not be available after be available after 5/31/09)5/31/09)


STUDIESSTUDIES PUP and PUP and PTPPTP

PUP and PUP and PTPPTP



PTPPTP

PUP in PUP in prgressprgress

EFFICACYEFFICACY 92-95% 92-95% Excellent/Excellent/

goodgood

80-90%80-90%

Excellent/Excellent/

goodgood

100% 100% surgerysurgery

92%92%


goodgood

86%86%


goodgood


92.5%92.5%


goodgood


HALF-LIFEHALF-LIFE 14.6+/-14.6+/-4.9hrs4.9hrs

13.3+/-13.3+/-1.6hrs1.6hrs

14.5+/-14.5+/-5.3hrs5.3hrs

12.0+/-12.0+/-4.3hrs4.3hrs

11.5+/-11.5+/-

5.2 hrs5.2 hrs

INHIBITORSINHIBITORS 32% in 32% in PUPPUP

16% in 16% in PUPPUP



PUP in PUP in prgressprgress

Ease of Use of FactorsEase of Use of FactorsRECOMBINARECOMBINATETE

KOGENATE FSKOGENATE FS

HELIXATE FSHELIXATE FSREFACTOREFACTO(*ReFacto will (*ReFacto will not be available not be available after 5/31/09)after 5/31/09)


VIAL VIAL RANGESRANGES

250, 500, 250, 500, 1000IU1000IU

250, 500, 250, 500, 1000, 2000IU1000, 2000IU

250, 500, 250, 500, 1000, 1500, 1000, 1500, 2000IU2000IU

250, 500, 250, 500, 1000, 1500, 1000, 1500, 2000, 2000, 3000IU3000IU

250, 500, 250, 500, 1000, 1000, 2000IU2000IU

FINAL FINAL VOLUMEVOLUME

10ml10ml 2.5ml2.5ml 4ml4ml 5ml5ml 4ml4ml

STORAGESTORAGE Refrigerate Refrigerate or room or room temptemp

Refrigerate or Refrigerate or room room temperature temperature for 3 monthsfor 3 months

Refrigerate Refrigerate or room or room temptemp



OTHER OTHER “PERKS”“PERKS”

Peel-off labelPeel-off label

Color-codedColor-codedPeel-off labelPeel-off label

Color-codedColor-coded

Butterfly Butterfly needleneedle



Peel-off labelPeel-off label





The Issue of CostThe Issue of Cost

Cost of Factor to Cost of Factor to FamilyFamily Co-pays directed by Co-pays directed by

insuranceinsurance Insurance formulariesInsurance formularies Insurance capsInsurance caps

Cost of Factor to Cost of Factor to Insurance CompanyInsurance Company Average wholesale Average wholesale

price of medicationprice of medication Contractual Contractual

agreementsagreements

Evidence Based Use of Evidence Based Use of Recombinant FactorsRecombinant Factors

Strong EvidenceStrong Evidence rVIIarVIIa

InhibitorsInhibitorsAllergic reactions to Allergic reactions to

IXIX Purified IXPurified IX

Patients with Patients with increased increased thrombotic risk thrombotic risk

““Subjective” Subjective” EvidenceEvidence Consumer Consumer

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

deficiency, platelet deficiency, platelet disorders, inhibitorsdisorders, inhibitors

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?

Gene TherapyGene Therapy Coagulation factors Coagulation factors

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 –

Pegylated liposomal Pegylated liposomal productsproducts

Decrease Decrease immunogenicityimmunogenicity

new treatment modalities; recombinant factor viii products – “factor viii after 2008” (more...

Documents

transmission of hepatitis

hiv antibody

transmission of viral

plasma products cdc

hivab screened plasma

s syphilis

s pasteurization

hiv transmissions