TREATMENT PRODUCTS IN HEMOPHILIA

Nairobi, Kenya

June 24, 2013

OBJECTIVES

• Identify historical approaches used to treat hemophilia• Describe treatment products currently available for use

in hemophilia• Distinguish classes of factor concentrates• Discuss donor screening and viral inactivation• List adjuvant therapies for treatment of hemophilia• Explore future therapies

ADDITIONAL TEXT EXAMPLE

HISTORICAL TREATMENT OF HEMOPHILIA

• Injections of adrenaline• Ingestion of such compounds as1:

− Strychnine − Turpentine− Lead − Female hormone− Bromide extracts of egg − Peanut flour2

whites

• Topical snake venom3

• First blood transfusion in 1840 by Dr. Samuel Lane4

1Rosendaal FR, Smit C, Briët E. Ann Hematol. 1991; 62:5-15.2Mainwaring D, Keldon S.E. Lancet. 1964; 19:647.3MacFarlane RG, Barnett, B. Lancet. 1934; ii: 985–987.4Lane, S. Lancet. 1840; i: 185-188.

CRYOPRECIPITATE DISCOVERED

1965:Discovery ofcryoprecipitate

Judith Graham Pool, MD

File photo courtesy of HANDI, NHF

Pool JG, Shannon AE. N Engl J Med. 1965:273:1443-1447.

FACTOR CONCENTRATES SOON APPEAR

1966: Hyland announces commercial availability of FVIII concentrates1969: FIX concentrate licensed1

Allowed for greater independence

1. Hoag MS, et al. N Engl J Med.1969;280(11):581-6

THE PRICE OF INDEPENDENCE

1983: Suspicion that HIV threatened the worldwide blood supply

1983: Hemofil-T, first heat-treated FVIII concentrate in the US

1984: Montagnier1 and Gallo2 discover HTLV-3 (HIV)

1984: Efficacy of heat treatment for viral inactivation demonstrated

1984: Recall of blood products initiated

1985: ELISA test used to detect HIV antibodies among blood donors

1985: Safety net:

1. Barre-Sinoussi F, et al. Science 1983; 220(4599):868-71.2. Gallo RC, et al. Science 1984; 4;224(4648):500-3.

1. Donor deferral2. Viral inactivation methods3. Antibody and NAT testing

CLOTTING FACTOR CONCENTRATES AND OTHER PLASMA PRODUCTS

Factor replacement therapy• Fresh frozen plasma (FFP)• Cryoprecipitate• Plasma-derived concentrates • Recombinant concentrates

WFH RECOMMENDATION

The WFH strongly recommends the use of viral-inactivated plasma-derived

or recombinant concentrates in preference to cryoprecipitate or

fresh frozen plasma for the treatment of hemophilia

Guidelines for the Management of Hemophilia, 2nd edition, WFH 2012

CHOICE OF TREATMENT PRODUCT

• Choice of treatment product is an important decision• Infusion products should be chosen with provider, NMO, and

patient/family input• Important issues regarding infusion products:

− Efficacy− Safety− Purity− Cost

PLASMA-DERIVED PRODUCTS: PURITY

Concentrates on the market vary widely in their purity● High purity

− Just the clotting factor in the vial exclusive of added stabilizers− Activity/protein ratio is very high

● Intermediate purity− More than just the clotting factor in the vial− Activity/protein ratio mid-range

● Concentrates of lower purity may give rise to allergic reactions

● FVIII concentrates may contain variable amounts of VWF● For treatment of FIX deficiency, a product containing only

FIX is more appropriate than PCCs

PLASMA-DERIVED PRODUCTS: SAFETY

Viral inactivation is the biggest contributor to safety of treatment products● Heat treatment: effective against enveloped and non-

enveloped viruses including (HIV, HAV, HBV and HBC)● Solvent/detergent treatment: effective against non-

enveloped viruses such as HIV, HBV, HCV but not HAV)● Some viruses resistant to both types of process (e.g.

parvovirus B19)● Products undergo one or two viral inactivation steps; if one,

preferably one that is effective against viruses with and without lipid envelopes

RECOMBINANT PRODUCTS

● All recombinant products are high purity● Not made from human plasma● 1st generation: Added albumin as stabilizer, human/animal

protein exposure during production● 2nd generation: Albumin removed as stabilizer, human/animal

protein exposure during production● 3rd generation: No added human or animal protein during

production or in final formulation

FRESH FROZEN PLASMA

• Contains all the coagulation factors• Due to concerns about safety and quality of FFP, it

is not recommended for treatment of hemophilia, if avoidable

• Possible to apply some forms of viral inactivation to packs of FFP but may have impact on coagulation factors

• Large volumes of plasma must be transfused, which can lead to a complication called circulatory overload

CRYOPRECIPITATE

• Prepared by slow thawing of FFP• Contains significant quantities of FVIII, VWF,

fibrinogen and FXIII but no FIX • Less safe from viral contamination than factor

concentrates; harder to store and administer• Virally-inactivated cryo has been described (S/D

cryo)• Preferable to FFP for the treatment of hemophilia A• Cryo cannot be used for treatment of hemophilia B

PLASMA-DERIVED PRODUCTS

ADDITIONAL TEXT EXAMPLE

Blood Donation in South Africa

Plasma Products:Fresh Frozen Plasma (FFP) and

Hyperimmune FFP

Whole Blood Donation from voluntary, non-paid blood donors

Blood Products: Cellular Products

PLASMA FOR NBI<24 hr FFP,

shock frozen to - 30°C

Hyperimmune Plasma donation from voluntary, non-paid Plasmapheresis donors

• Whole Blood• Red Cell Concentrate • Platelet Concentrate

• Cryofibrinogen • Cryoprecipitate• FFP – Therapeutic

NBI, WPBTS and SA Blood Transfusion Services work together to optimise the donor’s gift of life

HEMOPHILIA A: EVOLUTION OF THERAPY

Year Therapy

1950 Plasma (1-FVIII U/ml)

1966 Cryoprecipitate (5-FVIII U/ml)

1975 Lyophilized concentrates (30-FVIII U/ml)

1983 Heat treatment of lyophilized concentrates for viral attenuation

1985 Introduction of a solvent detergent for viral inactivation

1988 Monoclonal antibody-purified FVIII concentrates with heat or solvent detergent treatment

1992 Recombinant DNA products: 1st generation

2000s 2nd & 3rd generation recombinant products

HEMOPHILIA B: EVOLUTION OF THERAPY

Year Therapy

1950 Plasma (1-FIX U/ml)1975 Lyophilized prothrombin complex concentrates or

PCC (30-FIX U/ml)1985 Heat treatment of lyophilized concentrates for

viral attenuationDevelopment of a solvent detergent for viral inactivation

1992 Chromatographic/monoclonal antibody-purified FIX concentrate with ultrafiltration and thiocyanate treatment

1997 Recombinant DNA product

FACTOR REPLACEMENT PRODUCTS

• FVIII products– Advate [r-3rd gen]– Xyntha [r-3rd gen]– Kogenate FS [r-2nd gen]– Helixate FS [r-2nd gen]– Recombinate [r-1st gen]– Hemophil-M [pd-HP]– Monoclate-P [pd-HP]

• VWF products– Humate-P [pd-HP]– Alphanate [pd-HP]– Wilate [pd-HP]

• FIX products– BeneFIX [r-3rd gen]– Mononine [pd-HP]– Profilnine [pd-PCC]– Bebulin [pd-PCC]

• Bypassing agents– Novo Seven [r-3rd gen]

– FEIBA [pd-APCC]

http://www.hemophilia.org/research/masac/masac151.htmMASAC document #151 & 106

OTHER TREATMENT PRODUCTS

Desmopressin• Boosts plasma levels of FVIII and VWF• Does not affect FIX levels • May be treatment of choice for patients

with mild or moderate hemophilia A and carriers

• Lower cost than plasma products and no risk of viral transmission

• Test patient response prior to use• Administration:

- IV- SQ- Intranasal

OTHER TREATMENT PRODUCTS

Antifibrinolytic agents• Promote clot stability• Useful as adjunctive therapy, particularly for skin and

mucosal bleeding, e.g. oral bleeding, epistaxis, menorrhagia

• Tranexamic acid available orally, IV, mouthwash• Epsilon aminocaproic acid (EACA) similar but less

widely used• Do NOT use in patients with hemophilia B treated with

PCCs

OTHER TREATMENT PRODUCTS

Hormone therapy (women)• OCPs• IUDsTopical hemostatic agents• Fibrin sealant (fibrin glue)Replacement• Iron• Vitamin D

FUTURE TREATMENT THERAPIES FOR HEMOPHILIA

• Longer acting concentrates• Recombinant therapy for VWD• Alternate route therapies• Gene transplantation• Elimination of transfusion-associated infections• Understanding and overcoming inhibitor development• Quality of life issues

− Elimination of joint morbidity− Optimizing the individual’s social and academic performance

SUMMARY

• Treatment in hemophilia continues to progress• FFP and cryoprecipitate are still used in many parts of the

world• Replacement therapies are available in a variety of forms• Choosing a factor concentrate is important to all involved in

care• Efficacy, safety and cost remain important considerations

when choosing a treatment product• Adjuvant therapies are available to assist in hemophilia

treatment• The future of hemophilia treatment appears promising

WFH RESOURCES

• Guide for the Assessment of Clotting Factor Concentrates

• Registry of Clotting Factor Concentrates• Fibrinolytic Inhibitors in the Management

of Bleeding Disorders• Desmopressin (DDAVP) in the Treatment

of Bleeding Disorders• Guidelines for the Management of

Hemophilia, 2nd ed