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 of cryoprecipitate 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 concentrates 1969: 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: Donor deferral Viral inactivation methods Antibody and NAT testing 1. Barre-Sinoussi F, et al. Science 1983; 220(4599):868-71. 2. Gallo RC, et al. Science 1984; 4;224(4648):500-3.

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 attenuation Development 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.htm MASAC 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 IUDs Topical 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