IMPACT OF BIOTECHNOLOGY PRODUCTS ON QUALITY OF LIFE AND LONGEVITY

Biotechnology for haemophilia

Factor VIII for haemophilia A patients

Philippe Cramer, MD

France Biotech Julien Martinet, D pham France Biotech Text reviewed by Dr Valrie Robert
Centre de traitement des Hmophiles, Hpital Cochin, Paris

FEBRUARY 2004

www.bioimpact.org

The new Factor VIII, treatment without risk of infection

Haemophilia: a serious genetic disorder

Factor VIII (FVIII) is the blood coagulation factor whose deficiency results in Haemophilia A, one of the most important genetic disorders. This deficiency prevents the blood from clotting, causing haemorrhaging. Haemophilia A, representing 80% of haemophilia cases, is due to a genetic mutation causing the production of a nonfunctional factor VIII, or production in insufficient quantity. Depending on the type of mutation, a residual coagulation activity can be observed which enables classification of the various types of haemophilia according to their degree of severity (less than 1% activity for a severe form, between 5 and 30% activity for a minor form). Haemophilia only affects boys because transmission is recessive and X-linked. Incidence is approximately 5 to 6 for 100 000 live births per annum.

Plasma concentrates, a great leap forward becomes a health disaster

From the 1960s (beginning of the modern era of treatment for haemophilia) to the beginning of the 1990s, patients were treated with plasma concentrates of FVIII. But these concentrates were the cause of the disastrous infection of a large number of patients with the HIV virus (50% of haemophiliacs were infected between 1980 and 1985) and with the hepatitis B and C viruses (80% of haemophiliacs were infected by the hepatitis C virus before 1987). In 1987, the widespread use of heated blood plasma fractions put an end to these epidemics.

Biotechnology: treatment with no viral or infectious risk

The first recombinant FVIIIs (rFVIII), produced artificially without using human blood were commercialized at the beginning of the 1990s, and there are now rFVIIIs for which the production process and formulation require no animal or human protein at all, eliminating the risk of infection from pathogens. However, plasma-derived FVIII has not been totally abandoned, and it has benefited from different techniques (screening tests, immunopurification using monoclonal antibodies, nanofiltration) to reduce or eliminate the risk of transmission of diseases (AIDS, hepatitis C and B, Creutzfeld-Jacob disease, or others as yet not identified). These plasma-derived FVIIIs, which are still used, also have the advantage of a lower risk of occurrence of anti-FVIII antibody inhibitors during treatment.

BIOIMPACT Impact of Biotechnology products on quality of life and longevity Factor VIII for Treatment of Haemophilia A Patients

Anti-FVIII inhibitors, the main treatment pitfall

These inhibitors, which prevent the activity of synthetic FVIII, are currently the greatest limitation to the treatment of haemophilia A. Depending on patient profile, either a rFVIII, or a plasma-based FVIII will be used to limit the occurrence of inhibitors. For those with severe haemophilia, often subject to the production of inhibitors, circumvention procedures have been developed, for instance products able to bypass this harmful effect of FVIII, notably the recombinant coagulation factor VII. The most recalcitrant are even given immunosuppressor treatment, such as that used during organ transplants. Research into improving treatment with rFVIII is essentially based on decreasing the risk of the occurrence of inhibitors, but also on production costs. Genetic engineering programmes are also underway because even a very slight increase in the concentration of FVIII (1 to 2%) will very significantly improve the quality of life of haemophiliacs with the most severe form of haemophilia.

Costly treatment but effective and safe

Preventive treatment is very costly at around 100 000 per annum. For curative treatment (after a haemorrhage episode), the cost is between 10 000 and 20 000 per annum (taking a hypothetical 20 to 30 haemorrhage episodes a year). However, preventive treatment saves money in the long term less surgical operations required, and less, very costly, days in hospital. Only very economically strong countries can afford to treat severe haemophilias on a regular basis. In economically weaker countries, modern treatment of haemophilia is not easily applicable and in poor countries haemophiliacs often die before they are diagnosed.

BIOIMPACT Impact of Biotechnology products on quality of life and longevity Factor VIII for Treatment of Haemophilia A Patients

SOMMAIRE
HAEMOPHILIA .......................................................................................................... 5 TREATMENT OF HAEMOPHILIA A PATIENTS BEFORE THE ADVENT OF BIOTECHNOLOGY.................................................................................................... 5
History of product development...................................................................................................... 5 Plasma concentrates, a great leap forward becomes a health disaster. .................................... 6

CONTRIBUTION OF BIOTECHNOLOGY TO THE TREATMENT OF HAEMOPHILIA ................................................................................................................................... 6

Improvement of plasma-derived FVIII ............................................................................................ 6 Recombinant Factor VIII (rFVIII)....................................................................................................... 6 FVIII inhibitors .................................................................................................................................. 8

CURRENT METHODS OF TREATMENT FOR HAEMOPHILIACS........................... 8 FUTURE METHODS OF TREATMENT FOR HAEMOPHILIACS.............................. 9 COST-EFFECTIVENESS ........................................................................................... 9 APPENDIX GENERAL FEATURES OF FACTOR VIII................................................................ 11 PHARMACEUTICAL AND ECONOMIC DATA ....................................................... 11
Cost of treatment............................................................................................................................. 11 Market Data ...................................................................................................................................... 12

REFERENCES ......................................................................................................... 13

BIOIMPACT Impact of Biotechnology products on quality of life and longevity Factor VIII for Treatment of Haemophilia A Patients

HAEMOPHILIA
Haemophilia is a hereditary deficiency of coagulation which only occurs in males, since transmission is recessive and X-linked. Two blood coagulation factors are involved: factor VIII (haemophilia A) and factor IX (haemophilia B); haemophilia A represents 80 to 85% of haemophilia cases. Boys usually inherit the mutant gene from their carrier mother, but in 30% of cases there is no family history of haemophilia and the disorder is the result of spontaneous mutation. Haemophilia A is due to production of a non-functional coagulation Factor VIII (FVIII), or production in insufficient quantity, leading to dysfunction of haemostasis and therefore repeated haemorrhages within joints (haemarthroses) and muscles, and even to visceral or intracranial bleeding. In the long term, there are numerous complications, in particular blocking of joints and bone deformation (haemophilic arthropathy). Haemophilia is the most frequent disorder of coagulation. Incidence is approximately 1 in 5 000 male live births. Prevalence of haemophilia is 14 per 100 000 males. In France there are therefore just over 4 000 haemophiliacs treated at more than thirty specialist centres. The number of haemophiliacs in North America (excluding Mexico) and in the 25 European Union countries is respectively 22 000 and 28 5000. Haemophiliacs with no previous (de novo) family history of the disorder currently account for 40% of cases, probably due to the implementation of antenatal screening. Depending on the detectable level of plasma coagulation, haemophilia A occurs in three forms: severe (about half of all haemophiliacs) with less than 1% of the normal level of FVIII; moderate (10 to 20% of cases), between 1 and 5% production; and mild, 5 to 30% production. The severity of deficiency is related to the type of mutation. Preventative and curative treatments available only address the bleeding symptoms and consist in the intravenous administration of FVIII. However, despite substantial improvements over the last 20 years, in particular concerning viral safety, this treatment is not without undesirable side effects such as inhibitor formation.

TREATMENT OF HAEMOPHILIA A PATIENTS BEFORE THE ADVENT OF BIOTECHNOLOGY

History of product development
The discovery that haemophilia is caused by the absence of a plasma protein dates back to the 1930s. But it was only in the 1960s that the various coagulation factors were identified. The use of fresh plasma (or of whole blood) started in the 1960s, but these blood products did not contain sufficient factor VIII (or IX) to check severe haemorrhages and most haemophiliacs still died during childhood or adolescence. During the 1960s, the observation that the gelatinous substance floating above defrosted fresh plasma was rich in FVIII enabled the perfection of cryoprecipitates:
BIOIMPACT Impact of Biotechnology products on quality of life and longevity Factor VIII for Treatment of Haemophilia A Patients

for the first time severe haemorrhaging could be controlled and haemophiliacs could undergo surgical operations.

Plasma concentrates, a great leap forward becomes a health disaster.

Modern management of haemophilia began in the 1960s when the first FVIII plasma concentrates became available. This first generation of FVIII enabled a much more effective treatment than simple plasma. The life expectancy and quality of life of patients (treatment at home) saw unprecedented improvement. But these concentrates, because of the large number of donors required, lead to the infection of a large number of patients with HIV (1980s) and hepatitis B and C viruses, before heated concentrates became the general rule. Approximately 50% of haemophiliacs were infected with HIV between 1980 and 1985 (1 200 patients infected in France, half of whom have died from AIDS). Before 1987, 80% of haemophiliacs were infected with the hepatitis C virus. To prevent these infections, concentrates of FVIII with viral safety were developed, initially by heating blood plasma fractions, then by adding a phase of purification using a solvent-detergent mix and monoclonal antibodies (immunopurification). In 1987, the wide use of heated blood plasma fractions put a term to the epidemic.

CONTRIBUTION OF BIOTECHNOLOGY TO THE TREATMENT OF HAEMOPHILIA

Improvement of plasma-derived FVIII
Selection of donors and the various tests for screening viruses implemented in the period 1980 -1990 and used during treatment of plasma donation all help to improve viral safety. Biotechnology has also enabled improvement in the viral safety of plasma-derived FVIII, through immunopurification techniques which use monoclonal antibodies. The technique using solvent-detergent mixes does not eliminate viruses without an envelope. In order to reduce, or even eliminate, the risk of transmission of new variant Creutzfeldt-Jacob disease, a stage of nanofiltration has been added to the process of preparing plasma-derived FVIII.

Recombinant Factor VIII (rFVIII)

Following the sequencing of the FVIII gene in 1984, the various mutations were identified (meaning that the severity of haemophilia and probability of the occurrence of inhibitors could be predicted) and the first rFVIII were developed. The first generation of these rFVIII was licensed in 1993. Production of rFVIII using genetic engineering in theory eliminates the risk of infection by a human virus. However, preparation and formulation still require the use of human albumin and certain animal products.
BIOIMPACT Impact of Biotechnology products on quality of life and longevity Factor VIII for Treatment of Haemophilia A Patients

In 2000, a new generation of rFVIII was licensed. This formulation uses a sucrose in the place of human albumin and includes a purification stage with the use of a solvent-detergent mix. The risk of viral infection is even lower. The latest rFVIII, licensed by both the FDA and the EMEA in 2003, uses neither animal nor human proteins in the production process or in the final formulation.. However, this latest improvement in the production process is a precautionary measure rather than the reduction of a measured risk. The quantity of rFVIII available is not limited as was that of products using human plasma, which has enabled the development of preventive treatment.

Table. Factor VIII concentrates available. PHARMACEUTICAL TECHNOLOGICAL DEVELOPMEMNT COMPANY

Blood transfusion centres LFB, Kedrion, Alpha Therapeutic Corp 1994 AVENTIS-BEHRING BAXTER, 1996 LFB, 1994 immunopurification Decrease in risk of infection Viral inactivation using detergent
Safe transfusion

PRODUCT Lyophilised concentrate of VHP + SD (1) FVIII Factane Alphanate

Plasma derivatives

IMPROVEMENT OF QUALITY OF LIFE

Monoclate P Hemofilm M

Recombinate, octocog
Recombinant Kogenate, octocog products

BAXTER, 1993 BAYER, 1993

1st generation rFVIII

Easier access to preventive treatment

Refacto, mor-octocog (2) Kogenate FS, octocog HelixateNexGen, octocog

WYETH, 1999 BAYER, 2000 AVENTIS, 2000

Replacement of human albumin by sucrose

Risk of viral infection further considerably reduced

(1) VHP = Very high purity, SD = treatment with solvent-detergent mix (2) Refacto is a rFVIII with no B domain protein (not required for coagulation), therefore easier to produce and less costly because the protein is shorter.

The techniques of biotechnology have therefore brought considerable progress as far as viral safety is concerned, both in purification of products obtained by plasma extraction and in production using genetic engineering. The treatment of haemophiliacs today offers an excellent degree of safety. One of the residual uncertainties, apart from the existence of unidentified pathogens, remains the theoretical possibility of transmission of the new variant of Creutzfeld-Jacob Disease. However no cases have been identified amongst haemophiliac populations.
BIOIMPACT Impact of Biotechnology products on quality of life and longevity Factor VIII for Treatment of Haemophilia A Patients

FVIII inhibitors
The development of FVIII inhibitors is the greatest obstacle in the treatment of haemophilia A. These inhibitors are antibodies produced in response to the introduction of foreign FVIII. They block, or decrease, activity of FVIII, thus decreasing the effectiveness of treatment. Depending on the degree of their inhibiting activity, measured using a specific blood coagulation test, haemophiliacs are classified as high responders (> 5 Bethesda units) (administration of FVIII is ineffective), or low responders. Inhibitors are to be found in approximately 30% of severe forms. They are much rarer in moderate forms. It would appear that these inhibitors appear less frequently when plasma FVIII is used.

CURRENT METHODS OF TREATMENT FOR HAEMOPHILIACS

Methods of treatment offered to haemophiliacs vary according to whether they have already been treated (PTPs, Previously Treated Patients), or not (PUPs, Previously Untreated Patients), and depend on the practice of various specialist centres. At the haemophiliac treatment unit at Cochin Hospital in Paris (interview with Dr Valerie Roussel-Robert), the latest generation of rFVIII is usually offered to both categories of patient. With PUPs, family history (method of treatment for haemophiliacs in the family, existence of an inhibitor in the family) can, however, sometimes lead to the use of another type of concentrate, in particular a plasma derivative. The decrease in theoretical risk of infection from a pathogen through the use of rFVIII is balanced with the risk of the appearance of an inhibitor which seems to be lessened with the use of plasma-derived FVIII. With PTPs, previous methods of treatment are taken into account, as are the wishes of the patient, but the guarantee of the theoretical absence of viral infection in rFVIII is indicated and the very low, but not impossible, risk of the appearance of an inhibitor after a change in product is explained. The current trend is to offer young haemophiliacs with severe forms of the disorder preventive treatment from the second episode of haemarthrosis (an injection of FVIII 1 to 3 times a week). This approach enables prevention of haemorrhaging, in particular articular bleeding, and avoidance of long-term consequences. FVIII is mainly administered at home by the haemophiliacs themselves or their family. Bleeding episodes for patients with severe haemophilia and inhibitors are treated by bypassing FVIII, i.e. by using a complex of already activated factors (and therefore intervening downstream of FVIII in the coagulation cascade): for instance, a plasmabased, activated prothrombine-complex concentrate (Feiba from Baxter, LFB, Nabi, Alpha Therapeutic Corp.), or an activated recombinant FVII (Novoseven from NovoNordisk). In children who have only been treated with rFVIII, rFVII should be used in the first instance. Feiba, plasma-derived and with a risk of starting up inhibitor formation again, should therefore be avoided with patients waiting for immune tolerance or with those in whom one does not wish to see inhibitor formation begin again.

BIOIMPACT Impact of Biotechnology products on quality of life and longevity Factor VIII for Treatment of Haemophilia A Patients

Strong responders can, if necessary, benefit from an attempt to eradicate the inhibitor through immune tolerance protocols consisting of the repeated administration of FVIII, possibly combined with an immunosuppressant, or immunoadsorption of the antibodies responsible.

FUTURE METHODS OF TREATMENT FOR HAEMOPHILIACS

Efforts are being concentrated on reducing inhibitor levels, improving the kinetics of FVIII and production costs. Various approaches are being envisaged: modification of the most immunogenic domains of proteins, encapsulation of FVIII, antiidiotypic vaccination, production by transgenic animals. Haemophilia is an ideal target for gene therapy because a small increase in FVIII concentration (1 to 2%) would transform severe haemophilia into a moderate form. More than 25 patients are taking part in phase-1 gene therapy protocols but, to date, none of these studies has shown a significant increase in FVIII activity.

COST-EFFECTIVENESS
FVIII concentrates, whether plasma-derived or recombinant, are extremely costly, but essential for haemophiliacs. A number of new practices and new drugs still need to be assessed in terms of their cost/effectiveness ratio. A number of studies have shown the interest in preventive treatment, as opposed to treatment on demand, in terms of reducing frequency of haemorrhaging and of preventing bone deformation, as well as in terms of the impact on lifestyle/welfare costs that they represent. Insofar as preventive treatment is very costly, a number of cost/effectiveness studies have been carried out to justify the use of preventive treatment. Studies have thus assessed the gain achieved by avoiding haemarthrosis which, depending on the country, is between $US 1 200 and $US 1 400. Other studies currently underway are trying to assess when preventive treatment should kick in since, insofar as severity of deficiency is equal, the frequency of haemorrhaging is not necessarily the same. Other studies have shown that, in comparison with other treatments, rFVIII was useful for severe haemophiliacs with an inhibitor in terms of reduced number of repeat treatments required, duration of painful episodes, number of days requiring the use of crutches or wheel chair, number of urgent consultations and auxiliary nursing time. Quality-of-life improvements were observed in several important areas, as perceived by both patients and their families, at an incremental cost per QALY (units of quality of life) of 51 533. In patients with severe haemophilia, and before the marketing of rFVIII, choice of treatment was limited to two options: eliminate the inhibitor by inducing immune
BIOIMPACT Impact of Biotechnology products on quality of life and longevity Factor VIII for Treatment of Haemophilia A Patients

tolerance, or use considerable quantities of FVIII. A study published in 1996 indicated that despite its high cost (nearly $1 million on average for a 5-year old child), tolerance enabled an added survival of 4.6 years, and enabled an overall economy (during the life of the patient) of around $1.7 million.

BIOIMPACT Impact of Biotechnology products on quality of life and longevity Factor VIII for Treatment of Haemophilia A Patients

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APPENDIX
GENERAL FEATURES OF FACTOR VIII
FVIII is a plasma glycoprotein consisting of 2351 amino acids divided into three protein domains: A, B and C. The role of B domain is unknown, but it is not required for coagulation. Certain parts of FVIII are more immunogenic than others. FVIII is synthesized mainly by hepatocytes. It circulates in the plasma in liaison with noncovalent von Willebrand factor, the latter protecting it from plasma proteolysis. The half-life of endogenic FVIII is 12 hours.

The most frequent genetic anomaly, present in 45% of patients with severe haemophilia A, is an inversion of part of the FVIII gene. More than 300 other genetic anomalies have been described (sporadic mutations, deletions or insertions).

There seems to be a correlation between the type of mutation and the occurrence of an inhibitor: Patients with a mutation which suppresses, or severely affects, production of FVIII have a 35% higher frequency of development of inhibitors in comparison with other types of mutation. Recombinant FVIII is produced from mammalian cells (CHO).

PHARMACEUTICAL AND ECONOMIC DATA

Cost of treatment
In France the price of one FVIII unit (plasma-derived or recombinant) is approximately 0.8. Treatment of haemarthrosis requires the administration of 20 to 30 units per kilo of body weight, i.e. for a 30kg boy a cost of 480 to 720 (600 to 900 units). If this boy was to have 20 to 30 bleeding incidents, annual FVIII cost would be from 9600 to 21 600 per annum (12 000 to 27 000 units). For the same child, preventive treatment would cost 117 000. The price of 1mg of Novoseven is approximately 600; the dose required would be 90 g/kg body weight, one episode of haemarthrosis requiring 2 to 3 injections i.e. a cost of 3 240 to 4 860 for a 30kg boy. Feiba is less costly but indications for its use are limited.
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These prices only take into account the cost of the FVIII (or VIIa) product, not the entire medical cost. The cost of FVIII varies from country to country and according to the size of the market: for instance, in Germany the price is around 0.6 to 0,7 per unit and in the United States it is even less expensive (at around $0.3 to $0.4 per unit). In developing countries, use of modern treatments for haemophilia is difficult and in the poorest countries, haemophiliacs often die before being diagnosed.

Market Data
In practice, only severe haemophilia is treated on a regular basis. almost never, and moderate forms occasionally. Milder forms

In France The total number of haemophilia A patients is estimated to be approximately 4000, but the number treated per annum is under 2000. Individual consumption varies from 15 000 to 300 000 units per annum, depending on whether the patient is treated on demand, undergoes preventive treatment, or needs to undergo surgery. It can be higher in the case of inhibitor formation. Total consumption in 2003 should be around 255 million units (compared to 220 million units in 1997) (source: LFB). This growth, in the vicinity of 2% per annum, is due to the ever more frequent use of preventive treatment and perhaps also to the improvement in the state of health of haemophiliacs with AIDS who benefit from triple combination therapy and put on weight. Consumption in Europe, America and the world. World consumption of plasma-derived FVIII in 2000 was 2.2 billion units (source: LFB). Total world demand for FVIII in 2002 was 4.3 billion international units (source ?). Sales of rFVIII reached $ x million in 2002, i.e. y billion units (source: IMS).

Breakdown of recombinant FVIII versus plasma-derived FVIII The breakdown in use of recombinant FVIII versus plasma-derived FVIII varies according to country: in France, only 20% of haemophiliacs benefit from plasmaderived FVIII; in the United States it is 35%; in the whole of Europe 60%; and in Germany 66% (source: Marketing Research Bureau, Eurodata 2001). In world terms, the breakdown is similar to that in Europe, 58% of plasma-derived FVIII.

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REFERENCES
General Reviews Bolton-Maggs PHB, Pasi KJ. Haemophilias A and B. Lancet 2003; 361: 1801-09. Manucci PM, Tuddenham EGD. The Haemophilias - From Royal Genes to Gene Therapy. N Engl J Med.; Jun 2001; 344: 1773-9. Web Sites General information about coagulation: http://tollefsen.wustl.edu/projects/coagulation/coagulation.html; http://kowid.free.fr/pharmako/hemato/hemo2.htm Haemophiliac associations: www.wfh.org; www.afh.asso.fr; www.hemophilia.org Information from pharmaceutical companies: www.wyeth-hemophilie.com; www.hemophiliabayer.com; http://novoseven.com; www.advate.com Genetics of FVIII Toole JJ; Knopf JL; Wozney JM et al: Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 312: 342-347, 1984. Lillicrap D: The molecular basis of haemophilia B Haemophilia 1998; 4: 350-57 Clinical Studies Lusher JM. First and second generation recombinant factor VIII concentrates in previously untreated patients: recovery, safety, efficacy, and inhibitor development. Semin Thromb Hemost 2002 Jun;28(3):273-6 White GC II, Courter S, Bray GL, Lee M, Gomperts ED. A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. Thromb. Haemost. 1997;77:660-7 Courter SG, Bedrosian CL. Clinical evaluation of B-domain deleted recombinant factor VIII in previously treated patients. Semin Hematol. 2001 Apr;38(2 Suppl 4):44-51. Suiter TM. First and next generation native rFVIII in the treatment of hemophilia A. What has been achieved? Can patients be switched safely?. Semin Thromb Hemost. 2002 Jun;28(3):277-84. Inhibitors Dimichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas. Haemophilia. 2002;8(3):280-7. Gene Therapy Powell JS, Ragni V, White GC, Lusher JM et al. Phase I trial of FVIII gene transfer for severe haemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood, May 2003;10-1182 Tawa NE Jr,OBrien JM, Treco DA, Selden RF. Non viral Transfer of the Gene Encoding Coagulation Factor VIII in Patients with Severe Haemophilia A. N Engl J Med 2001; 344:1735-1742. Pharmacoeconomic data/ Quality of Life Schramm W. and Berger K.: Linking medicine and economics: health economics and quality of life in haemophilia care Haemophilia 2002; 8: 217-20 Miners AH, Sabin CA, Tolley KH, Lee CA. Cost-utility analysis of primary prophylaxis versus treatment ondemand for individuals with severe haemophilia. Pharmacoeconomics 2002;20(11):759-74 Smith PS, Teutsch SM, Shaffer PA, Rolka H, Evatt B. Episodic versus prophylactic infusions for hemophilia A: a cost-effectiveness analysis. J Pediatr 1996 Sep;129(3):424-31
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Galanaud JP, Pelletier-Fleury N, Logerot-Lebrun H, Lambert T.: Determinants of drug costs in hopitalised patients with haemophilia: impact of recombinant activated factor VII. Pharmacoeconomics. 2003;21(10):699-707. Colowick AB, Bohn RL, Avorn J, Ewenstein BM. Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper. Blood 2000;96(5):1698-702

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