TRENDS IN THE PLASMA DERIVED AND RECOMBINANT MARKETS A CLINICIANS PERSPECTIVE

1
TRENDS IN THE PLASMA DERIVED AND RECOMBINANT
MARKETS A CLINICIANS PERSPECTIVE

• P.M. MANNUCCI
• Bianchi Bonomi Hemophilia and Thrombosis Center,
  Department of Internal Medicine and Dermatology,
  University of Milan, Italy

2
M. BROOKER

• The World Federation of Hemophilias Third Global
  Forum on the Safety and Supply of Hemophilia
  Treatment Products
• 22-23 September 2003, Budapest

Haemophilia 2004 10 290-294
3
QUESTION

• What is the most critical issue facing the
  hemophilia community?
• Availability of products 48
• Supply of products 26
• Safety of products 26

Haemophilia 2004 10 290-294
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THE ISSUE OF AVAILABILITY AND SUPPLY
5
2002 Plasma ForumJune 10-12, 2002Arlington,
Virginia
Patrick Robert
The Marketing Research Bureau, Inc.
6
ACCESS TO THERAPY GOOD NEWS

• In the past fifteen years, a growing number of
  persons with hemophilia have been treated with
  plasma and recombinant products.
• The expanded production of these life-saving
  drugs has generally facilitated access to
  therapy, even in less rich countries

7
WORLDWIDE DEMAND FOR FACTOR VIII 1984-2004
(Est.) Million IUs, plasma-derived recombinant
6000
5000
4000
3000
2000
1000
0
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
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9
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10
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ACCESS TO THERAPY

• The introduction of recombinant factor VIII has
  dramatically increased the quantity of factor
  VIII available to hemophilia A patients in the
  world
• Today, recombinant factor VIII represents roughly
  42 of the quantity available to patients
• Almost all of it (88) is sold in North America
  and Europe

12
ACCESS TO THERAPY

• The production of plasma-derived factor VIII has
  climbed by about 60 in the past 18 years (1.3
  to 2.1 billion units) as a result of increasing
  fractionation throughput
• Much safer products were obtained, but less
  product per liter was manufactured

13
ACCESS TO THERAPY

• Plasma-derived factor VIII concentrate is now
  increasingly used in the emerging markets
• Factor VIII usage has been multiplied by a factor
  of 7 between 1990 and 2000 in South America, by a
  factor of 9 in the Middle East, and more than
  doubled in Asia Pacific

14
ISSUES OF SAFETY

• Bloodborne infections
• Inhibitors

15
HEPATITIS IN RECIPIENTS OF LARGE-POOL COAGULATION
FACTOR CONCENTRATES

• In the 1970s and early 1980s, practically all
  treated hemophiliacs developed non-A, non-B
  hepatitis (identified as hepatitis C in 1990)

16
HIV INFECTION IN RECIPIENTS OF COAGULATION FACTOR
CONCENTRATES

• Between 1978 and 1985
• 60-70 of patients became infected with the human
  immunodeficiency virus
• Thousands of them have died of AIDS

17
THE STEPS TOWARDS SAFETY

• DDAVP (1977- )
• Virucidal methods (1984- )
• Recombinant factors (1990- )

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DDAVPTREATMENT OF MILD HEMOPHILIA IN THE USA
AND ITALY IN 1977-1984, AT THE PEAK OF AIDS
EPIDEMICS

• USA mainly large-pool, unheated concentrates for
  both hemophilia A and B
• Italy for hemophilia B, mainly large-pool
  unheated concentrates for hemophilia A, mainly
  DDAVP

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HIV PREVALENCE IN PATIENTS WITH MILD HEMOPHILIA
A AND B
21 (90/425)
18 (240/1464)
13 (13/96)
2 (13/612)
Mannucci et al, 1997
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ISSUES

• Is DDAVP truly and widely available for treatment
  of mild hemophilia A and von Willebrand disease?
• Is DDAVP truly used in the established
  indications?

21
MONITORING OF HIV AMONG PERSONS WITH BLEEDING
DISORDERS (USA 1993-1996)

• Surveillance study conducted by the National
  Hemophilia Foundation, CDC and FDA
• No seroconversion to anti-HIV in 71 hemophilia
  treatment centers

From the Final Technical Report, FDA contract
223-95-1005, 1996
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MONITORING OF HEPATITIS AMONG PERSONS AMONG WITH
BLEEDING DISORDERS (USA 1998-2002)

• Since 1998, CDC collaborated with ca. 140
  hemophilia treatment centers
• Of 4952 tested patients, 1149 (23) seroconverted
  to hepatitis viruses
• None were attributable to blood products
• Vaccination, community-acquired infections and
  injection-drug use were the most frequent causes
  of seroconversions (mostly for HAV and HBV)

From the Centers for Disease Control and
Prevention. MMWR 2003 51 1152
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THE STEPS TOWARD MORE SAFETY OF RECOMBINANT
FACTORS
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RECOMBINANT COAGULATION FACTORS
Generation 1st 2nd 3rd
Proteins used for manufacturing Human albumin
and animal proteins Human albumin No protein
Formulation Human albumin No protein No protein
Brand Recombinate, Kogenate,
Helixate ReFacto, Kogenate FS Benefix, Advate
Except mouse IgG and hamster protein for
Advate and hamster protein only for Benefix
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CONCLUSIONS

• Manufacturing processes of recombinant and plasma
  derived coagulation factors have incorporated
  dedicated identification and virus inactivation
  steps
• These processes have dramatically decreased the
  risk of viral transmission in hemophilia
• Nevertheless, past and recent experience teaches
  us that pathogens will continue to emerge and
  reemerge
• Safety surveillance should not diminish

26
PRION TRANSMISSION BY PLASMA PRODUCTSONLY A
THEORETICAL RISK?

• Donor exclusion criteria
• Prion removing capacity (3-6 logs) by the
  fractionation process (Foster et al, 2000
  Stenland et al, 2002 Tarantino et al, 2002)

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FVIII INHIBITORSCUMULATIVE INCIDENCE IN
SEVERELY AFFECTED PUPs

• Multiple plasma products
• Mean 25.9 (range 20.3-33.0)
• Single plasma product
• Mean 6.8 (range 0-12.4)
• Single recombinant products
• Mean 37.5 (range 36.0-38.7)

White Paisley, Haemophilia 2003
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INCIDENCE OF INHIBITORS IN PUPS TREATED WITH
FVIII-VWF CONCENTRATES
patients with inhibitors
No. of severe PUPs
Concentrate
Author (Country)
22.8
57
various
W. Kreuz (Austria, Germany, Switzerland)
11.3
62
LFB
J Goudemand (France)
10.5
19
Octa
A. Glomstein (Norway)
5.0
19
Grifols
R. Rokicka-Milewska (Poland)
4.0
74
BPL
S. Brown (UK)
9.8
71
Kedrion
A. Gringeri (Italy)
11.0
299
OVERALL
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CONCLUSIONS ON INHIBITORS

• Preliminary data from retrospective studies
  indicate that in PUPs the use of plasma-derived
  FVIII concentrates containing large amounts of
  VWF is associated with a lower incidence of
  inhibitors
• However, inhibitor risk factors such as frequency
  of testing, genotype, ethnicity, age at first
  treatment and insensitivity of treatment are
  poorly controlled in these studies.
• The A. Bianchi Bonomi Hemophilia and Thrombosis
  Center is organizing a new prospective study in
  Eastern Europe and Middle East