TRENDS IN THE PLASMA DERIVED AND RECOMBINANT MARKETS –

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					     TRENDS IN THE PLASMA DERIVED
      AND RECOMBINANT MARKETS –
       A CLINICIAN’S PERSPECTIVE

               P.M. MANNUCCI

A. Bianchi Bonomi Hemophilia and Thrombosis
   Center, Department of Internal Medicine and
      Dermatology, University of Milan, Italy
                M. BROOKER

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

         Haemophilia 2004; 10: 290-294
            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
THE ISSUE OF AVAILABILITY AND SUPPLY
        2002 Plasma Forum
         June 10-12, 2002
         Arlington, Virginia


          Patrick Robert


The Marketing Research Bureau, Inc.
           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
       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
           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
          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
             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
ISSUES OF SAFETY

•Bloodborne infections
•Inhibitors
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)
   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
THE STEPS TOWARDS SAFETY

• DDAVP (1977-       )
• Virucidal methods (1984-     )
• Recombinant factors (1990-       )
                  DDAVP
TREATMENT 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
 HIV PREVALENCE IN PATIENTS
 WITH MILD HEMOPHILIA A AND B
                                                Hemophilia A
                                                Hemophilia B
                                      21%
25%
                          18%        (90/425)
                        (240/1464)
20%
               13%
15%           (13/96)


10%
      2%
5% (13/612)

0%
           Italy                USA
           Mannucci et al, 1997
                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?
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
 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
THE STEPS TOWARD MORE SAFETY
   OF RECOMBINANT FACTORS
       RECOMBINANT COAGULATION FACTORS
             Proteins used for
Generation   manufacturing        Formulation     Brand

1st          Human albumin and    Human albumin Recombinate®, Kogenate®,
             animal proteins                    Helixate®
2nd          Human albumin        No protein    ReFacto®, Kogenate FS®
3rd          No protein *         No protein    Benefix®, Advate®



             *Except mouse IgG and hamster protein for Advate®
                   and hamster protein only for Benefix®
                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
PRION TRANSMISSION BY PLASMA PRODUCTS:
        ONLY 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)
        FVIII INHIBITORS
    CUMULATIVE 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
         INCIDENCE OF INHIBITORS IN PUPS TREATED
                 WITH FVIII-VWF CONCENTRATES
                                        No. of   % patients
Author (Country)          Concentrate   severe      with
                                        PUPs     inhibitors
W. Kreuz (Austria,
                            various      57        22.8%
Germany, Switzerland)

J Goudemand (France)         LFB         62        11.3%

A. Glomstein (Norway)        Octa        19        10.5%
R. Rokicka-Milewska
                            Grifols      19        5.0%
(Poland)

S. Brown (UK)                BPL         74        4.0%

A. Gringeri (Italy)         Kedrion      71        9.8%
OVERALL                                  299       11.0%
         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