Global Use of Plasma-Derived Medicinal Products

Global Use of Plasma-Derived Medicinal Products Patrick Robert The Marketing Research Bureau, Inc. IPFA Workshop on Improving Access to Plasma and Plasma Products in the Southern African Region December 1-2, 2015 Cape Town, South Africa

SOURCE OF THE DATA The data used to develop the charts and tables shown in this presentation have been compiled from the Marketing Research Bureau s database, scientific articles, congress proceedings, companies annual reports, publications and statistics published by national and international organizations, as well as by various plasma industry stakeholders. GENERAL INFORMATION All the data and information come from sources generally available to the public. Their accuracy is not guaranteed, and the Marketing Research Bureau assumes no liability for their use.

Table of Contents Global Plasma Products Demand by Region Global Plasma Products Demand by Product. The Market Drivers Plasma Supply

THE WORLDWIDE PLASMA PROTEINS MARKET BY REGION - 2014 WITHOUT RECOMBINANT FACTORS Total Market $18,514.0 Million Europe 26.4% Middle-East 3.4% South America 5.6% World Population by Region - 2013 Asia & Pacific/Oceania 19.1% South America 8.8% North America 4.8% Middle East/Africa 17.9% Africa 1.2% North America 44.3% Asia & Pacific 57.8% Europe 10.7% North America holds 44% of the global market but has only 5% of the world population while Africa and the Middle East together hold 5% of the market with 18% of the world population

Table of Contents Global Plasma Products Demand by Region Per capita consumption of IVIG, factor VIII, albumin and alpha-1 antitrypsin Global Plasma Products Demand by Product. The Market Drivers Plasma Supply

IVIG/SCIG CONSUMPTION PER CAPITA IN SELECTED COUNTRIES 2010 AND 2005 (Grams per thousand Inhabitants) Canada USA Australia France 62.8 99.4 99.6 91.6 97.4 120.7 140.1 137.5 Spain UK Italy 52.5 58.3 51.9 56.5 50.3 69.6 Germany Japan Turkey Brazil China Russia 4.0 1.4 12.5 8.5 9.4 7.0 7.8 5.7 28.3 26.5 25.9 41.5 2010 2005

International differences in per capita consumption of IVIG/SCIG can be explained by: Market penetration of IVIG therapy, physicians awareness and training, diagnosis Use for chronic diseases treatment vs. acute conditions Competitive therapies and pharmaceutical drugs Absence of restrictions for and reimbursement of offlabel IVIG use Product promotion, brand competition Influence of patients advocacy groups And, above all, funding!

Consumption of Plasma Products by Country FACTOR VIII CONSUMPTION PER CAPITA IN SELECTED COUNTRIE RECOMBINANT & PLASMA-DERIVED 2007-2009 (International Units per Inhabitant) Sweden Germany United Kingdom United States Italy France Australia Canada Spain Russia Japan Argentina Iran Turkey Saudi Arabia Brazil Kuwait Mexico China Egypt India 0.16 0.08 0.01 0.70 0.56 1.15 1.08 1.05 1.05 2.08 2.91 3.60 5.98 5.90 5.40 6.30 6.20 6.98 6.93 8.45 11.20 The Factor VIII consumption per capita reflects the public policy toward hemophilia, financial resources, and mode of treatment - 2.00 4.00 6.00 8.00 10.00 12.00

AVERAGE FACTOR VIII CONSUMPTION BY COUNTRY 2010/2012 Recombinant & Plasma-derived (International Units per Capita) There is a huge gap between the industrialized and emerging countries Germany United States Italy 7.3 7.6 7.9 France 6.3 Canada Austria Russia 5.3 5.7 5.6 Spain 4.5 Japan Czech Republic 4.0 3.9 Greece 3.3 Brazil 2.4 Mexico 0.6 China India 0.1 0.0-1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0

GLOBAL FACTOR VIII CONSUMPTION BY REGION FROM 1984 TO 2010 PLASMA-DERIVED AND RECOMBINANT (International Units x 1,000) 4,000 3,500 3,000 2,500 2,000 1,500 1,000 500 South America North America Europe Asia & Pacific Middle East & Africa - 1984 1986 1988 1990 1992 1994 1996 1998 2000 2003 2005 2007 2010

THE WORLDWIDE FACTOR VIII MARKE FROM 1988 TO 2020 (Est.) (International Units x Million) 12,000 10,000 The recombinant products pushed the plasmaderived from the high income to the low-income countries 8,000 6,000 Recombinant Factor VIII 4,000 2,000 Plasmaderived 0 1988 1990 1992 1994 1996 1998 2000 2003 2005 2008 2010 2012 2014 2016 2018 2020 Market penetration of recombinant factor VIII in 30 years in units.

THE FACTOR VIII MARKET IN NORTH AMERICA FROM 1988 TO 2020 (Est.) (International Units x Million) 3,500 3,000 2,500 2,000 1,500 1,000 Recombinant Factor VIII 500 0 Plasmaderived 1988 1990 1992 1994 1996 1998 2000 2003 2005 2008 2010 2012 2014 2016 2018 2020 The units growth rate will decline as the extended half-life recombinant products gain market share, due to the lower consumption per patient

THE FACTOR VIII MARKET IN EUROPE FROM 1988 TO 2020 (Est.) (International Units x Million) 6,000 5,000 4,000 3,000 Recombinant Factor VIII 2,000 1,000 Plasma-derived Factor VIII 0 1988 1990 1992 1994 1996 1998 2000 2003 2005 2008 2010 2012 2014 2016 2018 2020 In Europe, recombinant products faced some initial resistance in some countries (France, Germany, Italy, etc)

THE FACTOR VIII MARKET IN ASIA & PACIFIC (including Australia & New Zealand FROM 1988 TO 2020 (Est.) (International Units x Million) 1,400 1,200 1,000 800 600 Recombinant Factor VIII 400 200 Plasma-Derived Factor VIII 0 1988 1990 1992 1994 1996 1998 2000 2003 2005 2008 2010 2012 2014 2016 2018 2020 43/55

THE FACTOR VIII MARKET IN SOUTH AMERICA & THE MIDDLE EAS FROM 1988 TO 2020 (Est.) (International Units x Million) 1,600 1,400 1,200 Hemophilia care policy and funding have resulted in a low penetration of recombinant factor products in low income countries Recombinant 1,000 Middle East & Africa 800 600 400 South America 200 0 1988 1990 1992 1994 1996 1998 2000 2003 2005 2008 2010 2012 2014 2016 2018 2020

Over the years, the importance of albumin in Asia has increased WORLDWIDE ALBUMIN DEMAND 1992-2011 (METRIC TONS) Worldwide Demand (Kilograms) 397 367 412 381 356 387 399 471 506 219 238 148 149 127 122 109 109 131 119 162 175 176 105101 100 79 157 158 139 122 125 126127 129 116 108 1992 1994 1996 1998 2000 2003 2005 2008 2011 North America Europe Asia & Pacific

Consumption of Plasma Products by Country ALBUMIN CONSUMPTION PER CAPITA IN SELECTED COUNTRIE 2008-2010 (Kilograms per Inhabitant) Belgium 513.7 United States 416.2 Australia 305.4 Spain 302.9 Japan 298.8 Canada 245.1 France 238.5 Sweden 194.1 Germany 148.2 Iran 117.6 China 110.2 Egypt 87.0 United Kingdom 82.1 Argentina Turkey Mexico Russia India 9.1 33.1 80.7 73.0 71.5 Medical practice, hospital budgets and tradition explain the differences in the consumption of albumin per capita Brazil 1.1-100 200 300 400 500 600

Consumption of Plasma Products by Country ALPHA-1 ANTITRYPSIN CONSUMPTION PER CAPITA IN SELECTED COUNTRIES 2008-2011 (Kilograms per million Inhabitants) United States 3.2 Germany 2.2 Spain 1.1 Canada 0.7 France 0.4 Brazil Mexico Saudi Arabia Denmark Norway Sweden 0.0 0.0 0.0 0.0 0.0 0.0 Restrictive health policies, cost of therapy and medical practice limit the use of alpha-1 antitrypsin usage to a few countries - 1 1 2 2 3 3 4

Table of Contents Global Plasma Products Demand by Region Global Plasma Products Demand by Product. The Market Drivers Plasma Supply

THE WORLDWIDE PLASMA PROTEINS MARKET BY PRODUCT - 2012 WITHOUT RECOMBINANT FACTORS Total Market $15,222 Million All Others 22.2% Hyperimmunes (IM & IV) 3.8% Factor VIII (Plasma Derived) 10.6% Albumin 13.3% Factor IX (Plasma Derived) 2.5% Polyvalent IVIG/SCIG 47.6%

THE WORLDWIDE PLASMA FRACTIONS MARKET BY PRODUCT - 2000 WITHOUT rfviii Total Market $5,100.6 (MM) Fraction V 28.9% Polyvalent IGIV 27.6% All Others (Fibrin glue, ATIII, A1-PI, etc) 14.4% Factor IX (Plasma Derived) 4.4% Hyperimmunes (IM & IV) 9.3% Factor VIII (Plasma Derived) 15.4% IVIG = 28% of total market, albumin 29%, factor VIII 15%

THE WORLDWIDE PLASMA FRACTIONS MARKET BY PRODUCT - 1986 (Without recombinant Factors) Total Market $1,853.7 (MM) Factor VIII (Plasma Derived) 16.8% Hyperimmunes (IM & IV) 13.7% Polyvalent IVIG 21.2% Factor IX (Plasma Derived) 1.9% All Others 1.4% Albumin 45.0% IVIG = 21% of total market, albumin 45%, factor VIII 17%

Market Drivers From 1974 to 1980, albumin drove the plasma market because neither factor VIII nor IVIG were available in large quantities. One liter of plasma generated approximately 28 grams of albumin. In 1980, plasma-derived factor VIII became the market driver: its global needs determined the quantity of plasma to fractionate. Its production yield was 150-180 international units per liter of plasma. IVIG took over as the market driver in 2000, and will keep this role in the foreseeable future. Its production yield ranges from 3 to 5 grams per liter of plasma.

WORLDWIDE ALBUMIN DEMAND 1974-2014 Metric Tons 800.0 780.1 700.0 716.3 600.0 500.0 400.0 300.0 200.0 100.0 302.6 267.1275.7 210.0 235.0 130.0 160.0180.0 455.7 439.6 450.5 433.8 414.4 427.0 405.8 365.6 549.2 521.8 608.0-1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 PLASMA REQUIREMENTS FOR ALBUMIN, FACTOR & IVIG 1974-2014 - Million Liters 30.0 25.0 20.0 15.0 10.0 5.0-1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 Plasma for Albumin

WORLDWIDE DEMAND FOR FACTOR VIII 1984-2014 Plasma-derived, Million International Units 4,000 3,942 3,500 3,000 3,319 3,617 2,500 2,881 2,000 1,500 2,129 1,837 1,878 1,308 1,438 1,481 1,612 1,663 2,124 2,115 2,375 2,496 1,000 500 0 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 PLASMA REQUIREMENTS FOR ALBUMIN, FACTOR & IVIG 1974-2014 - Million Liters 30.0 25.0 20.0 15.0 10.0 5.0-1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 Plasma for Factor VIII

WORLDWIDE DEMAND FOR INTRAVENOUS & SUBCUTANEOUS IMMUNE GLOBULIN (IVIG/SCIG) 1984-2014 Metric Tons 160.0 140.0 120.0 143.6 100.0 123.9 106.9 80.0 60.0 40.0 47.4 54.8 63.4 73.2 83.2 20.0 7.4 8.9 9.7 15.7 19.7 27.7 35.5 36.6 0.0 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 PLASMA REQUIREMENTS FOR ALBUMIN, FACTOR & IVIG 1974-2014 - Million Liters 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0-1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 Plasma for IVIG

PLASMA REQUIREMENTS FOR ALBUMIN, FACTOR & IVIG 1974-2014 - Million Liters 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0-1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 Plasma for Albumin Plasma for Factor VIII Plasma for IVIG

Market Drivers IVIG drives the North American market because of history, funding of non-approved indications, ample supply, role of patient organizations, company promotion, etc. Albumin drives the Asian market because IVIG is not yet widely accepted and albumin is prescribed more liberally than in the west. Increased sales of recombinant factor VIII have reduced the demand for plasma-derived of factor VIII, resulting in donations of the latter product to low-income countries by Canada, Denmark, Italy, etc.

Table of Contents Historical Development Plasma Fractionation Worldwide Plasma Products Demand Plasma Supply

Plasma for Fractionation by Region 2005 to 2013 (1000 x liters, recovered & apheresis) 30,000 25,000 20,000 15,000 10,000 5,000-2005 2007 2010 2013 Asia & Pacific Latin America North America Middle East/Africa Europe Source (apheresis) plasma collections grow the fastest, particularly in the United States

CONCLUSIONS The use of most plasma products continues to grow because of their safety and efficacy, and in spite of financial barriers, The growing demand will require that large quantities of plasma be collected and fractionated, The commercial and non-profit fractionators have the technical and logistical ability to meet future demand.

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