GLOBAL TRENDS IN PLASMA-DERIVED MEDICINAL PRODUCTS SUPPLY AND DEMAND Patrick Robert The Marketing Research Bureau, Inc.

GLOBAL TRENDS IN PLASMA-DERIVED MEDICINAL PRODUCTS SUPPLY AND DEMAND Patrick Robert The Marketing Research Bureau, Inc. L UTILIZZO DEI MEDICINALI PLASMADERIVATI IN ITALIA Istituto Superiore di Sanità 12 maggio 2016, Roma

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, such as patients advocacy groups. 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.

IMPORTANT NOTE ABOUT THE ITALIAN MARKET DATA The data used to describe the Italian market in this presentation are estimates based on information obtained from various private and public sources, which do not include the Italian Centro Nazionale Sangue and Istituto Superiore di Sanità. Therefore, some of the figures may differ markedly from any report published by these bodies. The data describing the Italian market will be revised by the Marketing Research Bureau if and when new, more accurate data become available from these or other sources.

Table of Contents Global Plasma Proteins Market 2014 By Product By Region and Country Average Consumption by Country Sales history & Forecast by Product IVIG and SCIG (IgG) Albumin Factor VIII

Table of Contents Global Plasma Proteins Market 2014 By Product By Region and Country Average Consumption by Country Sales history & Forecast by Product IVIG and SCIG (IgG) Albumin Factor VIII

THE WORLDWIDE PLASMA PROTEINS MARKET BY PRODUCT - 2014 Without Recombinant Factors Total Market $18,514.0 Million Factor VIII (Plasma Derived) 8.9% All Others 19.5% Hyperimmunes (IM & IV) 5.8% Factor IX & PCC (Plasma Derived) 4.4% Albumin 14.5% Polyvalent IVIG/SCIG 46.9% IVIG + SCIG = 47% of total market, albumin 15%, factor VIII, 9%

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%

THE PLASMA PROTEINS MARKET IN EUROPE - 2014 MARKET SHARES BY PRODUCT Without Recombinant Factors vw Factor 3% AAT 4% Factor IX PCC 3% 5% IVIG 38% Factor VIII 16% Fibrin Glue 2% All Others 4% Albumin 9% apcc 5% AT III 1% IMIG/SCIG 5% Hyperimmunes (IM) 5% Total Market: $5.49 Billion IVIG + SCIG = 38% of total market, albumin 9%, factor VIII, 16% 9

THE PLASMA PROTEINS MARKET IN ITALY - 2014 MARKET SHARES BY PRODUCT Without Recombinant Factors All others 3% Hyper IgG 5% vw Factor 2% IMIG 5% IGIV+SCIG 34% Factor VIII 12% Factor IX 1% Fibrin Sealant 4% Albumin 19% apcc 5% AT III 8% PCC 2% Total Market: $644.6 Million IVIG + SCIG = 34% of total market, albumin 19%, factor VIII, 12% 10

Consumption Trends by Product Over time, the consumption of polyvalent immune globulins and of several specialty products (C-1 esterase inhibitor, alpha-1 antitrypsin, fibrinogen, prothrombin complex) will increase, The use of plasma-derived coagulation factors will continue to shift to low income countries, Albumin consumption will grow in Asia, decline in southern Europe, and remain stable or grow moderately in northern Europe. These trends will apply to Italy, except for antithrombin III, the use of which may continue to increase.

ANTITHROMBIN III AND TETANUS IMMUNOGLOBULIN IN SELECTED COUNTRIES 2012-2014 Million Million AT III IUs Population IU/Capita Japan 204 127 1.6 Italy 145 61.2 2.4 Germany 65.7 82.5 0.8 Sweden 2 9.6 0.2 (000) Million Anti Tet Vials Population Vials/Capita Japan 56 127 0.4 Italy 440 61.2 7.2 Germany 335 82.5 4.1 Argentina 332 41.5 8.0 12

Table of Contents Global Plasma Proteins Market 2014 By Product By Region and Country Average Consumption by Country Sales history & Forecast by Product IVIG and SCIG (IgG) Albumin Factor VIII

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

THE PLASMA PROTEINS MARKET IN EUROPE - 2014 TOTAL MARKET BY COUNTRY Without Recombinant Factors Eastern Europe 12.3% Spain 7.5% Italy 11.7% Other Western Europe 17.3% United Kingdom 7.8% Germany 28.5% France 15.0% Total Market $5.49 billion 15

THE PLASMA PROTEINS MARKET IN EUROPE - 2014 TOTAL MARKET BY COUNTRY With Recombinant Factors Other Western Europe 18.6% Eastern Europe 10.8% Spain 6.8% Italy 13.4% United Kingdom 8.6% Germany 25.7% France 16.1% Total Market $8.24 billion 16

Table of Contents Global Plasma Proteins Market 2014 By Product By Region and Country Average Consumption by Country Sales history & Forecast by Product IVIG and SCIG (IgG) Albumin Factor VIII

INTRAVENOUS/SUB-CUTANEOUS (IVIG/SCIG) CONSUMPTION BY COUNTRY (Kilograms per Million People) USA 99.6 200.1 Canada Australia 99.4 91.6 179.5 174.0 France 62.8 127.7 Germany 28.3 92.7 UK 51.9 85.0 Spain Italy Japan Turkey 14.0 8.5 34.0 27.4 69.6 52.5 50.3 66.0 The IVIG consumption per capita has virtually doubled in many countries between 2005 and 2014 China 11.1 5.7 2005 2014 Brazil 9.4 7.0 Russia 4.5 1.4

International differences in per capita consumption of IVIG/SCIG can be explained by: Number of patients diagnosed and treated, physicians awareness and training, Use for chronic diseases treatment vs. acute conditions Competition from alternative therapies and pharmaceutical drugs off-label use and reimbursement of Product promotion, brand competition Influence of patients advocacy groups Most important, funding.

AVERAGE ALBUMIN USAGE IN EUROPE 2011-2014 (Kg. per Million Population) Italy Greece Austria Sweden Slovenia Spain Belgium France Denmark Serbia Germany Portugal Average Slovakia Croatia Poland Montenegro United Kingdom Norway Switzerland Finland 174.1 249.4 180.0 227.7 216.8 223.0 189.3 199.1 205.6 172.9 197.1 193.2 115.4 190.0 146.1 189.9 117.5 181.1 119.2 168.0 187.5 147.7 118.7 273.2 361.3 255.7 339.6 304.9 337.8 299.6 336.3 281.5 278.9 280.3 247.5 258.7 405.5 522.6 2011 2014 19.4 611.5 680.9 677.9 Southern European countries generally use more albumin than northern European countries

International differences in per capita consumption of albumin can be explained by: Medical practice and specific countries regulations, Epidemiology, Limited competition from non plasma-based plasma volume replacement solutions, Availability of supply, Funding.

FACTOR VIII CONSUMPTION PER CAPITA IN EUROPE 2011 & 2014 Plasma-derived & recombinant (International Units/Inhabitant) Sweden Ireland Germany Italy Hungary Slovenia United Kingdom 9.6 8.3 9.2 8.1 9.1 7.9 8.8 7.3 8.6 7.3 8.3 6.6 7.9 7.2 Finland Belgium France Poland Norway 4.7 5.4 6.1 7.7 6.3 6.9 6.8 6.6 7.5 7.6 In 2014, Italy had the fourth factor VIII per capita consumption ratio in Europe Denmark Average Switzerland Slovakia Austria 5.0 5.9 6.4 6.1 5.3 5.8 4.7 5.8 5.7 5.6 2014 2011 22

International differences in factor VIII consumption per capita can be explained by: Diagnosis, prophylactic treatment, immune tolerance Availability of funding Product promotion, brand competition Influence of hemophilia patients organizations The new recombinant extended half-life factor products, as well as of monoclonal antibodies and subsequently of gene therapy, will cause a sea-change in hemophilia care in the coming years. Patients in low income countries are likely to benefit from the availability of numerous plasma-derived and recombinant factor products at reduced cost.

Table of Contents Global Plasma Proteins Market 2014 By Product By Region and Country Average Consumption by Country Sales history & Forecast by Product IVIG and SCIG (IgG) Albumin Factor VIII

WORLDWIDE DEMAND FOR IVIG/SCIG FROM 1984 TO 2014 Metric Tons 160.0 140.0 120.0 Compounded Average Growth Rate (CAGR) +10.2% per year since 1984 +7.9% per year since 2000 143.6 100.0 80.0 106.9 123.9 60.0 40.0 20.0 7.4 8.9 9.7 15.7 19.7 27.7 35.5 36.6 47.4 54.8 63.4 73.2 83.2 0.0 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014

GLOBAL DEMAND FOR POLYVALENT INTRAVENOUS/SUBCUTANEOUS IMMUNE GLOBULIN (IVIG/SCIG) (Metric Tons) 2008-2020 200.0 180.0 160.0 140.0 120.0 100.0 80.0 81.9 102.6 115.4 130.5 153.3 167.0 180.2 60.0 40.0 20.0-2008 2010 2012 2014 2016 2018 2020

FACTORS INFLUENCING THE FUTURE IGG DEMAND IVIG & SCIG usage will continue to grow as more patients are diagnosed, new indications are approved and funding becomes available. In the low income countries, IVIG is primarily prescribed for acute situations. Patients with chronic conditions need to resort to other treatment modalities. By 2020, some 180 tons of IgG is forecasted

Table of Contents Global Plasma Proteins Market 2014 By Product By Region and Country Average Consumption by Country Sales history & Forecast by Product IVIG and SCIG (IgG) Albumin Factor VIII

WORLDWIDE ALBUMIN DEMAND 1974-2016 Metric Tons 1,200.0 1,000.0 CAGR +3.6% per year since 1984 +4.8% per year since 2000 845.3 1,014.3 800.0 716.3 600.0 400.0 200.0 365.6 235.0 267.1 275.7 302.6 210.0 160.0180.0 130.0 414.4 439.6 455.7 427.0 549.2 521.8 433.8 450.5 405.8 608.0-1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016

THE GLOBAL ALBUMIN MARKET FROM 1986 TO 2020 (Kilograms) 1,400,000 1,200,000 1,227,303 1,000,000 1,014,300 1,115,730 800,000 600,000 549,152 608,000 716,300 845,300 400,000 200,000-2008 2010 2012 2014 2016 2018 2020

FACTORS INFLUENCING THE FUTURE ALBUMIN DEMAND Albumin usage will continue to grow as health care services improve in a growing number of countries, new indications are approved and plasma volume replacement solutions are less popular. By 2020, a global consumption of about 1,200 tons of albumin is forecasted.

Table of Contents Global Plasma Proteins Market 2014 By Product By Region and Country Average Consumption by Country Sales history & Forecast by Product IVIG and SCIG (IgG) Albumin Factor VIII

WORLDWIDE DEMAND FOR FACTOR VIII 1984-2014 Plasma-derived, Million International Units 4,000 3,500 3,000 2,500 CAGR +3.7% per year since 1984 +4.5% per year since 2000 2,881 3,319 3,617 3,942 2,000 1,500 1,308 1,438 1,481 1,612 1,837 2,129 1,878 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 5/55

WORLDWIDE DEMAND FOR FACTOR VIII 1984-2014 Plasma-derived & Recombinant - Million International Units 10,000 9,760 9,000 8,956 8,000 7,000 6,000 CAGR +6.9% per year since 1984 +7.2% per year since 2000 6,020 6,908 8,000 5,000 4,943 4,000 3,000 2,000 3,705 3,963 2,664 3,038 1,8372,129 1,308 1,4381,481 1,612 1,000 0 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 5/55 Total Market Plasma-Derived

THE WORLDWIDE FACTOR VIII MARKET FROM 2008 TO 2020 Est. (International Units x Million) 12,000 10,000 Global annual growth 2012-20: 2.1% 8,952 8,959 9,455 9,990 10,566 8,000 8,114 6,905 6,000 4,000 4,024 2,881 4,693 3,421 5,192 5,241 3,759 3,718 5,553 3,902 5,888 4,102 6,246 4,320 2,000 0 2008 2010 2012 2014 2016 2018 2020 Plasma-derived Recombinant Total Market

FACTORS INFLUENCING THE FUTURE FACTOR VIII DEMAND The global factor VIII usage will grow at a more modest rate than in the past, particularly in the high income countries, due to the market penetration of extended half-life (EHL) recombinant factor products. More patients will have access to plasma-derived clotting factors in low income countries By 2020, a global consumption of about 10.5 billion factor VIII units is forecasted, including 6.2 billion units of recombinant products (standard and EHL).

Thank you www.marketingresearchbureau.com