Critical Care Therapeutics in Major Developed Markets to 2020 New and Late-Stage Four-Factor Pccs and Recombinant Products to Drive Market

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Critical Care Therapeutics in Major Developed Markets to 2020 New and Late-Stage Four-Factor PCCs and Recombinant Products to Drive Market

GBI Research Report Guidance

GBI Research Report Guidance  Chapter two gives an overview of the epidemiology, pathogenesis, diagnosis, and the therapeutic unmet need of critical care indications. The indications covered in this report are limited to those that are treated with albumin, anti-thrombin concentrates, factor XIII concentrates, fibrinogen concentrates and prothrombin complex concentrates.  Chapter three describes the therapeutic landscape of the critical care market covering marketed products in the eight major developed markets.  Chapter four provides an overview of the drugs in the critical care therapeutic pipeline. This includes in-depth analysis of the promising molecules in late-stage trials, which look set to make an impact on the market.  Chapter five confers revenue forecasts until 2020 for the critical care market in the eight major developed markets – the US, UK, France, Germany, Italy, Spain, Japan and Canada.  Chapter six addresses strategic consolidations and deals that took place in the global critical care market during the 2011–2013 period.

Executive Summary

Executive Summary Critical Care Market to Reach $XX Billion in the Major Developed Markets by 2020 The critical care market in the eight major developed markets (the US, UK, France, Germany, Italy, Spain, Japan and Canada) was worth an estimated $XX billion in 2013 and is expected to grow to $XX billion by US held the largest 2020 at a Compound Annual Growth Rate (CAGR) of XX%. The majority of this revenue was due to albumin share with XX% of sales which amounted to $XX billion in 2013 and are expected to grow to $XX billion by 2020. In terms of the total critical markets, the US held the largest share with XX% of the total critical care market in 2013 and is projected to care market in grow at the highest rate of any market at XX% during the 2013–2020 period. 2013. Albumin was used to treat the highest share of the critical care treatment population across all eight markets with XX million patients of a total of XX million in 2013. Expectedly, the highest share of these patients was in the US, a total of XX% in 2013. A further XX% of the 2013 treatment population were located in the top five countries of Europe, followed by Japan with XX% and rest from Canada. The treatment population in the US is estimated to grow at a CAGR of XX% until 2020 with highest growth expected in the number of patients treated with Prothrombin Complex Concentrate (PCC) which is expected to grow at a CAGR of XX%. Globally, the treatment population receiving Anti-Thrombin (AT) concentrates and PCCs is expected to be larger than any other category and will grow at a CAGR of XX% during the 2013–2020 period.

Critical Care, Major Developed Markets, Revenue ($bn), 2013–2020 Revenue($bn)

2013 2014 2015 2016 2017 2018 2019 2020

Low variance Medium variance High variance Projected

Source: GBI Research, Proprietary Marketed Products Database

The projected high growth rate of revenues in the US market of XX% is mainly due the increased uptake of factor concentrates over older alternatives (such as Fresh-Frozen Plasma (FFP)), higher price inflation and the launch of new drugs such as Kcentra (PPC, human) and Tretten (Factor XIII concentrate, recombinant) in 2013. Kcentra is the first four-factor PCC in the US and Tretten is the first recombinant factor XIII concentrate. In the top five European critical care markets there have been no recent significant product launches and none are expected during the forecast period. These markets are therefore anticipated to grow slowly during the forecast period, the UK market will grow at a CAGR of XX%, followed by France at XX%, Germany and Spain will each grow at XX% and Italy at XX%.

Table of Contents

1 Table of Contents 1 Table of Contents ...... 5 1.1 List of Tables ...... 8 1.2 List of Figures...... 9 2 Introduction...... 10 2.1 Albumin in Critical Care ...... 10 2.1.1 Overview ...... 10 2.1.2 Diseases or Conditions Indicated for Albumin ...... 10 2.1.3 Epidemiology ...... 11 2.1.4 Other Treatment Options ...... 11 2.1.5 Treatment Patterns ...... 11 2.2 Anti-Thrombin III Concentrates in Critical Care ...... 12 2.2.1 Overview ...... 12 2.2.2 Anti-Thrombin Deficiencies ...... 12 2.2.3 Epidemiology ...... 12 2.2.4 Treatment Options ...... 13 2.2.5 Treatment Patterns ...... 13 2.3 Factor XIII Concentrates in Critical Care ...... 13 2.3.1 Overview ...... 13 2.3.2 FXIII Deficiencies ...... 14 2.3.3 Epidemiology ...... 14 2.3.4 Treatment Options ...... 14 2.3.5 Treatment Patterns ...... 14 2.4 Fibrinogen Concentrates in Critical Care ...... 15 2.4.1 Overview ...... 15 2.4.2 Fibrinogen Deficiencies ...... 15 2.4.3 Epidemiology ...... 16 2.4.4 Treatment Options ...... 16 2.4.5 Treatment Patterns ...... 16 2.5 Prothrombin Complex Concentrate in Critical Care ...... 17 2.5.1 Overview ...... 17 2.5.2 Diseases or Conditions Indicated for Prothrombin Complex Concentrate ...... 17 2.5.3 Epidemiology ...... 18 2.5.4 Treatment Options ...... 18 2.5.5 Treatment Patterns ...... 19 3 Therapeutic Landscape ...... 20 3.1 Albumin Products ...... 20 3.1.1 Buminate (albumin, human) – Baxter ...... 20 3.1.2 Zenalb (human albumin) – Bio Products Laboratory ...... 20 3.1.3 Human Albumin Biotest (albumin, human) – Biotest...... 20 3.1.4 AlbuRx (albumin) – CSL Behring ...... 20 3.1.5 Albuminar (albumin, human) 5% – CSL Behring ...... 21 3.1.6 Albutein (albumin (human)) – Grifols ...... 21 3.1.7 Albuked (human albumin) – Kedrion ...... 21 3.1.8 Vialebex (human albumin) – French Fractionation and Biotechnology Laboratory ...... 22 3.1.9 Albunorm (human albumin) – Octapharma ...... 22 3.1.10 Alburaas (human albumin) – Shanghai RAAS...... 22 3.2 Anti-Thrombin Concentrates ...... 22 3.2.1 Atryn (antithrombin alfa) – rEVO Biologics ...... 22 3.2.2 Thrombate III (AT III human) – Grifols ...... 24 3.2.3 Anbinex (AT III human) – Grifols ...... 24

Table of Contents

3.2.4 Kybernin P (AT III human) – CSL Behring ...... 24 3.2.5 Aclotine (AT III, human) – French Fractionation and Biotechnology Laboratory ...... 25 3.2.6 Anti-Thrombin III (AT III human) – Baxter ...... 25 3.2.7 AT III Kedrion (AT III human) – Kedrion ...... 25 3.2.8 Neuart (AT III, human) – Mitsubishi Tanabe ...... 25 3.3 Factor XIII Concentrates ...... 26 3.3.1 Fibrogammin/Corifact (factor XIII) – CSL Behring ...... 26 3.3.2 NovoThirteen/Tretten (catridecacog) – Novo Nordisk ...... 26 3.4 Fibrinogen Concentrates ...... 27 3.4.1 Haemocomplettan P/Riastap (fibrinogen concentrate, human) – CSL Behring ...... 27 3.4.2 Clottafact/Clottagen (fibrinogen concentrate, human) – French Fractionation and Biotechnology Laboratory ...... 28 3.4.3 Other Marketed Fibrinogen Concentrates ...... 28 3.5 Prothrombin Complex Concentrates ...... 28 3.5.1 Beriplex P/N/Confidex/Kcentra (Prothrombin Complex Concentrate [Human]) – CSL Behring ...... 28 3.5.2 Bebulin VH (factor IX complex, vapor heated) – Baxter ...... 28 3.5.3 Cofact (prothrombin complex concentrate) – Sanquin ...... 29 3.5.4 Octaplex 500 (human prothrombin complex) – Octapharma ...... 29 3.5.5 Profilnine SD – Grifols ...... 29 3.5.6 Uman Complex DI – Kedrion ...... 29 4 Pipeline for Critical Care Market ...... 30 4.1 Overview of Pipeline ...... 30 4.2 Promising Pipeline Candidates ...... 30 4.2.1 Octaplex 500 (human prothrombin complex) – Octapharma ...... 31 4.2.2 KW-3357– Kyowa Hakko Kirin...... 31 4.2.3 Human AT Concentrate – Grifols ...... 31 5 Critical Care Market Forecast to 2020 ...... 32 5.1 Geographical Markets ...... 32 5.1.1 Major Developed Markets ...... 32 5.1.2 US...... 35 5.1.3 Top Five European Countries ...... 37 5.1.4 Japan ...... 40 5.1.5 Canada ...... 42 5.2 Drivers and Barriers ...... 45 5.2.1 Drivers ...... 45 5.2.2 Barriers ...... 46 6 Deals and Strategic Consolidations ...... 48 6.1 Major Deals ...... 48 6.1.1 Octapharma Enters Into an Agreement with Pfizer ...... 48 6.1.2 Grifols to Acquire Blood Transfusion Diagnostics Business from Novartis ...... 48 6.1.3 Shin Poong Pharmaceutical and French Fractionation and Biotechnology Laboratory form a Korea-based Bio-pharmaceutical Joint Venture ...... 48 6.1.4 Bain Capital Acquires 80% Stake in Plasma Resources UK ...... 48 6.1.5 Biomat Acquires Three Plasma Donation Centers from Cangene ...... 49 6.1.6 BioRx Enters into Co-Marketing Agreement with CSL Behring for Corifact ...... 49 6.1.7 Baxter Announces Collaboration with Sanquin to Expand Capacity for Plasma Therapies ...49 6.1.8 Shire Enters into Licensing Agreement with Sangamo BioSciences ...... 49 6.1.9 Baxter Completes Acquisition of Rights to OBI-1 and Related Assets from Ipsen and Inspiration Biopharma ...... 49 7 Critical Care Market to 2020 – Appendix ...... 51 7.1 Abbreviations ...... 51

Table of Contents

7.2 References ...... 52 7.3 Pipeline Products ...... 55 7.4 Market Forecasts to 2020 ...... 56 7.4.1 Major Developed Markets ...... 56 7.4.2 US...... 57 7.4.3 UK ...... 59 7.4.4 France ...... 60 7.4.5 Germany ...... 62 7.4.6 Italy ...... 63 7.4.7 Spain ...... 65 7.4.8 Japan ...... 66 7.4.9 Canada ...... 68 7.5 Research Methodology ...... 69 7.5.1 Coverage ...... 69 7.5.2 Secondary Research ...... 70 7.5.3 Primary Research ...... 70 7.5.4 Therapeutic Landscape ...... 70 7.5.5 Geographical Landscape ...... 72 7.5.6 Pipeline Analysis...... 73 7.6 Expert Panel Validation ...... 73 7.7 Contact Us ...... 73 7.8 Disclaimer...... 73

Table of Contents

1.1 List of Tables Table 1: Critical Care Market, Atryn, Development Timeline, 2007–2013 ...... 23 Table 2: Critical Care Market, Global, Pharmaceutical Pipeline, 2014 ...... 55 Table 3: Critical Care Market, Major Developed Markets, Market Forecast, 2013–2020 ...... 56 Table 4: Critical Care Market, Major Developed Markets, Albumin, Market Forecast, 2013–2020 ...... 56 Table 5: Critical Care Market, Major Developed Markets, Anti-Thrombin Concentrates, Market Forecast, 2013–2020 ...... 56 Table 6: Critical Care Market, Major Developed Markets, FXIII Concentrates, Market Forecast, 2013– 2020 ...... 56 Table 7: Critical Care Market, Major Developed Markets, Fibrinogen Concentrates, Market Forecast, 2013–2020 ...... 57 Table 8: Critical Care Market, Major Developed Markets, Prothrombin Complex Concentrates, Market Forecast, 2013–2020 ...... 57 Table 9: Critical Care Market, US, Market Forecast, 2013–2020 ...... 57 Table 10: Critical Care Market, US, Albumin, Market Forecast, 2013–2020 ...... 57 Table 11: Critical Care Market, US, Anti-Thrombin Concentrates, Market Forecast, 2013–2020 ...... 58 Table 12: Critical Care Market, US, FXIII Concentrates, Market Forecast, 2013–2020 ...... 58 Table 13: Critical Care Market, US, Fibrinogen Concentrates, Market Forecast, 2013–2020 ...... 58 Table 14: Critical Care Market, US, Prothrombin Complex Concentrates, Market Forecast, 2013–2020 ....58 Table 15: Critical Care Market, UK, Market Forecast, 2013–2020 ...... 59 Table 16: Critical Care Market, UK, Albumin, Market Forecast, 2013–2020 ...... 59 Table 17: Critical Care Market, UK, Anti-Thrombin Concentrates, Market Forecast, 2013–2020 ...... 59 Table 18: Critical Care Market, UK, FXIII Concentrates, Market Forecast, 2013–2020 ...... 59 Table 19: Critical Care Market, UK, Fibrinogen Concentrates, Market Forecast, 2013–2020 ...... 60 Table 20: Critical Care Market, UK, Market Forecast, Prothrombin Complex Concentrates, 2013–2020 ....60 Table 21: Critical Care Market, France, Market Forecast, 2013–2020 ...... 60 Table 22: Critical Care Market, France, Albumin, Market Forecast, 2013–2020 ...... 60 Table 23: Critical Care Market, France, Anti-Thrombin Concentrates, Market Forecast, 2013–2020 ...... 61 Table 24: Critical Care Market, France, FXIII Concentrates, Market Forecast, 2013–2020 ...... 61 Table 25: Critical Care Market, France, Fibrinogen Concentrates, Market Forecast, 2013–2020 ...... 61 Table 26: Critical Care Market, France, Prothrombin Complex Concentrates, Market Forecast, 2013–2020 ...... 61 Table 27: Critical Care Market, Germany, Market Forecast, 2013–2020 ...... 62 Table 28: Critical Care Market, Germany, Albumin, Market Forecast, 2013–2020 ...... 62 Table 29: Critical Care Market, Germany, Anti-Thrombin Concentrates, Market Forecast, 2013–2020 ...... 62 Table 30: Critical Care Market, Germany, FXIII Concentrates, Market Forecast, 2013–2020 ...... 62 Table 31: Critical Care Market, Germany, Fibrinogen Concentrates, Market Forecast, 2013–2020 ...... 63 Table 32: Critical Care Market, Germany, Prothrombin Complex Concentrates, Market Forecast, 2013– 2020 ...... 63 Table 33: Critical Care Market, Italy, Market Forecast, 2013–2020 ...... 63 Table 34: Critical Care Market, Italy, Albumin, Market Forecast, 2013–2020 ...... 63 Table 35: Critical Care Market, Italy, Anti-Thrombin Concentrates, Market Forecast, 2013–2020 ...... 64 Table 36: Critical Care Market, Italy, FXIII Concentrates, Market Forecast, 2013–2020 ...... 64 Table 37: Critical Care Market, Italy, Fibrinogen Concentrates, Market Forecast, 2013–2020 ...... 64 Table 38: Critical Care Market, Italy, Prothrombin Complex Concentrates, Market Forecast, 2013–2020 ..64 Table 39: Critical Care Market, Spain, Market Forecast, 2013–2020...... 65 Table 40: Critical Care Market, Spain, Albumin, Market Forecast, 2013–2020 ...... 65 Table 41: Critical Care Market, Spain, Anti-Thrombin Concentrates, Market Forecast, 2013–2020 ...... 65 Table 42: Critical Care Market, Spain, FXIII Concentrates, Market Forecast, 2013–2020 ...... 65 Table 43: Critical Care Market, Spain, Fibrinogen Concentrates, Market Forecast, 2013–2020 ...... 66 Table 44: Critical Care Market, Spain, Prothrombin Complex Concentrates, Market Forecast, 2013–2020 66 Table 45: Critical Care Market, Japan, Market Forecast, 2013–2020 ...... 66 Table 46: Critical Care Market, Japan, Albumin, Market Forecast, 2013–2020...... 66 Table 47: Critical Care Market, Japan, Anti-Thrombin Concentrates, Market Forecast, 2013–2020 ...... 67 Table 48: Critical Care Market, Japan, FXIII Concentrates, Market Forecast, 2013–2020 ...... 67 Table 49: Critical Care Market, Japan, Fibrinogen Concentrates, Market Forecast, 2013–2020 ...... 67 Table 50: Critical Care Market, Japan, Prothrombin Complex Concentrates, Market Forecast, 2013–202067 Table 51: Critical Care Market, Canada, Market Forecast, 2013–2020...... 68

Table of Contents

Table 52: Critical Care Market, Canada, Albumin, Market Forecast, 2013–2020 ...... 68 Table 53: Critical Care Market, Canada, Anti-Thrombin Concentrates, Market Forecast, 2013–2020 ...... 68 Table 54: Critical Care Market, Canada, FXIII Concentrates, Market Forecast, 2013–2020 ...... 68 Table 55: Critical Care Market, Canada, Fibrinogen Concentrates, Market Forecast, 2013–2020 ...... 69 Table 56: Critical Care Market, Canada, Prothrombin Complex Concentrates, Market Forecast, 2013–2020 ...... 69

1.2 List of Figures Figure 1: Critical Care Market, Global, Overall Pipeline Analysis (%), 2013 ...... 30 Figure 2: Critical Care Market, Major Developed Markets, Treatment Use Patterns, 2013–2020...... 33 Figure 3: Critical Care Market, Major Developed Markets, Revenue ($bn), 2013–2020 ...... 34 Figure 4: Critical Care Market, US, Treatment Use Patterns, 2013–2020 ...... 35 Figure 5: Critical Care Market, US, Annual Cost of Therapy and Revenue, 2013–2020 ...... 36 Figure 6: Critical Care Market, Top Five European Countries, Treatment Use Patterns, 2013 and 2020 ....38 Figure 7: Critical Care Market, Top Five European Countries, Annual Cost of Therapy ($), 2013–2020 .....39 Figure 8: Critical Care Market, Top Five European Countries, Revenue ($m), 2013–2020 ...... 40 Figure 9: Critical Care Market, Japan, Treatment Use Patterns, 2013–2020 ...... 41 Figure 10: Critical Care Market, Japan, Annual Cost of Therapy and Revenue, 2013–2020 ...... 42 Figure 11: Critical Care Market, Canada, Treatment Use Patterns, 2013–2020 ...... 43 Figure 12: Critical Care Market, Canada, Annual Cost of Therapy and Revenue, 2013–2020 ...... 44 Figure 13: GBI Research Market Forecasting Model ...... 72

Introduction

2 Introduction 2.1 Albumin in Critical Care 2.1.1 Overview Albumin, a low-molecular-weight protein, is produced in the liver and accounts for around XX% of total human plasma mass. It is fundamental to the maintenance of blood volume and the stability of blood circulation and has a serum half-life of approximately XX days. Around XX–XX grams (g) of albumin is present in one liter (l) of blood plasma with the normal range of albumin concentration occurring at XX–XXg per deciliter (dl). Large blood or plasma loss following traumatic injury or in high-risk clinical settings could lead to hypotension (low blood pressure), necessitating the replacement of plasma volume with albumin. Albumin plays an important role in the management of many clinically significant high-risk conditions such as cardiopulmonary bypass surgery, burn cases, acute liver failure, or in other critically ill patients. It can also be used in the emergency treatment of shock and in other similar conditions where blood volume must be urgently restored. 2.1.2 Diseases or Conditions Indicated for Albumin

2.1.2.1 Albumin in Hypoalbuminemia Low levels of blood albumin cause albumin deficiency or hypoalbuminemia. Hypoalbuminemia may result in generalized edema (swelling) via a decline in oncotic pressure and usually correlates with increased morbidity and mortality in critically ill patients. Disease conditions such as liver disease (failure to synthesize albumin), excessive loss of albumin (through protein-losing enteropathy or in burn patients), and nephrotic syndrome (increased excretion of albumin in the urine) could result in hypovolemia and/or hypoalbuminemia. A low serum-albumin level may be indicative of liver failure or other liver diseases such as cirrhosis or chronic hepatitis, or possibly an indicator of chronic malnutrition or protein-losing enteropathy. Hypoalbuminemia is a common problem among patients with acute and chronic conditions. It has been reported that around XX% of all admitted patients with acute or chronic conditions have hypoalbuminemia at the time of hospital admission (Peralta, 2012; Vincent, 2003). Albumin is used in the treatment of hypoalbuminemia. The effect would be temporary if the underlying conditions causing hypoalbuminemia were not reversed, but it would serve as a useful adjunct in cases linked with severe injuries, infections or pancreatitis, which cannot be quickly reversed.

2.1.2.2 Albumin in Hypovolemia The usefulness of albumin in reversing hypovolemia is primarily dependent upon its ability to draw interstitial fluid into the systemic circulations. Although alternatives to albumin (such as crystalloid solutions and colloid-containing plasma substitutes) can be used in the emergency treatment of shock and other critical conditions, the use of albumin is preferable, by virtue of its efficacy and prolonged intravascular half- life. Human albumin can be used to treat severe hypovolemia, which usually occurs during the first few months of pregnancy, however, there have been no controlled studies on the volume of replacement required to correct such hypovolemia. Albumin use in such cases should therefore be used with caution. The effectiveness of human albumin for the management of hypovolemia in trauma patients has not been shown to have better results in terms of survival rate in comparison with other alternatives such as crystalloids or any other colloidal volume substitutes (Boldt, 2010).

2.1.2.3 Albumin in Cardiopulmonary Bypass The use of albumin has been suggested prior to or during cardiopulmonary bypass surgery. Although its advantage over crystalloid solutions has not yet been clearly established, a retrospective analysis has appeared to demonstrate a lower mortality rate in cardiac surgery patients with the use of human albumin (Boldt, 2010).

Pipeline for Critical Care Market

4 Pipeline for Critical Care Market 4.1 Overview of Pipeline The critical care pipeline is considerably weak with very few innovative drugs expected to be launched during the forecast period. There are some currently marketed products that are expected to be approved as line extensions for new indications or in new clinical settings. The largest share of pipeline drugs, especially in late-stage trials, are fibrinogen concentrates, indicated for congenital or acquired factor I or fibrinogen deficiency. A proportion of XX% of the critical care pipeline is fibrinogen concentrates followed by albumin at XX%. A total of XX% of the pipeline products is in Phase III of development followed by XX% in discovery Phase. CSL’s Haemocomplettan P (also marketed as Kcentra or Beriplex), which is a widely used fibrinogen concentrate, is currently under phase three clinical trials for fibrinogen deficiency in complex cardiac surgery in collaboration with Isala Klinieken (CSL Behring, NCT01124981). CSL’s fibrinogen concentrate is also under investigation for surgical or post-operative blood loss (CSL Behring, NCT01475669). Four other leading companies Biotest, Grifols, LFB and Octapharma also have fibrinogen concentrates in late-stage trials. Octapharma’s Octaplex, which is already marketed in the EU and Australia, is currently in late-stage development in the US and would be the second PCC to be approved in the US after Kcentra. Kyowa Hakko Kirin, the Japanese drug maker has a novel fucose-deficient recombinant AT preparation in late-stage development in Japan, expected to be launched in 2014. The product is in Phase I in EU clinical trials.

Figure 1: Critical Care Market, Global, Overall Pipeline Analysis (%), 2013

Pipeline by type of product Pipeline by stage of development

Prothrombin complex concentrates Discovery

Albumin AT Phase III concentrates Phase I n = XX n = XX

Preclinical

Phase II Pre-registration Fibrinogen concentrates

Source: GBI Research, Proprietary Pipeline Products Database Abbreviations: IND: Investigational New Drug; CTA: Clinical Trial Applications

Critical Care Market Forecast to 2020

5.1.3.2 Annual Cost of Therapy The ACoT for the critical care market in top five EU is an average of the ACoT for the five blood product categories in these five countries and is calculated based on the total revenues from the five categories divided by the total treatment population. The ACoT for products in critical care markets in the top five EU countries was estimated to be $XX in 2013 and is expected to increase at a CAGR of XX% to reach $XX by 2020. Lower levels of inflation and a lack of significant product launches have contributed towards a slow growth rate. The highest growth in ACoT is expected to occur in FXIII products at a CAGR of XX% due to increased uptake of NovoThirteen, the recombinant FXIII for prophylactic treatment during the forecast period as it has a higher cost than plasma-derived products. Albumin ACoT is also expected to increase at a CAGR of XX% during the forecast period as the demand for albumin is expected to increase in some of the regions. The ACoT for prophylactic treatment with fibrinogen concentrates is highest in Europe with $XX in 2013 followed by prophylactic treatment with rFXIII concentrates at $XX.

Figure 7: Critical Care Market, Top Five European Countries, Annual Cost of Therapy ($), 2013–2020

A) UK B) Germany ($) ($) ACoT ACoT

2013 2014 2015 2016 2017 2018 2019 2020 2013 2014 2015 2016 2017 2018 2019 2020 C) France D) Italy ($) ACoT ($) ACoT ACoT

2013 2014 2015 2016 2017 2018 2019 2020 2013 2014 2015 2016 2017 2018 2019 2020

E) Spain

($) Low variance

Medium variance ACoT

High variance

Projected

2013 2014 2015 2016 2017 2018 2019 2020

Source: GBI Research, Proprietary Marketed Products Database

Critical Care Market to 2020 – Appendix

7 Critical Care Market to 2020 – Appendix 7.1 Abbreviations AcoT: Annual Cost of Therapy AMBAR: Alzheimer Management By Amyloid Removal ARDS: Adult Respiratory Distress Syndrome AT: Anti-Thrombin BCSH: British Committee For Standards In Hematology BLA: Biologics License Application CAGR: Compound Annual Growth Rate CTA: Clinical Trial Agreement DIC: Disseminated Intravascular Coagulation dl: deciliter EU: European Union EU-5: Top Five Countries in European Union EMA: European Medicine Agency F: Factor FDA: Food and Drug Administration FEIBA: Factor Eight Inhibitor Bypass Activity g: grams HES: Hydroxyethyl Starch IND: Investigational New Drug INR: International Normalized Ratio IU: International Unit IV: Intravenous JV: Joint Venture kg: kilograms LFB: Laboratoire Français Du Fractionnement Et Des Biotechnologies LMWH: Low-Molecular-Weight Heparin mg: milligrams ml: milliliter PCC: Prothrombin Complex Concentrate PPH: Postpartum Hemorrhage Treatment & Management PT: Prothrombin Time PRUK: Plasma Resources UK rFVIIa: Recombinant Activated Factor VII rFXIII: Recombinant Factor XIII Concentrate rFXIIIa: Recombinant Factor XIII A-Subunit SAFE: Saline Versus Albumin Fluid Evaluation

Critical Care Market to 2020 – Appendix

SD: Solvent Detergent VTE: Venous Thromboembolism ZFP: Zinc Finger DNA-binding Protein 7.2 References  Acharya, S.S. and DiMichelle, M., (2008). Rare inherited disorders of fibrinogen. Hemophilia. Vol.: 14 (6), pp: 1151–1158  Aird, W., (2003). The Hematologic System as a Marker of Organ Dysfunction in Sepsis. Mayo Clinical Process; vol.: 78, pp: 869–881  Bershad E, et al. (2009). Prothrombin Complex Concentrates for Oral Anticoagulant Therapy-Related Intracranial Hemorrhage: A Review of the Literature. Neurocritical Care; 12(3): 403–413  Board P.G. et al., (1993). Factor XIII: inherited and acquired deficiency. Blood Review, Vol.: 7(4), pp: 229–42.  Boldt J (2010). Use of albumin: an update. British Journal of Anesthesia; 104(3): 276–284.  Boldt J, Papsdorf M. (2008). Fluid management in burn patients: results from a European survey – more questions than answers. Burns; Vol.: 34(3); pp:328-38  BPRO (2013). Blood Program in Japan. Blood Products Research Organization. Available from http://bpro.or.jp/english/pdf_annual/BPRO2013.pdf  Calizzani, G. et al., (2013). The evolution of the regulatory framework for the plasma and plasma- derived medicinal products system in Italy. Blood Transfusion; vol.: 11(4), pp: 6–12.  CIHI (2013). Highlights of 2011–2012 Emergency Department Visits and Inpatient Hospitalizations. Canadian Institute for Health Information (CIHI). Available from: https://secure.cihi.ca/free_products/DAD-NACRS_Quick%20Stats_Highlights_2011-2012_EN_web.pdf Cochrane Injuries Group Albumin Reviewers (1998). Cochrane Injuries Group Albumin Reviewers. Why albumin may not work. British Medical Journal; pp: 317:235  CSL Behring, Haemocomplettan® P During Elective Complex Cardiac Surgery, NCT01124981. http://http://clinicaltrials.gov/ct2/show/NCT01124981 Accessed on [April 29, 2012]  CSL Behring, Study of Fibrinogen Concentrate (Human) (FCH) to Control Bleeding During Complex Cardiovascular Surgery (REPLACE), NCT01475669. http://clinicaltrials.gov/show/NCT01475669 Accessed on [April 29, 2012]  CSL Behring, Fibrinogen Concentrate In Children After Cardiac Surgery (FiCCS), NCT01187225. http://clinicaltrials.gov/ct2/show/NCT01187225 Accessed on [July 01, 2012]  CSL Behring, The ZEro PLASma Trial (ZEPLAST): Avoidance of Fresh Frozen Plasma in Cardiac Surgery, NCT01471730. http://clinicaltrials.gov/ct2/show/NCT01471730 Accessed on [July 01, 2012]  DeBois, W. et al., (2005). Cardiopulmonary Bypass in Patients With Pre-existing Coagulopathy. The Journal of The American Society of Extra-Corporeal Technology; vol.: 37, pp: 15–22  Farrugia, A and Cassar, J., (2012). Plasma-derived medicines: access and usage issues. Blood Transfusion; vol.: 10(3) pp: 273–278  Franchini, M and Lippi, G (2012). Fibrinogen replacement therapy: a critical review of the literature. Blood Transfusion; 10(1): 23–27  Gando, S. et al., (2013). A randomized, controlled, multicenter trial of the effects of Anti-Thrombin on disseminated intravascular coagulation in patients with sepsis. Critical Care, vol.: 17: R297; doi:10.1186/cc13163  Garcia, D.A., and Crowther, M.A. (2012). Clinician Update: Reversal of Warfarin – Case-Based Practice Recommendations. Circulation; 125: 2944-2947  Grazzini, G., Mannucci, P.M., and Oleari, F. (2013). Plasma-derived medicinal products: demand and clinical use. Blood Transfusion 2013; vol.: 11 (4), pp: s2–5

Critical Care Market to 2020 – Appendix

7.3 Pipeline Products

Table 2: Critical Care Market, Global, Pharmaceutical Pipeline, 2014 Stage of Drug/project name Company Indication Molecule type development

Source: GBI Research, Proprietary Pipeline Products Database [Accessed: April 10, 2014]

Critical Care Market to 2020 – Appendix

7.4 Market Forecasts to 2020 7.4.1 Major Developed Markets

7.4.1.1 Critical Care Market

Table 3: Critical Care Market, Major Developed Markets, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020 CAGR (%) Treatment population (million) Maximum revenue ($bn) Projected revenue ($bn) Minimum revenue ($bn)