4/5/ Is This What Comes to Mind?

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1 Pathogen Reduction: A Proactive Approach to Improving Blood Product Safety in the Hospital Setting Presented by: Joanne Meisner, MPH, Hospital Affairs Director Completion of this program will provide: 1 contact hour of P.A.C.E. Continuing Education Credit 1 contact hour of CBRN (California Board of Registered Nursing) Continuing Education Credit) Joanne Meisner, MPH Senior Medical Science Liaison About Your Speaker Master of Public Health degree from UMASS Amherst; Bachelors of Arts from Simmons College. More than 20 years of extensive Medical Affairs experience in transfusion medicine, rare diseases, immunology, critical care, pulmonology and neonatology. Formerly Director of the Conquering Diseases Clinical Research program at the University of Massachusetts School of Medicine. Senior Medical Science Liaison at Cerus Corporation. Responsible for medical professional education regarding new technologies to enhance blood product infusion safety. 1 2 Speaker Disclosure Joanne Meisner, Senior Medical Science Liaison, is an employee and shareholder of Cerus Corporation. I have no other information to disclose relative to this content. Objectives Define the mechanisms of action and safety parameters of the available methods for pathogen reduction for platelets and plasma. Review the clinical, in vitro, and hemovigilance data for pathogen reduction. Describe the current developments and clinical aims for the future pathogen reduction of red blood cells. Identify the implementation processes for using pathogen reduced blood products for patient transfusions. 3 4 Is This What Comes to Mind? When you think of the risks associated with blood product transfusions, what comes to mind? Hepatitis C HIV Courtesy CDC Public Health Image Library Courtesy CDC Public Health Image Library 6 1

2 Risk per unit transfused Cost per unit 4/5/2018 The Evolution of Transfusion Risks History of Blood Safety: Development Time, Cost, & Continued Addition of New Tests 1/10 1/100 1/1,000 1/10,000 1/100,000 1/1,000,000 Risks of Transfusion-Transmitted Infections in the United States 1 HCV HIV Bacteria (platelets) HBV Emerging pathogens? $250 $200 $150 HIV-1 Ab $ years of testing Partial protection against limited agents 2 HIV, Hepatitis B, Hepatitis C, HTLV, bacteria, West Nile virus, T. Cruzi, Zika HBcALT HTLV HCV 1 HIV-1/2, HCV Widespread Leukoreduction HIV-1 p24 HIV- HCV NAT WNV NAT Bacterial Detection AABB Rule T.Cruzi Diversion pouch Zika Emerging pathogens Can tests keep up? Babesia Chikungunya Dengue Plasmodium SFTS virus Zika Virus Others Klein HG, et al. Transfusion 2007;47: Custer B, et al. Transfus Med Rev 2009;23: Do Emerging Pathogens Present a Reason for Concern? Or Does CMV Still Present the Greatest Risk? Cytomegalovirus, (CMV) is a common herpes virus. The Centers for Disease Control and Prevention (CDC) estimates that over 50% of adults in the United States are infected by age Leukoreduction is reasonably effective for cell-associated CMV, but not cell-free, plasma CMV. 4 CMV Serology has limitations due to the long window period, i.e., the period between infection and antibody response, which may miss acute CMV infections and reactivation CDC. Cytomegalovirus (CMV) and congenital CMV infection. Available at: Accessed August 9, Furui F, et al. Transfusion 2013;53: Yeager et al. J Pediatr 1981;98: Drew WL, et al. Transfusion 2003;43: Bowden RA, et al. Blood 1995;86: Roback JD, et al. Transfusion 2003;43: Ziemann M, et al. Transfusion 2013;53: Ziemann M, et al. Transfusion 2013;53: What About the Risk of CMV? Units that are either leuko-reduced or CMV-seronegative are often referred to as CMV-safe by blood banks. CMV-safe units still carry a 1-6.5% risk of CMV transmission 11 Bone Marrow Transplant (BMT), pediatric, and neonate patients are most susceptible 15-20% mortality rate among BMT patients that get CMV. 12 CMV pneumonia is associated with mortality rate of 80-90%. 12 Transfusion Associated Risks Residual Risks Exist Despite Current Screening and Testing Measures New and emerging pathogens A risk that current safety measures cannot eliminate Leukocytes Residual cells and cytokines can cause harmful posttransfusion reactions such as transfusion-associated graftversus-host disease (TA-GVHD) Bacteria The most frequent transfusion-transmitted infection (TTI) Screening limitations Gaps in current defenses exist, due to the window period and limited screening sensitivity Known pathogens Routine testing covers only a limited number 11. Roback JD, et al. Transfusion 2013;53: Sable CA, et al. Clin Infect Dis. 1994;18:

3 Current Pathogen Reduction Technologies Approved Worldwide 13 Technology FDA Approval for Routine Use in USA Approvals for Routine Use Outside USA Comparison of Energy and Dose of Photoinactivation Technologies for Platelets and Plasma 13 (trademark of Cerus) (trademark of Cerus) (trademark of Terumo) Platelets: Psoralen with UVA light Plasma: Psoralen with UVA light Platelets: Riboflavin with UVB light (trademark of Terumo) (trademark of Maco Pharma) Plasma: Riboflavin with UVB light Plasma: Methylene blue with visible light Platelets: UVC light (no routine use) (trademark of Octapharma) Plasma: Solvent detergent 13. Prowse CV. Vox Sang. 2013;104: Prowse CV. Vox Sang. 2013;104: Pathogen Reduction Psoralen/UVA Light Treatment Broad Spectrum of Effectiveness Viruses PATHOGEN REDUCTION PSORALEN/UVA LIGHT TREATMENT Gram-positive bacteria Gram-negative bacteria Spirochetes Parasites Leukocytes There is no pathogen inactivation process that has been shown to eliminate all pathogens. Certain non-enveloped viruses (e.g., HAV, HEV, B19, and poliovirus) and Bacillus cereus spores exhibit resistance to inactivation by the psoralen/uva light process Psoralen/UVA light treatment for Inactivation A Proactive Approach to Reducing Transmitted Transfusion Infections GRAM-NEGATIVE BACTERIA Klebsiella pneumoniae* # Yersinia enterocolitica* # Escherichia coli* Pseudomonas aeruginosa* Salmonella choleraesuis* Enterobacter cloacae* Serratia marcescens* Anaplasma phagocytophilum # GRAM-POSTIVE BACTERIA Staphylococcus epidermidis* # Staphylococcus aureus* Streptococcus pyogenes* Listeria monocytogenes* Corynebacterium minutissimum* Bacillus cereus (vegetative)* Lactobacillus species* Bifidobacterium adolescentis* Propionibacterium acnes* Clostridium perfringens (vegetative)* There is no pathogen inactivation process that has been shown to eliminate all pathogens. Certain non-enveloped viruses (e.g., HAV, HEV, B19, and poliovirus) and Bacillus cereus spores have demonstrated resistance to the psoralen/uva light process. 14. INTERCEPT Blood System for Plasma [Package Insert]. Concord, CA: Cerus Corporation; August 17, INTERCEPT Blood System for Platelets [Package Insert]. Concord, CA: Cerus Corporation; March 15, ENVELOPED VIRUSES HIV-1* # DHBV (model for HBV)* # BVDV (Model for HCV)* # HTLV-I* # HTLV-II* # NON-ENVELOPED VIRUSES Bluetongue virus* # Adenovirus* # Parovirus B19 # PROTOZOA Trypanosoma cruzi* # Plasmodium falciparum* # Babesia microti* # SPIROCHETES Treponema pallidum* # Borrelia burgdorferi* # LEUKOCYTES Human T-Cells* # CMV* WNV* # Chikungunya* # Dengue* Influenza A*# * pathogen reduced Amicus apheresis platelets in PAS-3 pathogen reduced Trima apheresis platelets in 100% plasma # pathogen reduced plasma Psoralen/UVA Light Treatment for Pathogen Reduction: Key Processing Steps Platelet or Plasma Product Sterile connect 1. Sterile connect the platelet or plasma product to a sterile processing set. 2. Gravity-transfer the platelets or plasma and psoralen into the illumination container and mix. 3. Illuminate the product. Psoralen Illumination CAD* Final Storage *CAD: Compound Adsorption Device 14. INTERCEPT Blood System for Plasma [Package Insert]. Concord, CA: Cerus Corporation; August 17, INTERCEPT Blood System for Platelets [Package Insert]. Concord, CA: Cerus Corporation; March 15, Storage & Distribution 4. Platelets: Transfer the platelets by gravity into the CAD bag. Incubate the platelet product with continuous agitation. 5. Plasma: On plasma sets, the CAD is a flow-through device. Gravitytransfer the plasma through the CAD. 6. Transfer the product by gravity into the final storage container(s)(1or 2 platelet containers, 3 plasma containers). 3

4 Mechanism of Action: Targeting DNA & RNA to Prevent Pathogen Proliferation PATHOGEN REDUCTION PLATELETS 14. INTERCEPT Blood System for Plasma [Package Insert]. Concord, CA: Cerus Corporation; August 17, INTERCEPT Blood System for Platelets [Package Insert]. Concord, CA: Cerus Corporation; March 15, Psoralen/UVA Light Treatment Method for Pathogen Reduction of Platelets 15 First FDA-approved pathogen reduction system for platelets Safety and efficacy demonstrated in prospective clinical trials 14+ years routine, global use Reduces transfusion-transmitted infectious (TTI) risk, including sepsis Broad spectrum of bacteria frequently implicated in TTI Emerging pathogens, such as chikungunya, dengue, Plasmodium species Established threats such as HIV-1, HBV*, HCV*, WNV Potentially reduces the risk of transfusion-associated graftversus-host disease (TA-GVHD) by reducing contaminating T-cell activity There is no pathogen inactivation process that has been shown to eliminate all pathogens. Certain non-enveloped viruses (e.g., HAV, HEV, B19, and poliovirus) and Bacillus cereus spores have demonstrated resistance to pathogen inactivation by psoralen/uva light treatment. *Pathogen reduction demonstrated for DHBV and BVDV, model viruses for HBV and HCV, respectively. 15. INTERCEPT Blood System for Platelets [Package Insert]. Concord, CA: Cerus Corporation; March 15, >4 Logs of Inactivation for Most Pathogens Tested in Psoralen/UVA Light Treated Platelets 15 Viruses HIV-1, cell-associated DHBV (model virus for HBV) BVDV (model virus for HCV) HTLV-I HTLV-II West Nile Virus Chikungunya virus (CHIKV) Dengue virus (DENV) Cytomegalovirus (CMV), cellassociated Influenza A virus Bluetongue virus Adenovirus Protozoan Parasites Plasmodium falciparum Babesia microti Trypanosoma cruzi PAS-3/Plasma 5.4/ / /> / b 5.1/ b 5.7/> /> / (PRV) 5.9/ b 4.4/ b 4.9/ 5.3 PAS-3/Plasma 5.6/ d 4.9/ d 5.3/>5.5 Bacteria Escherichia coli Yersinia enterocolitica PAS-3/Plasma 6.3/> />6.3 Klebsiella pneumoniae 5.8/5.9 Serratia marcescens 6.7 c />7.1 Staphylococcus epidermidis Staphylococcus aureus 6.1/> / 6.1 Streptococcus pyogenes 6.8 c />6.1 Bacillus cereus (vegetative) Bacillus cereus (spore forming) Clostridium perfringens (vegetative) 5.5 / c / b 6.5/>6.0 Propionibacterium acnes 6.5 />6.7 Treponema pallidum Borrelia burgdorferi Leukocytes 15. INTERCEPT Blood System for Platelets [Package Insert]. Concord, CA: Cerus Corporation; March 15, Human T-Cells 4 a = In clinical trial b = Not tested c = Based on culture of full platelet unit (300mL) d = Study in progress 6.4/ a 6.8/ a Mitigation Options for Zika Virus: Zika Testing or Pathogen Reduction 16 Clinical Trials Using Psoralen/UVA Light Treatment Pathogen Reduction for Platelets Over 800 subjects evaluated in several trials Study Description Patients Design Primary Endpoint Primary Endpoint Met? Viability of test platelets, clearance of amotosalen, 65 healthy patients 17 Safety/efficacy of test platelets, thrombocytopenic patients 18 Safety/efficacy of test platelets, thrombocytopenic patients Safety/efficacy of test platelets, 32 thrombocytopenic patients 20 Randomized, single-blind, cross-over Randomized, doubleblind, parallel Randomized, doubleblind, parallel Randomized, doubleblind, cross-over Recovery/survival, clearance of amotosalen WHO Grade 2 bleeding 1 hour CCI Bleeding time Safety of test Routine setting Single-arm, open label Frequency of acute transfusion reactions was 1.6% Safety of test Routine setting Single-arm, open label Frequency of acute transfusion reactions was 2% 17. Snyder E, et al. Transfusion. 2004;44: McCullough J, et al. Blood. 2004;104: Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components. FDA 19. Janetzko K, et al. Transfusion. 2005;45: Guidance for Industry, August Slichter SJ, et al. Transfusion. 2006;46: Schlenke P, et al. Ann Hematol. 2011;90: Infanti L, et al. Transfus Apher Sci. 2011;45:

5 IL-8 (pg/ml) IL-1β (pg/ml) 4/5/2018 Comparison of Platelet Use During the 21 months Before and After Psoralen/UVA Light Treatment Introduction in Innsbruck, Austria 23 All Patients Pre-psoralen/UVA treatment (N=1797) Mean ± SD Post-psoralen/UVA treatment (N=1694) Mean ± SD P Value Platelets transfused 4.8 ± ± Courses 1.5 ± ± Average Interval 0.9 ± ± Irradiation Versus Psoralen/UVA Light Treatment for Prevention of TA-GVHD There are no randomized clinical trials confirming the efficacy of any methods used to potentially prevent TA-GVHD. These trials would not be ethical or feasible to perform. However, other data do exist that demonstrates the effectiveness of both irradiation and psoralen/uva light treatment. Days of Support 5.9 ± ± 11.8 <0.01 RBCs Transfused 13.7 ± ± Plasma Transfused 7.0 ± ± AE per patient 24/1797 (1.3%) 23/1694 (1.4%) 1.00 vs. AE per transfusion 32/8611 (0.4%) 24/7705 (0.3%) Amato, et al. Vox Sang. 2016; 112(1): Irradiation Versus Psoralen/UVA Light Treatment Types of Evidence Available in TA-GVHD Mechanistic: DNA Modifications Resulting from Irradiation vs. Psoralen/UVA Light Treatment Evidence Type Psoralen/UVA light treatment Irradiation (gamma/x-ray) High DNA modification densities help ensure inactivation of most genes: I Randomized clinical trials of TA-GVHD X X Gamma irradiation 1:37,000 strand-break:base pair II Mechanistic Psoralen/UVA Light-Treated Platelets 1:83 amotosalen adduct formed:base pair 26,28 III In vitro 9-11 IV Hemovigilance Systems Pelszynski et al. Blood. 1994; 83: Luban et al. Transfusion. 2000; 40: Grass et al. Blood. 1998; 91: Knutson F, et al. Vox Sang. 2015;109: Grass JA, et al. Blood. 1998;91: Setlow R, et al. Annu Rev Biophys Bioeng. 1972;1: In Vitro: Cytokine Production in Platelets: Psoralen/UVA Light Treatment vs. Gamma Irradiation 29 Leukocytes in untreated controls produced high levels of IL-8 & IL-1β during storage of random donor platelet concentrates Gamma irradiation partially inhibited cytokine synthesis Psoralen/UVA light treatment blocked production of IL-8 & IL-1β IL-8 production 29. Hei DJ, et al. Transfusion. 1999;39: Days Control Gamma INTERCEPT IL-1β production 2 3 Days Control Gamma INTERCEPT 4 5 Relationship Between Platelet Unit Age, White Cell Count, Cytokine Levels, & Adverse Patient Reactions Older platelets contain significantly more cytokines. 30,31 Older platelets cause significantly more transfusion reactions. 32,33 Leukocyte filtration significantly reduces cytokine accumulation. 34 High levels of leukocyte derived cytokines are implicated in febrile transfusion reactions to platelet concentrates, independent of antigen-antibody reactions Muylle L, et al. Transfusion. 1993;33: Stack G, et al. Transfusion. 1994;34: Muylle L, et al. Transfus Med. 1992;2: Heddle NM, et al. Transfusion. 1993;33: Aye MT, et al. Transfusion. 1995;35: Heddle NM, et al. New Engl J Med. 1994;331:

6 Psoralen/UVA Light Treatment for Platelets Routine Use Demonstrates Sepsis Risk Reduction Hemovigilance programs - a comprehensive view of transfusions and potential adverse events. Over 600,000+ psoralen/uva light-treated platelet units have been transfused in France, Switzerland and Belgium. No reported transfusion-transmitted infections (TTIs) or sepsis-related fatalities, acute respiratory distress syndrome (ARDS), or TA-GVHD to date. Report 36. Sweeney J, et al. Platelet Transfusion Therapy. Bethesda: AABB Press, French National Agency for Medicine and Health Product Safety/ANSM, Hemovigilance Activity Reports, SwissMedic Haemovigilance Annual Reports, Benjamin, R. et al. Transfusion (e-pub) doi: /trf July Conventional Platelets Platelet Units Transfused TTBIs* (Fatalities) UVA and Psoralen-Treated Platelets Platelet Units TTBIs* Transfused (Fatalities) France ,37 2,575, (9) 214,293 0 (0) Switzerland ,39 156, (3) 167,200 0 (0) Belgium ,809 9 (0) 227,797 0 (0) *TTBI: Transfusion Transmitted Bacterial Infections Total 2,984, (12) 609,290 0 (0) No reports of TA-GVHD in routine use Study Multi-center European hemovigilance network 1-5 Psoralen/UVA light treated platelet doses HV1* 40 5, HV2 41 7,437 1,400 HV France ,293 ~36,000 HV Switzerland 38 HV Belgium ,200 ~28, ,378 ~37,000 Total 620,414 ~103,000 *Transfusion reports from Belgium, Norway, Spain, Italy Transfusion reports from Belgium, France, Spain 40. Osselaer JC et al. Transfusion 2008;48: Osselaer JC, et al. Vox Sang 2008;94: French National Agency for Medicine and Health Product Safety/ANSM, Hemovigilance Activity Reports, SwissMedic Haemovigilance Annual Reports, Benjamin, R. et al. Transfusion (e-pub) doi: /trf July 2017 Patients Outcome Timing American Association of Blood Banks (AABB) Revised Standards-April 2016 The AABB Blood Bank Transfusion Services (BBTS) Standards Program Unit (SPU) oversees the standards for irradiation of blood products. AABB has issued approval 42 for the use of apheresis platelets, leukocytes reduced, psoralen-treated products as equivalent to irradiated platelets for patients at risk for transfusion-associated graft-vs-host disease (TA-GVHD) as follows: BBTS 30th Edition (Effective April 1, 2016) PATHOGEN REDUCTION PLASMA Standard Number Standard Language Available at: Methods known to prevent transfusion-associated graft-vs-host disease shall be used, and include either irradiation or the use of a pathogen reduction technology that is known to inactivate residual leukocytes and is cleared or approved by the FDA or Competent Authority. 42. AABB. Association Bulletin #16-05: Changes to the 30th edition of Standards for Blood Banks and Transfusion Services Psoralen/UVA Light Treatment for Pathogen Reduction of Plasma 14 FDA-approved pathogen reduction systems for plasma Safety and efficacy demonstrated in prospective clinical trials 10+ years of routine, global use Reduces transfusion-transmitted infectious (TTI) risk Broad spectrum inactivation with 4 log reduction for most pathogens Emerging pathogens, such as chikungunya, Plasmodium species Established threats such as HIV-1, HBV*, HCV*, WNV Approved for use with whole blood-derived or apheresis plasma Psoralen/UVA Light Treatment for Plasma Populations Studied in Clinical Trials 14 Acquired coagulation factor deficiencies 14,43 Congenital coagulation factor deficiencies 14,44 Those undergoing therapeutic plasma exchange (TPE) due to thrombotic thrombocytopenic purpura (TTP) 14,45 Those undergoing liver transplantation 14,46 *Pathogen reduction demonstrated for DHBV and BVDV, model viruses for HBV and HCV, respectively. There is no pathogen inactivation process that has been shown to eliminate all pathogens. Certain non-enveloped viruses (e.g., HAV, HEV, B19, and poliovirus) and Bacillus cereus spores have demonstrated resistance to pathogen inactivation by psoralen/uva light treatment. 14. INTERCEPT Blood System for Plasma [Package Insert]. Concord, CA: Cerus Corporation; August 17, The INTERCEPT Blood System for Plasma [Package Insert]. Concord, CA: Cerus Corporation; August 17, Mintz PD, et al. Blood. 2006;107: de Alarcon P, et al. Transfusion. 2005;45: Mintz PD, et al. Transfusion. 2006;46: Cinqualbre J, et al. Vox Sang. 2012;103(Suppl 1):

7 37 Psoralen/UVA Light Treated Plasma Evaluated in Several Prospective Trials 14 Population (sample size*) Healthy subjects (N=15) Healthy subjects, warfarin anticoagulated (N=27) Multiple coagulation deficiencies (N=13) Congenital coagulation deficiencies (N=34) Acquired coagulation deficiencies (N=121) Thrombotic thrombocytopenic purpura (TTP) (N=35) Phase (Ph)/ Study Design Ph1; Randomized, single-blind, crossover. Ph2; Randomized, single-blind, crossover. Ph2; Randomized, double-blind, parallel group. Ph3A; Open label, single arm. Ph3B; Randomized, double-blind, parallel group. Ph3C; Randomized, double-blind, parallel group. *Sample size (N) is the total of test and control patient samples. 14. INTERCEPT Blood System for Plasma [Package Insert]. Concord, CA: Cerus Corporation; August 17, Mintz PD, et al. Blood. 2006;107: de Alarcon P, et al. Transfusion. 2005;45: Mintz PD, et al. Transfusion. 2006;46: Hambleton J, et al. Transfusion. 2002;42: Primary Result(s) Comparable coagulation factor levels attained between test and control FFP. 47 Comparable prothrombin time and FVII kinetics between test and control FFP. 47 UVA and psoralen-treated plasma was safe and well tolerated by patients with impaired hepatic function. Comparable hemostatic activity attained between test and control FFP. 44 Comparable recovery, pharmacokinetic performance, and PT/PTT attained between test and control FFP. 44 Comparable coagulation responses and clinical hemostasis were attained between test and control FFP. 43 Remission rates, time to remission, relapse rates, and time to relapse, as well as number of TPE and volume of FFP required were comparable between UVA and psoralen-treated plasma and conventional FFP. 45 >4 Logs of Inactivation for Most Pathogens Tested in Psoralen/UVA Light Treated Plasma 14 Viruses HIV-1 IIIB, cell-associated 6.2 DHBV (model virus for HBV) BVDV (model virus for HCV) 4.5 HTLV-I 4.1 HTLV-II 4.7 West Nile Virus 6.7 Chikungunya virus (CHIKV) 6.5 SARS Associated Coronavirus 4.0 Influenza A virus (H 5N 1 Avian Influenza) 5.7 Parvovirus B Bluetongue virus 4.0 Adenovirus Bacteria Yersinia enterocolitica 6.6 Klebsiella pneumoniae 6.7 Staphylococcus epidermidis 6.6 Treponema pallidum 5.4 Borrelia burgdorferi 9.9 Anaplasma phagocytophilum (HGE agent) Leukocytes For a full list of pathogens, see the INTERCEPT Blood System for Plasma package insert, August 17, INTERCEPT Blood System for Plasma [Package Insert]. Concord, CA: Cerus Corporation; August 17, Protozoan Parasites 3.6 Plasmodium falciparum 5.9 Babesia microti 4.9 Trypanosoma cruzi >5.0 Human T-Cells 4 Pathogen What About Zika Virus with Psoralen/UVA Light Treatment? West Nile virus Chikungunya virus Dengue virus Zika virus Psoralen/UVA Light Treatment for Plasma Demonstrated Safety and Efficacy in Routine Use 14 Hemovigilance (HV) programs - a comprehensive view of transfusions and potential adverse events. HV programs tracking the routine use of >200,000 psoralen/uva light treated plasma units in Europe have demonstrated therapeutic efficacy with an adverse event profile consistent with untreated plasma. 49,50 Routine use of INTERCEPT Plasma demonstrates low adverse transfusion reaction (ATR) rates through a French national HV program Year Product Plasma Units ATRs per 1,000 Units Untreated plasma 348, Psoralen/UVA light treated plasma 22, Untreated plasma 329, Psoralen/UVA light treated plasma 52, Please note: these data have not been submitted to the FDA yet 2011 Untreated plasma 311, Psoralen/UVA light treated plasma 68, INTERCEPT Blood System for Platelets [Package Insert]. Concord, CA: Cerus Corporation; March 15, Aubry M, et al. Transfusion. 2016;56: INTERCEPT Blood System for Plasma [Package Insert]. Concord, CA: Cerus Corporation; August 17, Cazenave JP, et al. Transfusion. 2010;50: Bost V, et al. Vox Sang. 2013;104: Afssaps Rapport Annuel Hemovigilance Afssaps Rapport Annuel Hemovigilance ANSM Rapport Annuel Hemovigilance Pathogen Reduction of Plasma Solvent/Detergent (S/D) Treatment FDA Approved Pathogen Reduction Method for Plasma 54 Clinical Indications Replacement of multiple coagulation factors in patients with acquired deficiencies due to: Liver disease Undergoing cardiac surgery or liver transplant Plasma exchange in patients with thrombotic thrombocytopenic purpura (TTP) Solvent/Detergent (S/D)-Treated Plasma Mechanism of Action 54 Destruction of lipid layers of only enveloped viruses Virus inactivation by solvent-detergent (S/D) treatment No effect on non-enveloped viruses Processing Specifications Manufactured from pooled plasma of a single AB0 blood group (A, B, AB, or 0). Plasma pools are treated with S/D reagents for hours at +30 C (86 F) to inactivate enveloped viruses. The S/D reagents are then removed by sequential oil and solid phase extraction procedures. S/D removed by oil extraction and hydrophobic chromatography Final steps include sterile filtration, aseptic filling, fast freeze at -60 C for each 200 ml/bag 54. Octaplas Package Insert, B USA Octaplas Package Insert, B USA 42 7

8 Log Kill Following Solvent/Detergent (S/D) Treatment of Pooled Human Plasma 54 Virus Inactivation by S/D Treatment TNBP and Triton X-100, 4 hours 30 C HIV-1 PRV Pseudorabies Virus: A model virus for large, enveloped, DNA-containing viruses, such as Hepatitis B BVDV Bovine Viral Diarrhea: Model virus for Hepatitis C SBV Sindbis Virus PATHOGEN REDUCTION RED BLOOD CELLS S/D Treatment (log10) Octaplas Package Insert, B USA Pathogen Reduction System for Red Blood Cells: In Development US BARDA Support to Advance Development Pathogen Reduction of Red Blood Cells CLINICAL TRIAL TYPE SUBJECT TYPE European Phase III Clinical Trials Acute Anemia Patients Thalassemia Patients USA Phase II Clinical Trials Recovery and Survival Study in Healthy Subjects Pathogen Reduction System for Red Blood Cells: In Development: Mechanism of Action The S-303 Treatment System for RBCs uses the compound amustaline (S-303) and a quencher glutathione (GSH) in a ph-dependent reaction to crosslink nucleic acids resulting in the inactivation of infectious pathogens and leukocytes in RBC components. Pathogen Reduction System for Red Blood Cells 55 In Development: Log Kill The S-303 Treatment System for RBCs inactivates a variety of pathogens including gram-negative/positive bacteria, enveloped/non-enveloped viruses, and parasites. Viruses Mean a HIV-1, cell-associated > BVDV c (model virus for HCV) > Adenovirus type 5 > DHBV (Model for HBV) > Bacteria Mean a Escherichia coli b Yersinia enterocolitica Serratia marcescens Staphylococcus aureus b (1) Amustaline rapidly passes through membranes to target nucleic acids and (2) intercalates or docks between nucleic acid base pairs. (3) Degradation yields unreactive by-products. The S-303 treatment system for red blood cells is in development and not yet approved. Bluetongue virus Zika Virus > Protozoan Parasites 55. Kleinman et al. Transfusion. 2015; 55: Laughhunn A, et al. Transfusion. 2017(epub). 57. Tonnetti L et al. AABB SP Mean a Babesia microti > a) Log reduction is calculated as Log (untreated titer/posttreatment titer). When titer is expressed as 10x/mL b) One replicate of E coli and one replicate of S. aureus used blood that had not been leukoreduced. c) Bovine Viral Diarrhea Virus The S-303 treatment system for red blood cells is in development and not yet approved. 8

9 4/5/2018 Pathogen Reduction: Psoralen/UVA Light Treatment of Platelets and Plasma RISK Bacterial Contamination ZIKA Virus TTI GUIDANCE OR STANDARD PATHOGEN REDUCTION TECHNOLOGY (PRT) FDA Draft Guidance:58 Recommends PRT or bacterial testing PRT can eliminate the need for primary and secondary testing, including rapid testing. AABB Standard : Methods required to detect bacteria or use PRT in platelet components59 PRT can be used as an alternative to bacterial detection. ECDC Guidance for Zika60 WHO Guidance61 Revised FDA Guidance for Zika16 PRT can be used in place of Zika testing for platelet and plasma components.** Recommend testing, import or PRT CMV TTI AABB Standard :59 Policy required to reduce the risk of CMV INTERCEPT PRT demonstrates inactivation of CMV in platelets in PAS-3 with 4.9 pfu/ml log reduction.15 TA-GVHD* AABB Standard :59 Methods known to prevent TA-GVHD required; include irradiation or PRT PRT meets AABB standard which allows for irradiation or Pathogen Reduction. HOSPITAL IMPLEMENTATION ENSURING HOSPITAL READINESS FOR THE TRANSFUSION OF PATHOGEN REDUCED OR PSORALEN TREATED BLOOD PRODUCTS *Transfusion-Associated Graft vs. Host Disease **Data for pathogen reduction of ZIKA by the INTERCEPT Blood System, pathogen reduction system, has not been submitted for FDA review. INTERCEPT Blood System for Platelets [Package Insert]. Concord, CA: Cerus Corporation; March 15, FDA Guidance for Industry, August FDA Draft Guidance for Industry, March AABB. Standards for Blood Banks and Transfusion Services. 30th edition. Bethesda, MD: AABB Press, Zika Virus and Safety of Substances of Human Origin. ECDC, July Interim guidance. WHO, February Hospital Implementation Process Requires Blood Center and Hospital Collaboration At initial introduction Growth Drivers: Over time - Hospital Demand/Readiness - Manufacturing Volume - BLA approvals Blood Center Manufacturing What determines The rate of conversion? -Previous TTI -Clinical Advocates -Replace Irradiation -Reimbursement -Supplier inventory Hospital Adoption Cerus Hospital Affairs Support Field based Cerus personnel who provide clinical, operational and economic analysis support to assist with hospital readiness for the transfusion of psoralen treated (pathogen reduced) platelets. Engaging Blood Bank leadership to ensure that decisions related to adoption and implementation of psoralen treated blood products are tracking on the same timeline as the Blood Center manufacturing schedule. Clinical Educational Support Activities Key Components of Cerus Hospital Support Services PREPARING FOR THE IMPLEMENTATION OF PSORALEN TREATED PLATELETS SUPPORTING BLOOD CENTERS AND HOSPITAL AND THEIR CLINICAL STAKEHOLDERS Transfusion Medicine/Blood Bank Physicians & Staff Blood Center Grand Rounds Department meetings Transfusion Committee Medical Executive Committee Educating Blood Center Medical Directors & other Hospital Liaisons Clinical HemeOnc, Peds, NICU, Anesthesia Cardiac Surgery, Trauma Physicians History/Need for Blood Safety ISBT Product codes Blood Bank Staff Review of Emerging Pathogens Billing codes IT system changes Nursing Professionals New bag characteristics Additional Physicians Mechanism of Action/effectiveness Clinical studies Indications / Contraindications / Warnings Hemovigilance Special Populations Committee approval process Storage considerations New Labeling Irradiation/CMV process substitution policy addendums In-services Hospitals Operational Ordering changes Inventory 100% or Partial Cost Analysis 9

10 Cerus Hospital Implementation Cerus MSL Functions 4/5/2018 Hospital Implementation Materials Ensuring Hospital Readiness in Partnership with the Blood Center Hospital Implementation Overview Hospital Process Checklist Hospital In-service and Reference Materials Economic Analysis-Hospital Cost Analysis Tool Referenced resource for calculating hospital costs of acquiring, storing and administering conventional or psoralen treated platelets Blood product Transfusions Key Elements Outdate rate - reduction due to early release with psoralen treated units CMV and irradiation replacement Secondary Bacterial testing on D4/D5/D6/D7 labor, rate of false positive, retesting, wastage of platelet units due to false positive results. Zika Testing replacement Patient Safety Considerations Key Elements Adverse Events Septic Transfusion Reactions including under-reporting factor CMV positive work up costs Delays in transfusion due to wait time for secondary testing results. Risk of emerging pathogens in the blood supply Outpatient Use Considerations Hospital Implementation Key Processes New Psoralen Treated Platelets Psoralen-Treated Platelet Bag Size Blood Bank IT System Changes ISBT CODE IMPORT TEST LABELS Hospital Blood Bank psoralen treated storage changes and additional labeling procedures(if any) IT System changes Irradiation vs. psoralen treated equivalence table Plan hospital staff education program- Coordinate with Nurse Educator Blood Bank SOP changes Irradiation, CMV equivalence, labeling changes Execute Hospital Staff Education Program 1-2 weeks prior to go live Lab/Blood Bank Nursing/MD s Conventional Platelet Bag Size 1.3 LITER BAG INTERCEPT BLOOD SYSTEM embossed across the top of the bag No IRRADITION Sticker Psoralen Treated Platelet Labeling Labeled as: APHERESIS PLATELETS LEUKOREDUCED PSORALEN TREATED Platelet dose is the same as conventional platelets. Pre-meds and hang time are the same as conventional platelets. The blood bank may have a mixed inventory for some time The new platelets can be transfused in he same line as conventional platelets if a patient needs more than one bag of platelets. Successful Hospital Implementation of Psoralen Treated Platelets Pre-Implementation Activity/Identify Team Members Hospital Readiness Preparations Manufacturing Capacity Engage Transfusion Medical Director Department Meetings/Grand Rounds Heme Onc MDs Cardiac MDs Peds/NICU MDs Review and Implement BB IT changes/codes Hospital Implementation Steps Transfusion Policy Changes BB Inventory Management BB Logistics In-service planning Anesthesia MDs Engage Transfusion Medicine Director, BB Officer in Charge; Nursing Educator Finalize Clinical Adoption Hospital Staff Education In-Services Hospital Committee Approval Transfusion Practice Committee Medical Executive Committee Release First Unit Administrative Approval for any SOP changes Nursing/BB/MD In-services CERUS DEPLOYMENT TEAM COORDINATION WITH CERUS HOSPITAL AFFAIRS TEAM 60 10

11 REFERENCES REFERENCES 1. Klein HG, et al. Pathogen activation: making decisions about new technologies. Report of a consensus conference. Transfusion 2007;47: Custer B, et al. Cost-effectiveness analysis: what it really means for transfusion medicine decision making. Transfus Med Rev 2009;23: CDC. Cytomegalovirus (CMV) and congenital CMV infection. Available at: Accessed August 9, Furui F, et al. Cytomegalovirus (CMV) seroprevalence in Japanese blood donors and high detection frequency of CMV DNA in elderly donors. Transfusion 2013;53: Yeager AS, et al. Prevention of transfusion-acquired cytomegalovirus in newborn infants. J Pediatr 1981;98: Drew WL, et al. Frequency and duration of plasma CMV viremia in seroconverting blood donors and recipients. Transfusion 2003;43: Bowden RA, et al. A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant. Blood 1995;86: Roback JD, et al. CMV DNA is rarely detected in healthy blood donors using validated PCR assays. Transfusion 2003;43: Ziemann M, et al. The impact of donor cytomegalovirus DNA on transfusion strategies for at-risk patients. Transfusion 2013;53: Ziemann M, et al. Window period donations during primary cytomegalovirus infection and risk of transfusion-transmitted infections. Transfusion 2013;53: Roback JD, et al. New insights for preventing transfusion-transmitted cytomegalovirus and other white blood cellassociated viral infections. Transfusion 2013;53: Sable CA, et al. Infections in bone marrow transplant recipients. Clin Infect Dis 1994;18: Prowse C. Component pathogen inactivation: a critical review. Vox Sang 2013;104: INTERCEPT Blood System for Plasma [Package Insert]. Concord, CA: Cerus Corporation; August 17, INTERCEPT Blood System for Platelets [Package Insert]. Concord, CA: Cerus Corporation; March 15, Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components. FDA Guidance for Industry, August Snyder E, et al. Recovery and life span of 111 indium-radiolabeled platelets treated with pathogen inactivation with amotosalen HCl (S-59) and ultraviolet A light. Transfusion. 2004;44: McCullough J, et al. Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial. Blood. 2004;104: Janetzko K, et al. Therapeutic efficacy and safety of photochemically treated apheresis platelets processed with an optimized integrated set. Transfusion. 2005;45: Slichter SJ, et al. Platelets photochemically treated with amotosalen HCl and ultraviolet A light correct prolonged bleeding times in patients with thrombocytopenia. Transfusion. 2006;46: Schlenke P, et al. Safety and clinical efficacy of platelet components prepared with pathogen inactivation in routine use for thrombocytopenic patients. Ann Hematol. 2011;90: Infanti L, et al. Pathogen-inactivation of platelet components with the INTERCEPT Blood System : A cohort study. Transfus Apher Sci. 2011;45: Amato M, et al. Impact of platelet pathogen inactivation on blood component utilization and patient safety in a large Austrian Regional Medical Centre. Vox Sang 2016; 112(1): Pelszynski MM, et al. Effect of gamma irradiation on T-cell inactivation as assessed by limiting dilution analysis: Implications for preventing transfusion associated graft vs. host disease. Blood. 1994;83: Luban NL, et al. Irradiation of platelet components: inhibition of lymphocyte proliferation assessed by limiting-dilution analysis. Transfusion. 2000;40: Grass JA, et al. Inactivation of leukocytes in platelet concentrates by photochemical treatment with psoralen plus UVA. Blood. 1998;91: Knutson F, et al. A prospective, active hemovigilance study with combined cohort analysis of 19,175 transfusions of platelet components prepared with amotosalen-uva photochemical treatment. Vox Sang. 2015;109: Setlow R, et al. Effects of radiation on polynucleotides. Annu Rev Biophys Bioeng. 1972;1: Hei DJ, et al. Elimination of cytokine production in stored platelet concentrate aliquots by photochemical treatment with psoralen plus ultraviolet A light. Transfusion.1999;39: REFERENCES 30. Muylle L, et al. Increased tumor necrosis factor alpha (TNF-alpha), interleukin 1, and interleukin 6 (IL-6) levels in the plasma of stored platelet concentrates: relationship between TNF-alpha and IL-6 levels and febrile transfusion reactions. Transfusion. 1993;33: Stack G, et al. Cytokine generation in stored platelet concentrates. Transfusion. 1994;34: Muylle L, et al. Reactions to platelet transfusion: The effect of the storage time of the concentrate. Transfus Med. 1992;2: Heddle NM, et al. A prospective study to identify risk factors associated with acute reactions to platelet and red cell transfusions. Transfusion. 1993;33: Aye MT, et al. Effect of filtration of platelet concentrates on the accumulation of cytokines and platelet release factors during storage. Transfusion. 1995;35: Heddle NM, et al. The role of plasma from platelet concentrates in transfusion reactions. New Engl J Med. 1994;331: Sweeney J, Lozano M. Platelet Transfusion Therapy. Bethesda, MD: AABB; French National Agency for Medicine and Health Product Safety/ANSM. Hemovigilance Activity Reports SwissMedic. Haemovigilance Annual Reports Benjamin, R. et al. Transfusion (e-pub) doi: /trf July Osselaer JC et al. A prospective observational cohort safety study of 5106 platelet transfusions with components prepared with photochemical pathogen inactivation treatment. Transfusion 2008;48: Osselaer JC, et al. An active haemovigilance programme characterizing the safety profile of 7437 platelet transfusions prepared with amotosalen photochemical treatment. Vox Sang 2008;94: AABB. Association Bulletin #16-05: Changes to the 30th edition of Standards for Blood Banks and Transfusion Services. REFERENCES REFERENCES 43. Mintz PD, et al. Photochemically treated fresh frozen plasma for transfusion of patients with acquired coagulopathy of liver disease. Blood. 2006;107: de Alarcon P, et al. Fresh frozen plasma prepared with amotosalen HCl (S-59) photochemical pathogen inactivation: transfusion of patients with congenital coagulation factor deficiencies. Transfusion. 2005;45: Mintz PD, et al. A randomized, controlled Phase III trial of therapeutic plasma exchange with fresh-frozen plasma (FFP) prepared with amotosalen and ultraviolet A light compared to untreated FFP in thrombotic thrombocytopenic purpura. Transfusion. 2006;46: Cinqualbre J, et al. Comparative effectiveness of plasma prepared with pathogen inactivation (Intercept ) and quarantine for support of liver transplantation. Vox Sang. 2012;103(Suppl 1): Hambleton J, et al. Pharmacokinetic study of FFP photochemically treated with amotosalen (S-59) and UV light compared to FFP in healthy volunteers anticoagulated with warfarin. Transfusion. 2002;42: Aubry M, et al. Inactivation of Zika virus in plasma with amotosalen and ultraviolet A illumination. Transfusion. 2016;56: Cazenave JP, et al. An active hemovigilance program characterizing the safety profile of 7483 transfusions with plasma components prepared with amotosalen and UVA photochemical treatment. Transfusion. 2010;50: Bost V, et al. A regional haemovigilance retrospective study of four types of therapeutic plasma in a ten-year survey period in France. Vox Sang. 2013;104: Afssaps Rapport Annuel Hemovigilance Afssaps Rapport Annuel Hemovigilance ANSM Rapport Annuel Hemovigilance Octaplas Package Insert. Octaplas, Pooled Plasma (Human), Solvent/Detergent Treated Solution for Intravenous Infusion, B USA. 55. Kleinman S, et al. Risks associated with red blood cell transfusions: potential benefits from application of pathogen inactivation. Transfusion. 2015; 55: Laughhunn A, et al. Amustaline (S-303) treatment inactivates high levels of Zika virus in red blood cell components. Transfusion 2016; 00: Tonnetti L, et al. Inactivation of Babesia microti with Amustaline/GSH in Red Blood Cells. AABB. 2016; SP Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion. FDA Draft Guidance for Industry, March Available at: Accessed February 2, AABB. Standards for Blood Banks and Transfusion Services. 30th edition. Bethesda, MD: AABB Press, Zika Virus and Safety of Substances of Human Origin. ECDC, July Maintaining a safe and adequate blood supply during Zika virus outbreaks. Interim guidance. WHO, February How to Obtain Your Participation Credit If you wish to receive participation credit for this program please ensure you have signed the ATTENDANCE LOG with your name and address. You will receive an from Safety Online.com in the next few days with the link and instructions to create an account, complete the program evaluation; and receive your certificate of completion for this program. Available credit options for this activity 1 contact hour of P.A.C.E. Continuing Education Credit 1 contact hour of CBRN (California Board of Registered Nursing) Continuing Education Credit)