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Pathogen inactivation New progress Antonio Piga Hemoglobinopathies Centre Department of Clinical and Biological Science

Pathogen inactivation New progress Antonio Piga Hemoglobinopathies Centre Department of Clinical and Biological Sciences University of Torino, Italy antonio.piga@unito.it. Mechanism of action of pathogen inactivation. Requirements for pathogen inactivation.

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Pathogen inactivation New progress Antonio Piga Hemoglobinopathies Centre Department of Clinical and Biological Science

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  1. Pathogen inactivation New progress Antonio Piga Hemoglobinopathies Centre Department of Clinical and Biological Sciences University of Torino, Italy antonio.piga@unito.it

  2. Mechanism of action of pathogen inactivation

  3. Requirements for pathogen inactivation Effective to eliminate pathogens Maintaining the quality of blood products for transfusion Safe Simple and cost-effective to implement in the preparation of blood components

  4. Declining Risks of major TTVs linked to interventions, BUT accelerating rate of Emerging Infectious Diseases (EIDs) of concern to blood safety Revised Donor Deferral Criteria HBsAg Screening HIV Ab Screening HCV Ab Screening p24 Ag Testing NANB Hepatitis Surrogate Testing Risk per Unit Emerging Infectious Disease Threats HCV 1:100 H1N1 influenza Monkey Pox Leishmania DENV CHIKV T cruzi PTLVs XMRV 1:1000 SARS SFV WNV vCJD HBV ICL 1:10,000 HIV 1:100,000 1:1,000,000 <1984 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 HBV NAT T cruziAb Screening HCV and HIV NAT WNV NAT vCJD Deferral Criteria Adapted from Busch MP, TRANSFUSION 2006;46:1624-1640

  5. Why do infections emerge? Contributing Factors • Behavioral change among humans (HIV) • Inactivation resistant agents (B19, HAV, prions) • Intensive modern farming practices (vCJD) • Susceptible hosts (CMV) • Transport of agents, reservoirs, vectors (WNV) • Population movement (T.cruzi, chikungunya) Source New agent (vCJD) Species jump (HIV, SARS) Environmental change (Dengue virus) Failure of control-drug/vaccine resistance and mutations (HBV mutants)

  6. Movement of Hosts and Vectors courtesy of MP Busch

  7. Be a virus, see the world Daily airline traffic patterns

  8. Spatial epidemiology and evolution of WNV across N. America derived from phylogenetic analysis of viremic blood donations Pybus OG, PNAS, 2012

  9. West Nile virus (WNV) Clinical Activity reported to CDC,United States, 2012 (Sept. 18, 2012; N of Human Cases = 3,142)

  10. West Nile Virus Cases in EU and Neighbouring, 2011 Source: ECDC

  11. Rizzo C, Eurosurveillance, 2012

  12. Dengue Viruses • Members of the genus Flavivirus • Transmitted by the Aedes mosquito; mosquito => human cycle • 4 viruses: DENV1, 2, 3, and 4 • Over 2.5 billion people live in risk areas for dengue infection

  13. Dengue Risk in Puerto Rico Blood Donors 1995 - 2010 Peterson and Biggerstaff Transfusion 2012

  14. Dengue Virus, August-October 2012 activity

  15. Usutu Virus in Europe Culex pipiens pipiens • Flaviviruses (similar to WNV) • Enveloped, icosahedral • nucleocapsid • Ss + RNA strand, 11kb • 40-60 nm size • Mosquito transmitted • Infects birds & horses The icons signify cases of detection of the virus per species ENIVD: European Network for Diagnosis of Imported Viral Diseases 15 Vazquez et al. Euro Surveill. 201116(31) 19935

  16. The discovery curve for human virus species Rapid pace of viral discovery is providing many “orphan viruses” as candidate pathogens Woolhouse M E et al. Proc. R. Soc. B 2008;275:2111-2115

  17. Vazquez et al. Euro Surveill. 2011, 16(31) 19935

  18. Vazquez et al. Euro Surveill. 201116(31) 19935

  19. EID agent priority matrix Stramer SL, 2009

  20. Transfusion-transmitted Babesiosis in the US Herwaldt BH, 2011 Ann Int Med 162 cases from 1979-2009 with a 19% fatality rate

  21. US Babesiosis – 10 new cases

  22. Earliestknownrepresentationoflimbatrophypresumed due topoliomyelitis. Egypt, 1403–1365 BC. fromNyCarlsbergGlyptotek.

  23. http://www.aabb.org/Content/About_Blood/Emerging_Infectious_Disease_Agents/appendix2.htmhttp://www.aabb.org/Content/About_Blood/Emerging_Infectious_Disease_Agents/appendix2.htm

  24. EUFRAT: risk model scheme

  25. Testing for TTDs Summary • Expanding the testing for known pathogens has kept the blood safer over time • Each new test adds safety at exponentially increasing costs • Emerging pathogens keep testing invariably on delay and incomplete • Effective and safe pathogen inactivation is the answer

  26. - for platelets- for plasma- for red cells Pathogen Inactivation Technologies (PIT)

  27. Pathogen Inactivation Technologies (PIT) for platelets Solheim BG, Transfusion and Apheresis Science, 2008

  28. Current INTERCEPT Platelet and Plasma Use • Routine use at over 100 centers in 18 countries • More than 1,000,000 doses transfused : Routine Customers Chile Réunion CanaryIslands Martinique Guadeloupe FrenchPolynesia

  29. French National Hemovigilance: Platelet Transfusion 2006 to June 2012 P=0.07 AgenceFrancaise de Securite Sanitaire des Produits de Sante (2006-2011). Rapport Hemovigilance 2006. Paris, Afssaps. D Kientzet al. 13th International HaemovigilanceSeminar, Amsterdam, The NetherlandsFebruary 9 - 11th, 2011 L Corash et al. 14th International HaemovigilanceSeminar, Montreal, Canada, April 25-27 2012

  30. Pathogen Reduction Technologies (PIT) for plasma Solheim BG, Transfusion and Apheresis Science, 2008

  31. Pathogen Reduction Technologies (PIT) for plasma Solheim BG, Transfusion and Apheresis Science, 2008

  32. Pathogen Reduction Technologies (PIT) for red cells Solheim BG, Transfusion and Apheresis Science, 2008

  33. Pathogen Inactivation for all 3 Blood Components: S-303 Treated Red Blood Cells: William Reed, MD Director, Clinical Research and Medical Affairs Torino and CagliariSeptember, 2012

  34. INTERCEPT RBC: Mechanism of Action • S-303 is a nucleic acid-targeted alkylator that quickly diffuses into viruses, bacteria, parasites and blood cells and is designed to react quickly and decompose • Glutathione (GSH) is used to quench side reactions of the effector with other biological materials

  35. Second Generation INTERCEPT RBC Clinical Process

  36. Pathogen Inactivation Efficacy Evaluations *n=1-3 RBC units or tubes **Second generation process, n=4 full RBC units Henschler R, Transfus Med Hemother, 2011

  37. Pathogen Inactivation Process Optimization: Reduce interaction of S-303 with RBCs and improve process flexibility • First Generation Process • 0.2 mM S-303 • 2 mM GSH (acidic) • Compound adsorption device to remove residual S-303 • Erythrosol storage solution • Second Generation Process • 0.2 mM S-303 • 20 mM GSH (Na salt) • Diluent solution for PI • Removal of treatment solution and replacement with storage solution • Approved RBC storage solutions

  38. NEW Phase 1 Clinical, Second Generation: 24-Hour Recovery meets FDA Requirements (n=27) * p<0.05, ** p<0.001 • The 24-hour recovery was similar between groups and met FDA criteria • The median lifespan,T50, of Test RBC was within the reference range of 32 to 37 days using 51Cr label Cancellas et al. Transfusion 2011

  39. NEW Phase 1 Study, Second Generation: In Vitro RBCCharacteristics-- Day 35 (n=27) 1 Measured prior to storage 2 Measured after 35-days of storage * p-value <0.05 • The total hemoglobin, hemolysis and hematocrit meet the requirements for leukoreduced RBC in additive solution • The ATP concentration is well over the critical threshold of 2.0 mmol/g Hb(Hess JR, Greenwalt TG. Transf Med Rev., 16 (4), 283-295 (2002))

  40. North A, Transfusion, 2011

  41. Clinical Studies • Europe: Acute and chronic anemia separately • Chronic anemia – thalassemia major • Acute anemia – cardiac surgery • US: thalassemia and sickle cell anemia • Chronic transfusion • Final design will require Hgb increment data from Europe and US

  42. Italian Thalassemia Study Phase 3 study of efficacy and safety of S-303 treated RBC components Investigators: A Piga - Torino R Galanello – Cagliari

  43. Design • Randomized, controlled, double‑blind, crossover study to evaluate both efficacy and safety of S‑303 treated RBC components in 70 subjects • 4 transfusion cycles for Test and 4 for Control2 additional wash-n cycles for each period • Statistical hypothesis of non-inferiority • Non-inferiority margin of 15%

  44. Italian Thalassemia Study • Transfusion-dependent thalassemia major patients (n = 70) • Randomized, controlled, double‑blind, crossover study • Statistical hypothesis of non-inferiority • 1° efficacy endpoint = Hemoglobin usage • 1° safety endpoint = Immunogenicity with repeat exposure 2txns* 2 txns* 4 txns 4 txns 2 txns* 2 txns* 4 txns 4 txns Control INTERCEPT n=35 Screen, randomize n=35 Control INTERCEPT Each patient is on study ~9-12 months 45 * Patients receive 2 wash-in transfusions followed by 4 transfusions of INTERCEPT or control.

  45. Secondary Efficacy Endpoints • Hb percent decline per day • Hb increment 1-h post-Tx(Adjusted for mass of Hb transfused and body weight)

  46. Data and Safety Monitoring Board • A Cohen - thalassemia (Philadelphia) • L Pierelli – transfusion medicine (Rome) • T Peyrard - immunohematology (Paris)

  47. Proposed U.S. Phase III – chronic RBC transfusion Group A – Efficacy & Safety Assessment (n=82, cross-over) 1° efficacy endpoint = Hemoglobin usage Control INTERCEPT n=41 2txns* 2 txns* 3 txns 6 txns 6 txns Screen, randomize Safety Assessment:Groups A & B(n=373) 1° safety endpoint = % patients with S-303 Abs with clinically significant hemolysis 2 txns* 2 txns* n=41 3 txns 6 txns 6 txns Control INTERCEPT Group B – Safety Assessment Only (n=291, 3:1 ratio) INTERCEPT n=218 Screen, randomize n=73 Control * Group A patients receive 2 wash-in transfusions followed by 6 transfusions evaluated for efficacy.

  48. New RBC Biologic Component for Chronic Tranfusion? • Pathogen inactivated • WBC inactivated (without gamma damage) • Phenotyped/genotyped • Very low plasma content • Defined hemoglobin (gms) • Defined Fe (mg) • Diminished HLA and/or RBC alloimmunization potential?

  49. Acknowledgements William Reed Nina Mufti Anne North Cerus Corporation Concord, California USA RenzoGalanello University of Cagliari Cagliari, Italy Richard Benjamin American Red Cross Washington, DC, USA Filomena Longo Alessandro Sandri SimonaRoggero Marianna Genisio Hemoglobinopathies Center, University of Torino Torino, Italy Michael P Busch Blood Systems Research Institute University of California, San Francisco, USA

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