1. New Technology application for blood components preparation: Pathogen Inactivation for Platelets
By M. Slaedts,
Sr. Manager – Deployment, Cerus
Shenzhen, China
April 24th, 2015

2. Key areas for consideration
Current Challenges in Blood Safety
Pathogen inactivation is a Proactive Approach
Global Status & Regulatory Approvals
Pathogen Inactivation for Red Cells
Introducing INTERCEPT for Platelets in routine
Impact on the production of Blood Components

3. Current Challenges in Blood Safety

4. Patients and doctors fear infectious transfusion risks
1. Risks of transmission of infectious agents to patients are linked to contamination of blood donors and blood products. 2. Reactive measures do not account of the next viral risk, window period not closed. 3. While Preventive measures (Pathogen Inactivation) have reduced the risk of infectious diseases. 4. Time interval between risk recognition and screening test. 5. Emerging & re-emerging pathogens feared : WNV, Chikungunya, Dengue, Ebola, … 6. Epidemiological modifications of populations of donors and recipients: linked to migrations of populations and climate changes.

5. Community Keeping Up with Emerging Pathogens

6. Re-emerging Pathogens – e.g. Dengue World-Wide Burden
> 4-fold increase in cases reported over past 30 years, ~50M dengue illnesses/year. 1
Recognized increased transfusion-transmitted risk, reported per 10,000 donors:1, 2
~0.5 - Australia 2004
~18 - Singapore 2007
~7 - Puerto Rico
~19 - Key West, Florida, US
Peterson LR et al. Transfusion 2012;52:
CDC:

7. Average RBC Unit Charge (US) *
The Current Reactive Safety Approach Requires Continual Addition of Costly New Tests
Average RBC Unit Charge (US) *
HIV-1 Ab
HBc, ALT
HTLV-I
HCV 1.0
HIV-1/2,
HCV 2.0
HIV-1 p24
Widespread Leukoreduction
HIV-1/HCV NAT
Chagas’ Test
WNV NAT
25 years of testing, partial protection against just 7 agents:
HIV, Hepatitis B, Hepatitis C, HTLV, leukocytes, West Nile virus,
Chagas’ disease
Others?
$250
Dengue?
Chikungunya?
Babesia?
$200
Introduction of PI could stop and even reverse the cycle of additions
$150
$100
1985
1990
1995
2000
2005
2010
2015
* RBC price data adapted from B Custer & JS Hoch, Transfusion Medicine Reviews, Vol 23, No 1 (January), 2009: pp 1-12

8. Current Limitations of Testing: Infectious Window Periods with Nucleic Acid Testing (NAT)
Window Period in Days
Busch, MP; et al. Advances in Transfusion Safety – Volume IV, Developments in Biologicals, 2007, vol 127, pp
Kleinman, et al. J Clin Virol 36 Suppl. 1 (2006) S23-S29. Comanor L, et al. Vox Sanguinis (2006) 91: 1-12.

9. Need for a Robust Approach to Prevent Bacterial Contamination of Platelets
AABB Standard (first added in March 2004)
The blood bank or transfusion service shall have methods to limit and detect bacteria or inactivate bacterial contamination in all platelet components.
2010 Variance in favor of Pathogen Inactivation.

10. Why inactivate pathogens in labile blood components?
Increase transfusion safety by a proactive rather than passive approach
Prevent sepsis due bacterial contamination
Closing the window period
Save lives

11. Pathogen Inactivation: A Proactive Approach to Safety

12. INTERCEPT Mechanism of Action
Small molecules (amotosalen and S-303) penetrate cellular and nuclear membranes and intercalate into helical regions of DNA or RNA present in pathogens
Amotosalen forms covalent crosslinks to nucleic acid base pairs upon exposure to UVA light
DNA and RNA replication are blocked, inactivating pathogens and leukocytes
Nucleic acid intercalation
Docking
Crosslinking
Unable to replicate
UVA illumination
or pH reaction
Amotosalen
or S-303

13. INTERCEPT Blood System – for Platelets and Plasma
Step 1
Amotosalen
Step 2
Illumination
Step 3
CAD
Process Complete
Storage
Plasma 13

14. The importance of a Broad Spectrum of Inactivation
Routinely tested agents
ENVELOPED VIRUSES
GRAM-NEGATIVE BACTERIA
SPIROCHETES Treponema pallidum Borrelia burgdorferi
PROTOZOA Trypanosoma cruzi Plasmodium falciparum Leishmania sp. Babesia microti
LEUKOCYTES T-cells
HIV-1 HIV-2 HBV HCV HTVL-I HTLV-II
DHBV BVDV CMV WNV SARS Vaccinia1 Chikungunya Dengue2 Influenza A
Klebsiella pneumoniae Yersinia enterocolitica Escherichia coli Pseudomonas aeruginosa Salmonella choleraesuis Enterobacter cloacae Serratia marcescens Anaplasma phogocytophilum Orientia tsutsugamushi3
ENVELOPED VIRUSES
HIV-1 HIV-2 HBV HCV HTLV-I HTLV-II
NON-ENVELOPED VIRUSES
GRAM-POSITIVE BACTERIA
SPIROCHETES
Bluetongue virus, type 11 Simian Adenovirus-15 Feline calicivirus Parvovirus B19 Human adenovirus 5
Staphylococcus epidermidis Staphylococcus aureus Streptococcus pyogenes Corynebacterium minutissimum Listeria monocytogenes Propionibacterium acnes Bacillus cereus (vegetative) Lactobacillus sp Bifidobacterium adolescentis Clostridium perfringens
Treponema pallidum
(1) Sampson-Johannes A, et al Transfusion. 43:83A; (2) Lam S, et al. Transfusion 2007;47:131A; (3) Rentas F. Transfusion 2004;44:104A.

15. Synergistic Approach to Blood Safety: Closing The Window Period Risk with INTERCEPTPI
HBsAg
Anti-HCV
Days
Titer
Anti-HIV
MP-NAT
Peak Viremia in Asymptomatic Donor:
HIV: <10^7 geq/mL
HBV: ~10^9 geq/mL
HCV: ~10^8 geq/mL
Estimated concentration viable virions:
HIV: <10^4 viable virions/mL
HBV: ~10^6 viable virions/mL
HCV: ~10^5 viable virions/mL
PI log reduction in platelets:
HIV: ~6
HBV: ~6
HCV: ~4.5
Adapted from Kleinman SH et al. Transfusion 2009;49:

16. High Efficacy necessary for a Proactive Approach to Emerging Threats
Infectivity Log Reduction
Pathogen
INTERCEPT
West Nile virus
> 6.0
Chikungunya virus
> 6.4
H1N1 virus
> 4.1
H5N1 virus
> 5.9
Dengue virus
> 5.0
O. Tsutsugamushi
> 5.5
XMRV
> 4.0
T. Cruzi
> 5.3
B. Microti
L. Mexicana

17. No Sepsis Fatalities with INTERCEPT Platelets: French & Swiss National Hemovigilance Data
Conventional Platelets
INTERCEPT Platelets
Year
Units Transfused (n)
Transfusion Transmitted Infections (Fatalities)
Units Transfused (n)
Transfusion Transmitted Infections
2006
231,853
4 (0)
6,420
2007
232,708
9 (2)
15,393
2008
239,349
6 (1)
15,544
2009
241,634
9 (0)
21,767
2010
253,149
2 (1)
22,632
2011
267,785
3 (1)
22,392
2012
275,834
7 (2)
24,849
2013
278,234
4 (1)
25,089
29,900
1 (0)
6,600
26,500
34,265
34,750
Total
2,057,046
45 (8)
249,601
France: p = / Combined p = 0.006
French HV data: : Sweeney J, Lozano M. Platelet Transfusion Therapy. Bethesda: AABB Press, 2013.
: French National Agency for Medicine and Health Product Safety/ANSM, Hemovigilance Activity Reports.
Swiss HV data: SwissMedic Haemovigilance Annual Reports,

18. Status of Regulatory Approvals
2002
2003
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015 EU
CE Mark Class III
France
Afssaps
Germany
PEI *
Switzerland
Swissmedic
Singapore HSA
Mexico, COFEPRIS
US FDA
Platelets EU
CE Mark Class III
France
Afssaps
Switzerland
Swissmedic
Germany
PEI *
Mexico COFEPRIS
US FDA
Plasma
Phase I / II
Phase III
Reg. Review
Marketing
EU & ROW
EU & ROW
Platelets
Plasma
Red Cells
USA
Platelets
Plasma
Red Cells

19. INTERCEPT Blood SystemTM Global Status
● More than 10 years of routine use
● Kits sold to produce over 3,000,000 INTERCEPT platelet and plasma units
● Used in >100 Blood Centers in 20 countries
Centers in Routine Use
Commercially Available
Regulatory Activity Initiated / Application Pending Review

20. INTERCEPT Red Blood Cell Program

21. INTERCEPT RBC – Mechanism of Action
S-303 is a nucleic acid-targeted alkylator that quickly diffuses into viruses, bacteria, parasites and blood cells
Glutathione (GSH) is used to quench side reactions of the effector with other biological materials
Targeting
Docking & Permanent Crosslinking
(Helical regions of DNA & RNA)
Anchor
Linker
Effector
Reaction
Degradation

22. INTERCEPT RBC Process – Gen 2
Reconstitution Set
Integrated Processing Set
STEP 1
Add RBC and mix with reagents
STEPS 2 & 3
Inactivate & remove
STEP 4
Transfer RBC for storage

23. INTERCEPT RBC Activities are Global
NHSBT
United Kingdom
Evaluation
Completed
EFS Alsace
Alsace, France
Evaluation
Completed
Uppsala University
Sweden
Evaluation
Completed
DRK
Frankfurt, Germany
Clinical Study
In Progress
Hoxworth, Ohio/ Blood Center Wisconsin
USA
Clinical Study
In Progress
Innsbruck
Austria
Evaluation In Progress
Cagliari / Torino
Italy
Clinical Study
In Progress
ARCBS
Australia
Evaluation Completed
Clinical Studies
In vitro Evaluations

24. Design & timing for Phase III US study under evaluation
INTERCEPT RBC System – Development Status
Three clinical studies globally, 2 are completed:
Europe: Phase III acute anemia results reported. Primary endpoint met; no statistical differences in adverse events between INTERCEPT-treated and control RBCs.
Europe: Phase III chronic anemia trial ongoing.
US: Phase II recovery & survival study results reported. Primary endpoint met; FDA criteria for RBC recovery fulfilled.
Plan to submit for European approval H2-2016, possible approval 2017
2013
2014
2015
2016
2017 EU
Report Results
Approval Decision
Ph III acute – 50 pts
CE Mark Review
Ph III chronic – 70 pts (estimate ≥3 years for completion1) US
Report Results
Ph II R&S – 28 pts
Design & timing for Phase III US study under evaluation
1. Currently evaluating methods to accelerate enrollment & possibility of additional clinical sites.

25. Introducing INTERCEPT Blood System for Platelets An operational review

26. The INTERCEPT Blood System for Platelets
Production
Storage & distribution
Platelet connection
Amotosalen
Illumination
CAD
Final Storage
Transfer the platelets by gravity in the CAD bag. Incubate the platelet product by continuous agitation
Connect the Platelet Concentrate to the INTERCEPT Set
Transfer the platelets together with Amotosalen by gravity into the illumination container and ensure appropriate mixing prior to illumination
Transfer of the platelets by gravity into the final storage container
UVA Illumination ~5 mins

27. Intercept UVA Illuminator
2 Illumination chambers
2 illuminators can be stacked over each other
Average Throughput: 11 illumination cycles treatments per hour

28. Processing requirements - rational
RBC impede UVA light transmission
More plasma impedes UVA light transmission and decreases inactivation efficacy
Less plasma results in more UVA light transmission and may impact platelet viability
Amotosalen volume is fixed, so changes in component volume change the Amotosalen concentration in the illumination container
Low dose was set to meet Council of Europe Guidelines
High dose is the highest platelet dose that has been validated
Platelet Dose
Volume
RBC
Content
Plasma Content

29. INTERCEPT Platelets: Broad Processing requirements designed for flexibility
Parameter
Suspension Media
Suspension Medium
Platelet Additive Solution
Plasma
Platelets (x1011)
Volume (mL)
Plasma (%)
100
RBC/mL
<4×106
Adsorption Time (hr)
4 - 16
Apheresis collections
Pooled Random Platelets -
From Manual to Automated methods

30. Lessons learned from Implementation
Feedback from Blood Banks
Lessons learned from Implementation

31. INTERCEPT Blood SystemTM deployed at over 100 blood banks
Successful deployments are multiples, worldwide spread in various types of environments
Centers in Routine Use
Commercially Available
Regulatory Activity Initiated / Application Pending Review

32. Implementation context

33. Pathogen Inactivation: last production step prior to release components
Apheresis
Whole Blood donations
Collection of Blood
Pool Random Platelets
Variety of production methods
Component Preparation
PI Platelets
PI Plasma
PI Red Blood Cells (*)
Pathogen Inactivation

34. “… Pathogen inactivation or reduction systems that are applicable to platelets will further reduce the risk of transfusion reactions due to bacterial contamination…”
“…Thus, from the point of clinical relevance current evidence none of the products proofed superior.”
“… Therefore, to be on the safe side from the donor’s perspective we are in favor of using the abundance of platelets available from whole-blood donation.”

35. Quality Management drives the implementation steps
Personnel & Organization
Quality Assurance & Processing Managers different & independent
Changes to be documented
Master Validation plan
Planning for validation
Qualification
Documentation
Approvals
Implementations succeed because:
They are well planned
Staff is well trained
Management of risks is in place
Right Implementation Partners are involved
Blood Bank
Suppliers

36. 8 steps leading to INTERCEPT implementation
Site Assessment
Implementation planning
Adjustment of production, if any
Installation of Illuminator
Train the Blood Bank Trainers
Process Qualification
Operator training
Conversion to routine operations

37. Customer feedback: Switzerland – Introduction of INTERCEPT platelets for Apheresis and Pooled Random Donor platelet components during the
13 Blood Centers
2010
Red Blood Cells
Platelets Concentrates
29.900
Fresh Frozen Plasma
61.500
From nearly 100 % Apheresis collection, now converting platelet production
to reach 60% Pooled Random Donor Platelets.

38. Case study : Blood Transfusion Service Zurich, Switzerland – Workflow & Throughput
Dr. David Goslings – Head of Production

39. Towards Pathogen Inactivation Implementation at the NBTS Sri Lanka
NBTS evaluate successfully the INTERCEPT system for Platelets
Abstract published at ISBT Seoul
Conversion from single donor platelets to pooled random donor platelets.
2015 – Pilot phase includes 1500 Platelets transfusions

40. Hong Kong Red Cross Blood Transfusion Service - 2014
Preparation of Pooled Buffy-Coat Pathogen Reduction-treated Platelet Concentrates in
Platelet Additive Solution Using Top and Bottom Method.
Cindy Chan, Thomas Lau, Barry Chui, CK Lee, Elizabeth Chua, WC Tsoi, CK Lin
Hong Kong Red Cross Blood Transfusion Service, Hong Kong, China
In preparation for clinical evaluation of pathogen reduction-treated platelet
Pool of 5 Buffy Coat in SSP+
Preparation of INTERCEPT platelet concentrates in SSP+ PAS was successfully developed

41. Conclusions – Operational
Technology fit with platelets from both Apheresis and Pooled Random Donor Collections for optimal production efficacy
System has been designed for throughput capacity allowing the system to fit into small to large production sites
Demonstrates ability, in a quality manner, to support succeffull implementation of the technology in multiples environments conditions worldwide

42. Conclusions

43. Conclusions
Recognized challenges exist in ensuring blood safety today, including the bacterial contamination risk in platelets, or the increasing prevalence of emerging pathogens.
INTERCEPT is a proactive approach to address such risks, and has demonstrated high levels of inactivation for a broad range of clinically relevant pathogens.
INTERCEPT for platelets and plasma has been in use for over 10 years, and counts over 3’000’000 transfusions experience. The RBC system in advanced clinical development.
INTERCEPT received approval by multiple Regulatory Authorities around the world after thorough review (incl. CE mark III, US FDA).
The submission process for Registration of INTERCEPT started in China. 43

44. Thank you!
谢谢！