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New Technology application for blood components preparation:

Pathogen Inactivation for Platelets

By M. Slaedts, Sr. Manager – Deployment, Cerus

Shenzhen, ChinaApril 24th, 2015

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Key areas for consideration

1. Current Challenges in Blood Safety2. Pathogen inactivation is a Proactive Approach3. Global Status & Regulatory Approvals4. Pathogen Inactivation for Red Cells5. Introducing INTERCEPT for Platelets in routine 6. Impact on the production of Blood Components

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Current Challenges in Blood Safety

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Patients and doctorsfear infectious transfusion risks

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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.

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Community Keeping Up with Emerging Pathogens

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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 1995-2010• ~19 - Key West, Florida, US

1. Peterson LR et al. Transfusion 2012;52:1647-1651.2. CDC: http://www.healthmap.org/dengue/en/

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The Current Reactive Safety Approach Requires Continual Addition of Costly New Tests

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’ TestWNV NAT

1985 1990 1995 2000 2005 2010 2015

$100

$150

$200

$250

Introduction of PI could stop and even reverse the cycle of additions

25 years of testing, partial protection against just 7 agents:HIV, Hepatitis B, Hepatitis C, HTLV, leukocytes, West Nile virus, Chagas’ disease

Average RBC Unit Charge (US) *

Babesia?Chikungunya?

Others?Dengue?

* RBC price data adapted from B Custer & JS Hoch, Transfusion Medicine Reviews, Vol 23, No 1 (January), 2009: pp 1-12

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Current Limitations of Testing:Infectious Window Periods with Nucleic Acid Testing (NAT)

Busch, MP; et al. Advances in Transfusion Safety – Volume IV, Developments in Biologicals, 2007, vol 127, pp 87-112.Kleinman, et al. J Clin Virol 36 Suppl. 1 (2006) S23-S29.Comanor L, et al. Vox Sanguinis (2006) 91: 1-12.

Window Period in Days

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Need for a Robust Approach to Prevent Bacterial Contamination of Platelets

AABB Standard 5.1.5.1 (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.

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Why inactivate pathogens in labile blood components?

Increase transfusion safety by a proactive rather than passive approachPrevent sepsis due bacterial contaminationClosing the window periodSave lives

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Pathogen Inactivation: A Proactive Approach to Safety

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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

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Nucleic acid intercalation

Docking Crosslinking Unable to replicate

UVA illumination

or pH reaction

Amotosalen

or S-303

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INTERCEPT Blood System – for Platelets and Plasma

Step 2Illumination

Step 3CAD

Process CompleteStorage

Step 1Amotosalen

Plasma

Platelets

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The importance of a Broad Spectrum of Inactivation

HIV-1HIV-2HBVHCVHTVL-IHTLV-II

SPIROCHETESTreponema pallidumBorrelia burgdorferi

PROTOZOA Trypanosoma cruziPlasmodium falciparumLeishmania sp. Babesia microti

LEUKOCYTEST-cellsBluetongue virus, type

11Simian Adenovirus-15Feline calicivirus Parvovirus B19Human adenovirus 5

HIV-1HIV-2HBVHCVHTLV-IHTLV-II

SPIROCHETES

ROUTINELY TESTED AGENTS

ENVELOPED VIRUSES

Treponema

pallidum

ENVELOPED VIRUSES

Staphylococcus epidermidis Staphylococcus aureus Streptococcus pyogenes Corynebacterium minutissimum Listeria monocytogenes Propionibacterium acnes Bacillus cereus (vegetative) Lactobacillus sp. Bifidobacterium adolescentis Clostridium perfringens

Klebsiella pneumoniaeYersinia enterocoliticaEscherichia coliPseudomonas aeruginosa Salmonella choleraesuis Enterobacter cloacae Serratia marcescensAnaplasma phogocytophilumOrientia tsutsugamushi3

GRAM-NEGATIVE BACTERIA

NON-ENVELOPED VIRUSES

GRAM-POSITIVE BACTERIA

(1) Sampson-Johannes A, et al. 2003. Transfusion. 43:83A; (2) Lam S, et al. Transfusion 2007;47:131A; (3) Rentas F. Transfusion 2004;44:104A.

DHBVBVDVCMVWNVSARSVaccinia1

ChikungunyaDengue2

Influenza A

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Adapted from Kleinman SH et al. Transfusion 2009;49:2454-2489.

PI

PI

PI

PI

HBsAg

Anti-HCV

Days Days

Tite

r

Anti-HIV

MP-NAT

MP-NAT

MP-NAT

Peak Viremia in Asymptomatic Donor:HIV: <10^7 geq/mLHBV: ~10^9 geq/mLHCV: ~10^8 geq/mL

Estimated concentration viable virions:HIV: <10^4 viable virions/mL HBV: ~10^6 viable virions/mLHCV: ~10^5 viable virions/mL

PI log reduction in platelets:HIV: ~6 HBV: ~6HCV: ~4.5

Synergistic Approach to Blood Safety:Closing The Window Period Risk with INTERCEPT

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High Efficacy necessary for a Proactive Approach to Emerging Threats

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 > 5.3

L. Mexicana > 5.0

Infectivity Log Reduction

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No Sepsis Fatalities with INTERCEPT Platelets: French & Swiss National Hemovigilance Data

France: p = 0.039 / Combined p = 0.006

Conventional Platelets INTERCEPT Platelets

YearUnits

Transfused (n)Transfusion Transmitted

Infections (Fatalities)Units

Transfused (n)Transfusion Transmitted

Infections

2006 231,853 4 (0) 6,420 0

2007 232,708 9 (2) 15,393 0

2008 239,349 6 (1) 15,544 0

2009 241,634 9 (0) 21,767 0

2010 253,149 2 (1) 22,632 0

2011 267,785 3 (1) 22,392 0

2012 275,834 7 (2) 24,849 0

2013 278,234 4 (1) 25,089 0

2010 29,900 1 (0) 0 0

2011 6,600 0 26,500 0

2012 0 0 34,265 0

2013 0 0 34,750 0

Total 2,057,046 45 (8) 249,601 0

French HV data: 2006-2011: Sweeney J, Lozano M. Platelet Transfusion Therapy. Bethesda: AABB Press, 2013. 2012-2013: French National Agency for Medicine and Health Product Safety/ANSM, Hemovigilance Activity Reports.

Swiss HV data: SwissMedic Haemovigilance Annual Reports, 2010-2013.

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Status of Regulatory Approvals2002 2003 2006 2007 2008 2009 2010 2011 2012 2013 2014

EUCE Mark Class III

GermanyPEI *

Mexico, COFEPRIS

SingaporeHSA

USFDA

FranceAfssaps

SwitzerlandSwissmedic

EUCE Mark Class III

FranceAfssaps

SwitzerlandSwissmedic

GermanyPEI *

Mexico COFEPRIS

USFDA

20152005

Platelets

Plasma

EU & ROWEU & ROW

USA

Phase I / II Phase III Marketing

Platelets

Plasma

Red Cells

Platelets

Plasma

Red Cells

Reg. Review

● 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

Regulatory Activity Initiated /Application Pending Review

Commercially Available

INTERCEPT Blood SystemTM Global Status

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INTERCEPT Red Blood Cell Program

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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

LinkerEffector

Reaction Degradation

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INTERCEPT RBC Process – Gen 2

Reconstitution Set Integrated Processing Set

STEP 1Add RBC and mix

with reagents

STEPS 2 & 3Inactivate &

remove

STEP 4Transfer RBC

for storage

S- 303

G SH

0.57m g± 5%

3.5g± 5%

RBC

①

②

③

S- 303

G SH

0.57m g± 5%

3.5g± 5%

RBC

①

②

③

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Cagliari / TorinoItaly

Clinical StudyIn Progress

DRKFrankfurt, Germany

Clinical StudyIn Progress

ARCBSAustralia

Evaluation Completed

NHSBTUnited Kingdom

EvaluationCompleted

Uppsala UniversitySwedenEvaluationCompleted

EFS AlsaceAlsace, FranceEvaluationCompleted

Hoxworth, Ohio/ Blood Center Wisconsin USAClinical StudyIn Progress

InnsbruckAustria

Evaluation In Progress

Clinical Studies

In vitro Evaluations

INTERCEPT RBC Activities are Global

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INTERCEPT RBC System – Development Status

2013 2014 2015 2016

Ph III acute – 50 pts

Ph II R&S – 28 pts

Report Results

Ph III chronic – 70 pts (estimate ≥3 years for completion1)

US

EU

1. Currently evaluating methods to accelerate enrollment & possibility of additional clinical sites.

Design & timing for Phase IIIUS study under evaluation

Report Results

2017

CE Mark Review

Approval Decision

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

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Introducing INTERCEPT Blood System for Platelets

An operational review

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The INTERCEPT Blood System for Platelets

1. Connect the Platelet Concentrate to the INTERCEPT Set

2. Transfer the platelets together with Amotosalen by gravity into the illumination container and ensure appropriate mixing prior to illumination 3. UVA Illumination ~5 mins

4. Transfer the platelets by gravity in the CAD bag. Incubate the platelet product by continuous agitation

5. Transfer of the platelets by gravity into the final storage container

PlateletsProduction

Storage & distribution

Platelet connection

Amotosalen Illumination CAD Final Storage

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Intercept UVA Illuminator

2 Illumination chambers2 illuminators can be stacked over each other

Average Throughput: 11 illumination cycles treatments per hour

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

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INTERCEPT Platelets: Broad Processing requirements designed for flexibility

Parameter Suspension Media

Suspension MediumPlatelet Additive Solution

Plasma

Platelets (x1011) 2.5 -8.0 2.5 - 8.0

Volume (mL) 255 - 420 255 - 420Plasma (%) 32 - 47 100

RBC/mL <4×106 <4×106

Adsorption Time (hr) 4 - 16 16 - 24

Apheresis collections

Pooled Random Platelets-

From Manual to Automated methods

Lessons learned from Implementation

Feedback from Blood Banks

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Centers in Routine Use

Regulatory Activity Initiated /Application Pending Review

Commercially Available

INTERCEPT Blood SystemTM deployed at over 100 blood banks

Successful deployments are multiples, worldwide spread in various types of environments

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Implementation context

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Pathogen Inactivation: last production step prior to release components

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• 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

“… 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.”

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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

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8 steps leading to INTERCEPT implementation

1. Site Assessment2. Implementation planning3. Adjustment of production, if any4. Installation of Illuminator5. Train the Blood Bank Trainers6. Process Qualification7. Operator training8. Conversion to routine operations

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Customer feedback:Switzerland – Introduction of INTERCEPT platelets for Apheresis and Pooled Random Donor platelet components during the 2010-2011.

13 Blood Centers 2010

Red Blood Cells 308.670

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.

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Dr. David Goslings – Head of Production

Case study : Blood Transfusion Service Zurich, Switzerland – Workflow & Throughput

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Towards Pathogen Inactivation Implementation at the NBTS Sri Lanka

2013 - NBTS evaluate successfully the INTERCEPT system for Platelets

• Abstract published at ISBT Seoul - 2014

Conversion from single donor platelets to pooled random donor platelets.2015 – Pilot phase includes 1500 Platelets transfusions

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Hong Kong Red Cross Blood Transfusion Service - 2014

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

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

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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

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Conclusions

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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.

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Thank you!谢谢！