•Introduction to Octapharma

•Rationale for development of Octaplasma

•Manufacturing of OctaplasmaTM

•Safety and Efficacy of OctaplasmaTM in TTP

•Why OctaplasmaTM?

Overview

• Octapharma: one of the largest plasma product manufacturers • Commitment to coagulation disorders: >25 years• History of setting benchmarks for product and patient safety• First to apply SD-process• Patient in >80 countries treated with Octapharma products

Portfolio is divided into 3 areas:• Hematology (coagulation disorders)• Immunotherapy (immune disorders)• Intensive Care and Emergency Medicine

Octapharma– Committed to Patient Care

Our Commitment to Canada

Octaplex®: first PPC (prothrombin complex concentrate)

Wilate®: first double virally inactivated pd-VWF/FVIII concentrate

Octaplasma®: first SD-plasma

Octagam®: first liquid room temperature stable IVIG

7.2 million units of Octaplasma infused worldwide in ~2.4 million patients over two decades

OctaplasmaTM History

• Octaplasma was first approved in Germany in 1992

• Has become the standard treatment for TTP/HUS patients throughout most of Europe and the UK

• The clinical trial program comprised 1,385 patients

• Production facilities are based in Vienna (Austria) and Stockholm (Sweden)

The Rational for Development of OctaplasmaTM

• Reduce the risk of pathogen transmission

• Transmission of human immunodeficiency virus (HIV)

• Post-tranfusion hepatitis caused by

– Hepatitis B / Hepatitis C virus

• Meet the need for a cell free, standardized, high quality coagulation active plasma

• To reduce adverse events

• To improve the therapeutic accuracy of plasma treatment

Risks of Plasma Therapy

•Parasites

•Bacteria

•Viruses (especially HIV, HBV, and HCV)

•Prions [e.g. variant Creutzfeldt-Jakob disease (vCJD)]

Pathogen transmissions and infections

•Allergic reactions

•Anaphylactoid and anaphylactic reactions

•Transfusion-related acute lung injury (TRALI)

•Haemolysis (anti-AB0s IgM and IgG, irregular antibodies)

•Alloimmunisation (e.g. anti-D, anti-K, anti-HLA, anti-HNA)

Immune-mediated transfusion reactions

•Transfusion-associated circulatory overload (TACO)/fluid overload

•Reactions due to additives (e.g. citrate toxicity)

Physicochemical reactions

Fresh frozen plasma (FFP) transfusion plays a vital role in treatment of several specific clinical situations, however, FFP transfusion is not without complications

OctaplasmaTM: Multiple Steps Ensures Safety

Donor

Plasma donation center

Manufacturing

Patient

Relative Risk

Low

HighSelection of plasma

donors

Screening of donations (NAT tested: HIV, HBV, HCV)

Quality control measurements

Virus Inactivation/ Cell & Prion Removal

Screening of plasma pools (HIV, HBV, HCV)

Enveloped & Non-Enveloped Viruses

HIV

HAV

HBV

B19

Viruses Transmissible by Blood

Non-enveloped

Enveloped

2-3 log10 non-enveloped viruses can be removedduring removal of SD reagents

Transfusion Related Lung Injury (TRALI)

3. Kleinman et al. Transfusion. 2004; 4. Kopko P.M. et al. JAMA. 2002; 5. Looney MR et al. CHEST. 2004

• No confirmed cases of TRALI with Octaplasma in 20 years

• The incidence of TRALI has been reduced, but is still reported in Canada despite the introduction of male-only plasma

• TRALI remains the leading cause of Transfusion related fatalities in North America which is approximately 30% 1,2

• TRALI is significantly under diagnosed and consequently under reported due to the lack of awareness 3-5

OctaplasmaTM - Efficacy in TTP

Scully et al. (2007)

• 12 episodes were performed using CPP only; 21 episodes exclusively used OctaplasmaTM.

• No difference in the number of plasma exchange procedures between groups

• 17 CPP episodes had to be changed to OctaplasmaTM due to low age (n=1), severe allergic reactions to CPP (n=12) or due to refractory disease (n=4). This means that of the 29 episodes that started with CPP, as many as 12 (41%) had to be changed to Octaplasma® due to severe allergic reactions.

• No significant thrombotic episodes, no detectable viral transmissions, no cases of TRALI

Scully et al., Vox Sang. 2007; 93(2);154-158

±

or

TRALI

Allergic rx.(urticaria)

+

+

Optimised integration Cell removal & S/D treatment

Optimised integration Cell removal

÷

÷

Immune-mediated Reactions Caused by Plasmas

OctaplasmaTM

Fresh-frozenplasma

Cell and debris free- Removal of intracellular pathogens- Abolish cell-dependent adverse reactions- Standardized bags

Residual Blood Cells in Plasma

OctaplasmaTM demonstrates a low transfusion reaction rate

Serious Hazards of Transfusion Report (SHOT) 20101

ComponentFebrile reactions, incidence per

100,000 unitsAllergic or anaphylactic reactions,

incidence per 100,000 units

Red cells 11.4 2.7

Platelets 10.2 18.4

Plasma 1.0 8.7

OctaplasmaTM 0.0 0.17

1. http://www.shotuk.org/wp-content/uploads/2011/11/Paper18.3-Errata-2010.pdf

OctaplasmaTM Tolerability - Finland

10

0

20

3.8

17.315.2

18.3

▲ SAE

Rates of SAE: FFP vs. OctaplasmaTM in Finland in 2005-2006

Adverse events with FFP are common in large volume exchange procedures

Introduction of OctaplasmaTM in clinical use has decreased the rate of serious adverse events (SAE) by 84% (p=0.0005).

Authors concluded that OctaplasmaTM is a safe and well tolerated product1.

Uni

ts

# of

SA

E’s

/100

,000

Krusius et al.,, Sanguinis 2009;96 (Suppl. 1), 1–62.

OctaplasmaTM reduces both infectious and non-infectious risks of transfusions

1Svae et al, 2011; 2Krusius, 2009, 3Vaara & Nilsson 2010.

calculated risk, not actual

The overall reduction in transfusion complications (-94%)1 for Octaplasma® compared to FFP is similar to published experience from Finland, -84%2 and Sweden, -85%3, Austria -94.6%

With no confirmed case of TRALI in 20 years and the significantly reduced risk for allergic reactions are major advantages that Octaplasma® has over FFP.

OctaplasmaTM Delivers

Virus-inactivated plasma for transfusion

Standardized levels of coagulation factors

Efficacy comparable to FP and CSP

Significant reduction of allergic reactions

Prevention of TRALI

OctaplasmaTM Currently Funded For:

OctaplasmaTM Request

• Treating physician OR TM Medical Director need approval from local CBS medical director

• Octaplasma sent from local CBS warehouse to hospital on patient specific bases

• Form filled out, physician signed and faxed to CBS

Thank You

Manufacturing Process of OctaplasmaTM

PRE-VIAREA

POST-VIAREA

Fast thawing of the high quality FFP

Cell and debris removal by filtration [1.0 µm]

S/D treatment [1% TNBP/ 1% Octoxynol-9, 30°C / 4 - 4.5 hrs]

Liquid phase extraction of TNBP

Clear filtration [1.0 µm 0.45 µm]

Solid phase extraction of Octoxynol-9

Optimised integration of 630 to 1,520 single units of FFP

STERILE AREASterile filtration [0.45 µm + 0.2 µm]

Aseptic filling

Labelling and vacuum sealing

Freezing [-60°C] and storage [-30°C]

Full quality control and release

SD Treatment of OctaplasmaTM

• Treatment with SD is widely used for ensuring the virus safety of plasma products.

• SD mixtures disrupt the lipid membrane of enveloped viruses. Once disrupted, the virus can no longer bind to and infect cells.

• SD is gentle to plasma proteins

• SD treatment does not affect the final composition of OctaplasmaTM

Capacity to inactivate enveloped virus by the OctaplasmaTM SD treatment method

HIV HBV PRV HSV-2 HCV WNV DHBV VSV

≥ 7.2 ≥ 6.0 ≥ 6.3 ≥ 6.0 ≥ 5.0 ≥ 5.8 ≥7.3 ≥ 7.5

Clearance factor of OctaplasmaTM (log 10)

*adapted from Svae et al., 2011.

Non-lipid Enveloped Viral Safety

Virus Release Specifications

HAV PCR Negative

Parvovirus B19 PCR ≤ 10.0 IU/µL

HAV-Ab ≥ 1 IU/mL

Parvovirus B19-Ab ≥ 22 IU/mL

• Immune antibodies in SD treated plasma neutralize viral particles and are of importance in avoiding clinical disease with HAV and parvovirus B191.

• Octaplasma release specifications2:

1. Solheim BG et al. Transfusion 2000; 40: 84-902. Data on file

Non-lipid Enveloped Viral Safety by Immune Neutralization

• Immune antibodies in OctaplasmaTM neutralize viral particles and are of importance in avoiding clinical disease with HAV and Parvovirus B19.

• The capacity to neutralize non-enveloped viruses in OctaplasmaTM by immune antibodies is very high and thereby prevents transmission and infections in the recipients.

Capacity to neutralize non-enveloped viruses by immune antibodies

COX-B6 POL-1 HAV HEV B19

≥ 5.8 ≥ 7.5 ≥ 6.6 ≥ 5.9 ≥ 7.0

Clearance factor of OctaplasmaTM (log 10)

No Confirmed case of TRALI in 2 Decades

Octaplasma has eliminated the risk of TRALI: No detectable anti-leukocyte antibodies

Octaplasma reduces the risk of TRALI which remains a life threatening complication of TPE

Standardized Coagulation Factors

TTP: ADAMTS13 & vWF Multimers

ParametersReferenceRange FFP

OctaplasmaTM

Mean (n=3) Std.dev.

ADAMTS13 antigen [IU/ml] 0.75 – 1.101 0.99 0.06

ADAMTS13 activity [IU/ml] 0.50 – 1.101 0.91 0.17

Factor H antigen [IU/ml] 0.48 ± 0.092 0.47 ± 0.03

Std.dev., standard deviation; 1Reference range assays, 2Heger P et al. Vox Sang 2007; 92: 206-212.

(2010) Haemostasis Research Unit, University College London1

Reduced levels of HMW VWF in combination with well-conserved levels of ADAMTS-13 could be seen as a positive advantage in the treatment of patients with TTP

Lawrie A.S. et al. Vox Sang 2010 (99): 232-238.

OctaplasmaTM - Efficacy in TTP

Edel et al. (2010)

• Efficacy and tolerability of Octaplasma has been studied in TTP

• Overview: Retrospective analysis of 506 treatments (n=8) & 1999 L of plasma used over course of treatment

• Efficacy parameters: Platelet count above 150 x 109 achieved; ADAMTS13 inhibitory antibodies were partially or completely removed by therapeutic plasma exchange

• AEs: Use of S/D was well tolerable with no AEs and no thrombotic events

OctaplasmaTM Tolerability - Sweden

OctaplasmaTM Tolerability - Austria

Austria• Period 2003-2009 (minus 2007

and 2008 – not reported)

• Zero TRALIs among 267’000 Octaplas bags (FFP in 2009: 1:15’300)

• 94 allergic reactions in 112’600 FFP infusions, equivalent to 83 (95%CI = 66-103) allergic reactions per 100’000 bags

• 12 allergic reactions in 267’000 Octaplas infusions, equivalent to 4 (95%CI = 1-10) allergic reactions per 100’000 bags

Answering TTP – Community Survey

• 82% of survey respondents cited at least 1 type of adverse reaction during TTP treatment

“Counting down the bags of donor plasma is all you can do to wait for it to end. You don't know if you will have an allergic reaction to the next bag and how severe that reaction might be until it happens. Just cross your fingers and hope you don't react.”

“Although the risk of contracting a disease from [FP] is supposed to be quite low, the sheer volume of plasma I have received each time I have relapsed increases the risk quite a bit, and that is always in the back of my mind. I do not know the exact amount I have received but I am sure it is upwards of 150 units per relapse (the last relapse lasted 3 months and was far more than that). A safer product would make me feel a lot less stress.”

OctaplasmaTM Coagulation Factor Levels

Heger A et al. Transfusion and Apheresis Science 2005; 33: 257-267.

OctaplasmaTM Coagulation Factor Levels

Hellstern P et al. Transfus Med Hemother 2011 38: 65-70

Manufacturing Comparison: Plas+SD vs Octaplasma®

Manufacturing Comparison: Plas+SD vs Octaplasma®

Active Ingredients: Proteins & Coagulation Factors

Active Ingredients: Inhibitors & Antibodies

Other Parameters: Non-lipid Related

Other Parameters: Lipid Related

Haemostatic Balance Comparison

Octaplasma use in Neonates, Obstetric and Gynaecological patients

• 41 neonates received 67 transfusions (18.4 mL/kg)– 31 (76%) coagulopathy without haemorrhage (DIC or other)– 8 (19%) clinical haemorrhage

• 38 obstetric and gynaecological patients received 57 transfusions (15.3 mL/kg)

– 36 (95%) haemorrhage

• 15 children with liver disease received 33 transfusions (38 mL/kg)

• 17 adult patients with end-stage liver disease transfused either following liver transplant or prior to other invasive procedures (10.2 mL/kg)

Efficacy in Single Factor Clotting Deficiency

Inbal et al.■ Prospective and interventional study■ A total of 11 patients, 8 with hereditary (2 FVII, 2 FX, 4 FXI deficiencies) and 3 with

acquired complex coagulopathies, were treated with Octaplas®■ The amount of Octaplas® infused ranged between 6-12 ml/kg■ In all the 11 patients Octaplas® was sufficient to prevent or stop bleeding

Santagostino et al.■ An open-label multicenter trial of Octaplas® involving 17 patients with inherited

coagulation disorders (1 afibrinogenemia, 4 FV, 6 combined FV and FVIII, 1 FX and 5 FXI deficiencies)

■ Study evaluated the pharmacokinetics of the deficient factors and hemostatic efficacy of Octaplas®

■ The pharmacokinetic study used a median Octaplas® dose of 18 ml/kg (range: 15-20), whereas the treatment courses had a higher range with 6-29 ml/kg (median: 18)

■ Octaplas® was fully effective in 81% of patients. In the remaining patients bleeding was controlled by continuing or increasing treatment with Octaplas®

■ Treatment with Octaplas® was well tolerated and safeInbal et al., Blood Coagulation and Fibrinolysis. 1993; 4;599-604; Santagostino et al., Haematological. 2006; 91:634-639.

Octaplasma Dosing

The volume and frequency of plasma exchanges vary depending on the individual patient, the clinical situation and disease, but 12-15 mL/kg of body weight is an acceptable starting dose

Example: 70kg patient

Condition DosageTreatment

GoalCalculation

Number of Bags

TTP/HUS1.5 plasma volume 70-75 mL/kg daily

for 1-8 weeks

Platelets 150 x 109/L

TBC ~200

Single Factor Deficiency (FV, FXI

or FXIII)12-15 mL/kg

25% of coagulation

factor activity

70kg x 12mL = 840 mL/200mL

bags 4.2