Overview
•
Introduction to Octapharma
•
Rationale for development of Octaplasma
•
Manufacturing of OctaplasmaTM
•
Safety and Efficacy of OctaplasmaTM in TTP
•
Why OctaplasmaTM?
Octapharma– Committed to Patient Care
• 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
Our Commitment to Canada
Octaplex®: first PPC (prothrombin complex
concentrate)
Wilate®: first double virally inactivated pdVWF/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
Fresh frozen plasma (FFP) transfusion plays a vital role in treatment of several specific
clinical situations, however, FFP transfusion is not without complications
Pathogen transmissions and
infections
• Parasites
• Bacteria
• Viruses (especially HIV, HBV, and HCV)
• Prions [e.g. variant Creutzfeldt-Jakob disease (vCJD)]
Immune-mediated transfusion
reactions
• 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)
Physicochemical reactions
• Transfusion-associated circulatory overload (TACO)/fluid
overload
• Reactions due to additives (e.g. citrate toxicity)
OctaplasmaTM: Multiple Steps Ensures Safety
High
Selection of plasma
donors
Plasma donation center
Relative Risk
Screening of donations (NAT
tested: HIV, HBV, HCV)
Donor
Screening of plasma pools
(HIV, HBV, HCV)
Virus Inactivation/ Cell &
Prion Removal
Quality control
measurements
Manufacturing
Enveloped & NonEnveloped Viruses
Patient
Low
Viruses Transmissible by Blood
Enveloped
HIV
HBV
Non-enveloped
HAV
B19
2-3 log10 non-enveloped viruses can be removed
during removal of SD reagents
Transfusion Related Lung Injury (TRALI)
•
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
3. Kleinman et al. Transfusion. 2004; 4. Kopko P.M. et al. JAMA. 2002; 5. Looney MR et al. CHEST. 2004
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
Immune-mediated Reactions Caused by Plasmas
±
+
÷
Optimised integration
Cell removal &
S/D treatment
or
+
÷
Optimised integration
TRALI
Cell removal
Allergic rx.
(urticaria)
Residual Blood Cells in Plasma
Fresh-frozen
plasma
OctaplasmaTM
Cell and debris free
- Removal of intracellular
pathogens
- Abolish cell-dependent
adverse reactions
- Standardized bags
OctaplasmaTM demonstrates a low transfusion
reaction rate
Serious Hazards of Transfusion Report (SHOT) 20101
Component
Febrile reactions, incidence per
100,000 units
Allergic 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
18.3
15.2
20
17.3
Units
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.
10
# of SAE’s/100,000
Rates of SAE: FFP vs. OctaplasmaTM in Finland in 2005-2006
3.8
0 ▲ SAE
Krusius et al.,, Sanguinis 2009;96 (Suppl. 1), 1–62.
OctaplasmaTM reduces both infectious and noninfectious risks of transfusions
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.
1Svae
et al, 2011; 2Krusius, 2009, 3Vaara & Nilsson 2010. calculated risk, not actual
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 Octaplasma
Optimised integration of 630 to 1,520 single units of FFP
PRE-VI
AREA
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
POST-VI
AREA
Clear filtration [1.0 µm  0.45 µm]
Solid phase extraction of Octoxynol-9
Sterile filtration [0.45 µm + 0.2 µm]
STERILE AREA
Aseptic filling
Labelling and vacuum sealing
Freezing [-60°C] and storage [-30°C]
Full quality control and release
TM
SD Treatment of Octaplasma
TM
• 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
• 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.
2.
Virus
Release Specifications
HAV PCR
Negative
Parvovirus B19 PCR
≤ 10.0 IU/µL
HAV-Ab
≥ 1 IU/mL
Parvovirus B19-Ab
≥ 22 IU/mL
Solheim BG et al. Transfusion 2000; 40: 84-90
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
Parameters
Reference
Range 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.
Octaplasma - Efficacy in TTP
TM
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
Octaplasma Tolerability - Sweden
TM
Octaplasma Tolerability - Austria
TM
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.”
Octaplasma Coagulation Factor Levels
TM
Heger A et al. Transfusion and Apheresis Science 2005; 33: 257-267.
Octaplasma Coagulation Factor Levels
TM
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: 1520), 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 safe
Inbal 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
Dosage
Treatment
Goal
Calculation
Number
of Bags
TTP/HUS
1.5 plasma volume
70-75 mL/kg daily
for 1-8 weeks
Platelets
150 x 109/L
TBC
~200
12-15 mL/kg
25% of
coagulation
factor
activity
70kg x 12mL =
840 mL/200mL
bags
4.2
Single Factor
Deficiency (FV, FXI or
FXIII)