introduction to octapharma rationale for development of octaplasma manufacturing of octaplasma tm...
TRANSCRIPT
•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