LACHEN, Switzerland I June 3rd, 2013 I Octapharma AG submitted the marketing authorization application (MAA) for the first truly human recombinant coagulation factor VIII (FVIII) from a human cell line for the treatment of haemophilia A to the European Medicines Agency (EMA) on May 29th, 2013.
Octapharma’s human cell line recombinant factor VIII (Human-cl rhFVIII) has been developed with the primary aim of tackling the most serious risk for haemophilia A patients on coagulation FVIII replacement therapy: the development of FVIII inhibitors (FVIII- neutralizing antibodies). FVIII inhibitors may block one or more functional epitopes of coagulation FVIII, preventing the infused FVIII from restoring haemostasis. The development of FVIII inhibitors is considered to be the most serious complication and can be observed in up to 39% of haemophilia A patients treated with currently commercialized recombinant FVIII products1.
Human–cl rhFVIII is a highly pure product with no detectable process-related impurities. There is no addition of animal or human-derived materials during production2. Human- cl rhFVIII is the first unmodified recombinant FVIII (rFVIII) product produced in a human cell line (human embryonic kidney) without additive animal proteins. In contrast to the currently marketed rFVIII products produced in hamster cell lines, Human-cl rhFVIII is free of animal (non-human) proteins. Until now, recombinant human (rh) FVIII products have been produced in either Chinese hamster ovary (CHO) or baby hamster kidney cells (BHK). While these products show good pathogen safety profiles they display a non-human pattern of post- translational modifications (PTMs) creating non-human antigenic epitopes . PTMs impact rFVIII activity3 and are a strong determining factor of the immunogenic potential and thus of potential FVIII inhibitor development. In contrast, Octapharma’s Human-cl rhVIII undergoes human – like PTMs and does not carry non-human antigenic epitopes4.
The human embryonic kidney cell line (HEK 293) has been widely used as an expression host in scientific research but rarely in commercial product development. After selecting HEK 293 F as a host cell, Octapharma developed methods for industrial recombinant protein production in these cells. Octapharma generated the Human-cl rhFVIII production cell line by transfection of HEK 293 F cells with a human FVIII cDNA.
Human cl-rhFVIII shows a high specific activity and a FVIII:C to FVIII:Ag ratio close to 0.95
In preclinical studies, Human-cl rhFVIII has demonstrated a superior binding affinity to VWF, when compared to presently available rhFVIII products from hamster cell lines, thus minimizing circulating unbound FVIII and further reducing the potential risk of inhibitor development. Together with the absence of known antigenic epitopes, this may contribute to a strong pharmacokinetic (PK) profile and a low immunogenic product profile. The PK phase I studies have shown a PK profile with in vivo recoveries of 2.1 IU/dl per IU/kg and a median half life of 17.1 hours, thereby offering the opportunity of personalized prophylaxis treatment in patients with haemophilia A.
Human-cl rhFVIII has successfully completed all the clinical registration trials which have demonstrated excellent tolerability. During the trials, in which 135 previously treated adult and paediatric patients participated, there was not a single case of inhibitory antibody development against Human-cl rhFVIII.
In two phase II/III studies a total of 54 previously treated adult patients (PTPs) (>150 previous exposure days) with severe haemophilia A (<1% FVIII) and no history of inhibitors were enrolled. A total of 1016 bleeding episodes (BEs) were treated with Human-cl rh FVIII. The vast majority of bleeds could successfully be managed with one (91.4%) or two (5.8%) infusions. The median dose for treatment of a bleed was 30.9 IU/kg. In 94.4% of BEs patients assessed the efficacy as “excellent” or “good”.
Overall the clinical trials of Human-cl rhFVIII demonstrated no case of FVIII inhibitor development, no drug related “serious” or “severe” adverse events and no allergic reactions.
Wolfgang Marguerre, Chairman, Octapharma Group, said “This landmark represents a new era for Octapharma and there is a rather pleasing symmetry that in the year we celebrate our 30th anniversary we reach this milestone for our human recombinant FVIII. We have from the beginning been dedicated to improving the lives of patients with haemophilia.”
Ulrich Thibaut, PhD, Board Member R&D of the Octapharma Group said: “This is a significant step towards broadening our technology basis and successfully entering the arena of recombinant therapeutics. It shows Octapharma’s strong and sustained commitment to invest in R&D in order to secure the future of our patient’s health and safety”.
Olaf Walter, M.D., PhD., MBA, Senior Vice President and Head of Octapharma`s haematology therapeutic area, said, “The submission of the MAA is an exciting moment for us. Given what we have learnt from the clinical trials, the Human-cl rhFVIII is expected to have improved function, tolerability and the chance for a reduced immunogenicity compared to the recombinant FVIII products currently available on the market. This marks a new chapter for Octapharma with potentially significant positive consequences for the haemophilia community. We are looking forward to further discussing the details of our research with the clinical community at the International Society on Thrombosis and Haemostasis (ISTH) Congress in Amsterdam where we are sponsoring a symposium entitled ‘The first truly Human recombinant FVIII- a natural choice to satisfy unmet needs of haemophilia A patients’.
Octapharma remain dedicated to advancing a patient orientated corporate culture. This significant project achievement is a further demonstration of Octapharma’s passion and commitment to utilizing state of the art technology to improve the lives of patients.
About Haemophilia A
Haemophilia A is an X-linked hereditary disorder caused by factor VIII (FVIII) deficiency which if left untreated leads to hemorrhages in muscles and joints and consequently to arthropathy and severe morbidity. FVIII replacement prophylactic treatment reduces the number of bleeding episodes and the risk of permanent joint damage. This disorder affects one in every 5,000 to 10,000 men worldwide. Globally, 75% of haemophilia cases are left undiagnosed or untreated. The development of neutralizing FVIII antibodies (FVIII inhibitors) against infused FVIII represents the most serious treatment complication. The cumulative risk of FVIII inhibitor development is reported to be currently up to 39% .
About Octapharma
Headquartered in Lachen, Switzerland, Octapharma Group is one of the largest human protein products manufacturers in the world and has been committed to patient care and medical innovation for 30 years. Our core business is the development, production and sale of human proteins from human plasma and human cell-lines. Patients in over 100 countries are treated with products in the following therapeutic areas:
• Haematology (coagulation disorders)
• Immunotherapy (immune disorders)
• Intensive Care and Emergency Medicine
Octapharma owns five state-of-the-art production facilities in Austria, France, Germany, Sweden and Mexico. For more information visit www.octapharma.com
References
1 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review, published in Haemophilia 9 (2003), 418-435
2 Sandberg H, Kannicht K, Stenlund P, et al. Functional characteristics of the novel, human-derived FVIII protein product, human-cl-hrFVIII, published in the Thrombosis Research 130 (2012) 808-817
3 Sandberg H, Kannicht K, Stenlund P, et al. Functional characteristics of the novel, human-derived FVIII protein product, human-cl-hrFVIII, published in the Thrombosis Research 130 (2012) 808-817
4 Sandberg H, Kannicht K, Stenlund P, et al. Functional characteristics of the novel, human-derived FVIII protein product, human-cl-hrFVIII, published in the Thrombosis Research 130 (2012) 808-817
5 Sandberg H, Kannicht K, Stenlund P, et al. Functional characteristics of the novel, human-derived FVIII protein product, human-cl-hrFVIII, published in the Thrombosis Research 130 (2012) 808-817
SOURCE: Octapharma
Post Views: 295
LACHEN, Switzerland I June 3rd, 2013 I Octapharma AG submitted the marketing authorization application (MAA) for the first truly human recombinant coagulation factor VIII (FVIII) from a human cell line for the treatment of haemophilia A to the European Medicines Agency (EMA) on May 29th, 2013.
Octapharma’s human cell line recombinant factor VIII (Human-cl rhFVIII) has been developed with the primary aim of tackling the most serious risk for haemophilia A patients on coagulation FVIII replacement therapy: the development of FVIII inhibitors (FVIII- neutralizing antibodies). FVIII inhibitors may block one or more functional epitopes of coagulation FVIII, preventing the infused FVIII from restoring haemostasis. The development of FVIII inhibitors is considered to be the most serious complication and can be observed in up to 39% of haemophilia A patients treated with currently commercialized recombinant FVIII products1.
Human–cl rhFVIII is a highly pure product with no detectable process-related impurities. There is no addition of animal or human-derived materials during production2. Human- cl rhFVIII is the first unmodified recombinant FVIII (rFVIII) product produced in a human cell line (human embryonic kidney) without additive animal proteins. In contrast to the currently marketed rFVIII products produced in hamster cell lines, Human-cl rhFVIII is free of animal (non-human) proteins. Until now, recombinant human (rh) FVIII products have been produced in either Chinese hamster ovary (CHO) or baby hamster kidney cells (BHK). While these products show good pathogen safety profiles they display a non-human pattern of post- translational modifications (PTMs) creating non-human antigenic epitopes . PTMs impact rFVIII activity3 and are a strong determining factor of the immunogenic potential and thus of potential FVIII inhibitor development. In contrast, Octapharma’s Human-cl rhVIII undergoes human – like PTMs and does not carry non-human antigenic epitopes4.
The human embryonic kidney cell line (HEK 293) has been widely used as an expression host in scientific research but rarely in commercial product development. After selecting HEK 293 F as a host cell, Octapharma developed methods for industrial recombinant protein production in these cells. Octapharma generated the Human-cl rhFVIII production cell line by transfection of HEK 293 F cells with a human FVIII cDNA.
Human cl-rhFVIII shows a high specific activity and a FVIII:C to FVIII:Ag ratio close to 0.95
In preclinical studies, Human-cl rhFVIII has demonstrated a superior binding affinity to VWF, when compared to presently available rhFVIII products from hamster cell lines, thus minimizing circulating unbound FVIII and further reducing the potential risk of inhibitor development. Together with the absence of known antigenic epitopes, this may contribute to a strong pharmacokinetic (PK) profile and a low immunogenic product profile. The PK phase I studies have shown a PK profile with in vivo recoveries of 2.1 IU/dl per IU/kg and a median half life of 17.1 hours, thereby offering the opportunity of personalized prophylaxis treatment in patients with haemophilia A.
Human-cl rhFVIII has successfully completed all the clinical registration trials which have demonstrated excellent tolerability. During the trials, in which 135 previously treated adult and paediatric patients participated, there was not a single case of inhibitory antibody development against Human-cl rhFVIII.
In two phase II/III studies a total of 54 previously treated adult patients (PTPs) (>150 previous exposure days) with severe haemophilia A (<1% FVIII) and no history of inhibitors were enrolled. A total of 1016 bleeding episodes (BEs) were treated with Human-cl rh FVIII. The vast majority of bleeds could successfully be managed with one (91.4%) or two (5.8%) infusions. The median dose for treatment of a bleed was 30.9 IU/kg. In 94.4% of BEs patients assessed the efficacy as “excellent” or “good”.
Overall the clinical trials of Human-cl rhFVIII demonstrated no case of FVIII inhibitor development, no drug related “serious” or “severe” adverse events and no allergic reactions.
Wolfgang Marguerre, Chairman, Octapharma Group, said “This landmark represents a new era for Octapharma and there is a rather pleasing symmetry that in the year we celebrate our 30th anniversary we reach this milestone for our human recombinant FVIII. We have from the beginning been dedicated to improving the lives of patients with haemophilia.”
Ulrich Thibaut, PhD, Board Member R&D of the Octapharma Group said: “This is a significant step towards broadening our technology basis and successfully entering the arena of recombinant therapeutics. It shows Octapharma’s strong and sustained commitment to invest in R&D in order to secure the future of our patient’s health and safety”.
Olaf Walter, M.D., PhD., MBA, Senior Vice President and Head of Octapharma`s haematology therapeutic area, said, “The submission of the MAA is an exciting moment for us. Given what we have learnt from the clinical trials, the Human-cl rhFVIII is expected to have improved function, tolerability and the chance for a reduced immunogenicity compared to the recombinant FVIII products currently available on the market. This marks a new chapter for Octapharma with potentially significant positive consequences for the haemophilia community. We are looking forward to further discussing the details of our research with the clinical community at the International Society on Thrombosis and Haemostasis (ISTH) Congress in Amsterdam where we are sponsoring a symposium entitled ‘The first truly Human recombinant FVIII- a natural choice to satisfy unmet needs of haemophilia A patients’.
Octapharma remain dedicated to advancing a patient orientated corporate culture. This significant project achievement is a further demonstration of Octapharma’s passion and commitment to utilizing state of the art technology to improve the lives of patients.
About Haemophilia A
Haemophilia A is an X-linked hereditary disorder caused by factor VIII (FVIII) deficiency which if left untreated leads to hemorrhages in muscles and joints and consequently to arthropathy and severe morbidity. FVIII replacement prophylactic treatment reduces the number of bleeding episodes and the risk of permanent joint damage. This disorder affects one in every 5,000 to 10,000 men worldwide. Globally, 75% of haemophilia cases are left undiagnosed or untreated. The development of neutralizing FVIII antibodies (FVIII inhibitors) against infused FVIII represents the most serious treatment complication. The cumulative risk of FVIII inhibitor development is reported to be currently up to 39% .
About Octapharma
Headquartered in Lachen, Switzerland, Octapharma Group is one of the largest human protein products manufacturers in the world and has been committed to patient care and medical innovation for 30 years. Our core business is the development, production and sale of human proteins from human plasma and human cell-lines. Patients in over 100 countries are treated with products in the following therapeutic areas:
• Haematology (coagulation disorders)
• Immunotherapy (immune disorders)
• Intensive Care and Emergency Medicine
Octapharma owns five state-of-the-art production facilities in Austria, France, Germany, Sweden and Mexico. For more information visit www.octapharma.com
References
1 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review, published in Haemophilia 9 (2003), 418-435
2 Sandberg H, Kannicht K, Stenlund P, et al. Functional characteristics of the novel, human-derived FVIII protein product, human-cl-hrFVIII, published in the Thrombosis Research 130 (2012) 808-817
3 Sandberg H, Kannicht K, Stenlund P, et al. Functional characteristics of the novel, human-derived FVIII protein product, human-cl-hrFVIII, published in the Thrombosis Research 130 (2012) 808-817
4 Sandberg H, Kannicht K, Stenlund P, et al. Functional characteristics of the novel, human-derived FVIII protein product, human-cl-hrFVIII, published in the Thrombosis Research 130 (2012) 808-817
5 Sandberg H, Kannicht K, Stenlund P, et al. Functional characteristics of the novel, human-derived FVIII protein product, human-cl-hrFVIII, published in the Thrombosis Research 130 (2012) 808-817
SOURCE: Octapharma
Post Views: 295
