Hemophilia is a bleeding disorder caused by defective proteins, also called Factor, in the blood clotting cascade. Treatment for hemophilia has traditionally been through intravenous injections of adequate concentrations of the missing protein. At this time there is no cure for hemophilia, however, the condition is well controlled by such treatment. Recently, the replacement therapies have focussed on extending the half-life of Factors. Today there is one such Factor VIII (FVIII) and Factor IX (FIX) product available in the market. Eloctate for FVIII and Alprolix for FIX were approved in 2014 as the first extended half-life (EHF) product to market from Biogen-Idec. Baxter introduced Obizur (FVIII) to treat acquired hemophilia in 2015. This is a recombinant porcine FVIII. Baxter is awaiting FDA approval on a new EHF FVIII product- Adynovate (BAX855) a pegylated molecule. This is a full-length rFVIII protein.
There are a number of longer lasting Factor products in late phases of clinical trials or awaiting FDA approval. Biotechnology companies along with pharmaceuticals are actively developing and testing new molecules for their potential use to treat hemophilia. These novel approaches to Factor development fill the pharmaceutical pipeline. Additional molecules with extended half-life using pegylation or fusion to albumin are in clinical trials.
Various mechanisms to promote the formation of a stable clot are being investigated. A humanized bispecific monoclonal antibody (mAb) to FIXa and FX (ACE910) from Genentech is entering Phase 2 study. This is a small molecule and can be administered subcutaenously. Such a molecule provides two very significant advantage. First, it is a benefit to patients with venous access issues; the other it bypasses the need for FVIII by stiumulating the rate of FXa generation via the assembly of FIX1 and FX. The latter is a clear benefit to treat patients with inhibitors to FVIII. N9-GP is a EHF FIX product (NOVO Nordisk) is in Phase 3 clinical trials. N9-GP, a glycopegylated molecule, shows pharmacokinetics data (pK) with a half-life of 110 hours. CSL-Behring has submitted for FDA approval on a rFIX albuimin fusion protein (rFIX-FP) for use in hemophilia B. a rFVIIa-Albumin fusion protein (CSL Behring), a rVWF-Albumin fusion protein and a rFVIIa-CTP fusion protein (Prolor Biotech, Israel).
Four proteins- TFPI, protein C, protein S, ATIII - act as brakes in the coagulation cascade. Researchers are trying to takes these brakes off as a mechanism to bypass the FVIII, FIX requirement. These are currently being studied in animals. Neutralizing monolclonal antibody (mAb) negates the effect of TFPI on the extrinisic pathway activation. A Novo Nordisk product concizumab (mAb2021) demonstrates hemostatic effect by blocking the TFPI action on the active site of FXa in monkeys after subcutaneous administration. Reduction in thrombin formation has been attempted by suppressing the hepatocytes production of antithrombin (AT) mRNA via subcutaneous injection. Alnylam Pharmaecuticals reported a phase I study of a ALN-AT3 (short interfering RNA product), targeting thrombin.
Hemophilia has always been an attractive candidate for gene therapy, being a single gene abnormality. Gene therapy can also provide a lasting effect with a single treatment and become a cost-effective alternative to current treatments. Adeno-associated virus (AAV) or lentiviral vectors have been used for hemophilia. AAV is a single-stranded parvovirus and has the advantage of low immunogenicity, high safety and transferability to quiescent cells. AAV Serotype 8 (AAV8) allows gene expression in the liver, where coagulation factors are produced in animal studies. Nathwani et al recently reported therapeutic FIX expression for 3 years with AAV8 gene therapy in humans. Clinicaltrials.gov gave 7 hits on a search with "AAV + Hemophilia" in the criteria. Lentiviruses are low-risk vector compared to AAV. Lentiviruses are more efficient at transducing quiescent cells such as the hematopoietic stem cells than retroviral vectors. Lentiviral vectors have been used to transfer genes into hepatocytes by direct injection of the vector. The successes of gene therapy for FIX is not easily translated for FVIII due to the larger size of the FVIII gene (7 kbps). This will require an efficient high-yielding delivery system to achieve therapeutic levels. Glybera®is a commercial AAV vector approved in Europe.
Cell therapy involves transplanting and induction of Factor expressing cells. Cells such as mesenchymal stem cells, endothelial cells, hepatocytes are transduced with a Factor carrying vector such as a plasmid or a virus. The advantage is that these cells do not get disseminated in the body and the risk of triggering a anti-vector immune response is reduced. The majority of the studies on gene therapy and cell therapy are currently done in animal. This is because of an ideal non-human primate model of the disease state. Very recently hemophilia A pigs are being studied as a posible model.
Genome engineering is another area where rapid advancement is taking place. Gene-editing tools such as the CRISP/Cas9 system, Transcription activator-like effector neucleses (TALENs) and zinc finger nucleases, could have future application in hemophilia gene therapy.
Therapy for hemophilia has come a long way after the discovery of cryprecipitate to treatment. The landscape of the standard replacement therapy is likely to be supplemented by the new EHF Factor. A number of clinical trials are being conducted with alternate routes, Factor bypassing agents, disrupting anti-thrombin activity, gene and cell therapy.
There are a number of longer lasting Factor products in late phases of clinical trials or awaiting FDA approval. Biotechnology companies along with pharmaceuticals are actively developing and testing new molecules for their potential use to treat hemophilia. These novel approaches to Factor development fill the pharmaceutical pipeline. Additional molecules with extended half-life using pegylation or fusion to albumin are in clinical trials.
Various mechanisms to promote the formation of a stable clot are being investigated. A humanized bispecific monoclonal antibody (mAb) to FIXa and FX (ACE910) from Genentech is entering Phase 2 study. This is a small molecule and can be administered subcutaenously. Such a molecule provides two very significant advantage. First, it is a benefit to patients with venous access issues; the other it bypasses the need for FVIII by stiumulating the rate of FXa generation via the assembly of FIX1 and FX. The latter is a clear benefit to treat patients with inhibitors to FVIII. N9-GP is a EHF FIX product (NOVO Nordisk) is in Phase 3 clinical trials. N9-GP, a glycopegylated molecule, shows pharmacokinetics data (pK) with a half-life of 110 hours. CSL-Behring has submitted for FDA approval on a rFIX albuimin fusion protein (rFIX-FP) for use in hemophilia B. a rFVIIa-Albumin fusion protein (CSL Behring), a rVWF-Albumin fusion protein and a rFVIIa-CTP fusion protein (Prolor Biotech, Israel).
Four proteins- TFPI, protein C, protein S, ATIII - act as brakes in the coagulation cascade. Researchers are trying to takes these brakes off as a mechanism to bypass the FVIII, FIX requirement. These are currently being studied in animals. Neutralizing monolclonal antibody (mAb) negates the effect of TFPI on the extrinisic pathway activation. A Novo Nordisk product concizumab (mAb2021) demonstrates hemostatic effect by blocking the TFPI action on the active site of FXa in monkeys after subcutaneous administration. Reduction in thrombin formation has been attempted by suppressing the hepatocytes production of antithrombin (AT) mRNA via subcutaneous injection. Alnylam Pharmaecuticals reported a phase I study of a ALN-AT3 (short interfering RNA product), targeting thrombin.
Hemophilia has always been an attractive candidate for gene therapy, being a single gene abnormality. Gene therapy can also provide a lasting effect with a single treatment and become a cost-effective alternative to current treatments. Adeno-associated virus (AAV) or lentiviral vectors have been used for hemophilia. AAV is a single-stranded parvovirus and has the advantage of low immunogenicity, high safety and transferability to quiescent cells. AAV Serotype 8 (AAV8) allows gene expression in the liver, where coagulation factors are produced in animal studies. Nathwani et al recently reported therapeutic FIX expression for 3 years with AAV8 gene therapy in humans. Clinicaltrials.gov gave 7 hits on a search with "AAV + Hemophilia" in the criteria. Lentiviruses are low-risk vector compared to AAV. Lentiviruses are more efficient at transducing quiescent cells such as the hematopoietic stem cells than retroviral vectors. Lentiviral vectors have been used to transfer genes into hepatocytes by direct injection of the vector. The successes of gene therapy for FIX is not easily translated for FVIII due to the larger size of the FVIII gene (7 kbps). This will require an efficient high-yielding delivery system to achieve therapeutic levels. Glybera®is a commercial AAV vector approved in Europe.
Cell therapy involves transplanting and induction of Factor expressing cells. Cells such as mesenchymal stem cells, endothelial cells, hepatocytes are transduced with a Factor carrying vector such as a plasmid or a virus. The advantage is that these cells do not get disseminated in the body and the risk of triggering a anti-vector immune response is reduced. The majority of the studies on gene therapy and cell therapy are currently done in animal. This is because of an ideal non-human primate model of the disease state. Very recently hemophilia A pigs are being studied as a posible model.
Genome engineering is another area where rapid advancement is taking place. Gene-editing tools such as the CRISP/Cas9 system, Transcription activator-like effector neucleses (TALENs) and zinc finger nucleases, could have future application in hemophilia gene therapy.
Therapy for hemophilia has come a long way after the discovery of cryprecipitate to treatment. The landscape of the standard replacement therapy is likely to be supplemented by the new EHF Factor. A number of clinical trials are being conducted with alternate routes, Factor bypassing agents, disrupting anti-thrombin activity, gene and cell therapy.
Additional acronyms:
CTP = C-terminal peptide; F = factor; FcIg = Fc domain of immunoglobulin (Ig)G; kDa = kilodaltons; mAB = monoclonal antibody; mRNA = messenger RNA; PEG = polyethylene glycol; siRNA = small interfering RNA; T1/2 = circulating half-life; TFPI = tissue factor pathway inhibitor; vWF = von Willebrand factor
See also
No comments:
Post a Comment