Antihemophilic Factor (Porcine) - Hyate:C
Status: approvals withdrawn; OBI-1, a new recombinant version nearing filing phase
Organizations involved:
Ipsen, Inc. – USA mark.; Former
Ipsen Biopharm Ltd. – Manuf.; R&D; Tech.; Former
Ipsen Ltd. – Intl. mark.; Former
Ipsen S.A. – Parent; Former
Speywood Biopharm Ltd. – R&D; Tech.; Former
Porton International plc – Former
Cross ref.: See the Factor VIII Products entry (#715)
Description: Antihemophilic Factor (Porcine) or Hyate:C is a lyophilized (freeze-dried) formulation of concentrated porcine (pig) antihemophilic factor (porcine Factor VIII) fractionated and purified from pooled pig blood, with purification including affinity chromatography. The product was not subjected to specific viral inactivation processing.
Porcine Factor VIII has much the same ability as human Factor VIII to activate thrombin generation and assist in clot formation. Porcine Factor VIII epitopes (antigens) are different in many cases than human Factor VIII, allowing use of this product by persons having inhibitors (antibodies) to human Factor VIII, whether induced by plasma-derived, recombinant, or patient’s own Factor VIII.
Each vial contains between 400 and 700 units (U) of porcine Factor VIII for reconstitution with 20 mL Sterile Water for Injection, USP, for intravenous injection. Excipients used are trisodium citrate, sodium chloride, and tris buffer. The assayed amount of Factor VIII activity is stated on the label, and may vary from lot to lot. Variations in this stated amount may occur depending on the type of assay used. The final reconstituted product has a sodium ion concentration of 110-135 millimoles/L and a citrate ion concentration of 10-30 millimoles/L. The specific activity of Hyate:C is greater than 50 U/mg of protein. The ratio of porcine Factor VIII to porcine von Willebrand’s Factor (vWF) in Hyate:C is greater than 10 to 1. Each lot of Hyate:C is rigorously screened for certain porcine viruses. Hyate:C contains no preservatives, and no other animal- or human-derived products.
Nomenclature: Factor VIII, porcine [BIO]; Hyate:C [TR]; Antihemophilic Factor [Porcine] [FDA]; porcine Factor VIII [SY]; pig-derived Factor VIII [SY]
Biological.: Circulating antibodies (inhibitors) to human Factor VIII occur in 6-20% of severely affected hemophilia A patients receiving supplementation with Factor VIII (whether derived from plasma or recombinant), and in previously non-hemophilic patients who spontaneously develop autoantibodies to their own Factor VIII (acquired hemophilia A). About 1/million persons/year worldwide develop the autoimmune disease of acquired hemophilia.
Circulating human Factor VIII antibodies (inhibitors) in most inhibitor patients neutralize porcine Factor VIII less readily than human Factor VIII; and Hyate:C is primarily used for treatment of hemophilia A patients with inhibitors. The reported in vivo half-life for Hyate:C is 10-11 hours in patients without detectable inhibitors. The activity of the patient’s antibody against Hyate:C should be determined using dissolved Hyate:C as a substrate in a modified Bethesda assay, and the value obtained may be used as a guide to the likely effectiveness of Hyate:C.
History: Therapeutic Factor VIII concentrate from porcine plasma was first prepared in the mid-1950’s in U.K. This original product was effective in stopping bleeding, but had several drawbacks in terms of adverse effects, likely due to non-GMP-level manufacturing. By the end of the 1960’s, increased supplies of human plasma-derived Factor VIII become available, and more intensive treatment with human Factor VIII concentrates increased the incidence of development of inhibitors in Factor VIII patients.
Speywood Laboratories was formed in 1973 to develop a therapeutic concentrate of porcine Factor VIII for the clinical management of inhibitor patients. The freeze-dried purified concentrate, Hyate:C, was developed by 1980, and clinical studies began in inhibitor patients. The process used to manufacture Hyate:C was specifically designed to minimize the content of pharmacologically active, non-Factor VIII porcine blood proteins, which were largely responsible for the adverse effects of the original preparations. Hyate:C was first licensed for clinical use in 1984 in the U.K. U.S. FDA approval followed in 1986, with the addition of the first-line indication for the treatment of spontaneous acquired hemophilia in 1988.
Companies.: Hyate:C was originally manufactured by Speywood Laboratories, later Spey-wood Biopharm Ltd., formerly a subsidiary of Porton International plc, now Ipsen Biopharm Ltd. (Wrexham, Wales, U.K.), CBER/FDA est. no. 1014, a subsidiary of Ipsen S.A. Hyate:C was marketed in the U.S. by Ipsen, Inc. (technically, by its Porton International Inc. subsidiary). It was marketed internationally by Ipsen Ltd., subsidiaries of Ipsen S.A.
Manufacture: Cryoprecipitate is prepared from porcine plasma, with the Factor VIII fraction purified by affinity chromatography using a proprietary polyelectrolyte resin and lyophilized. No additional stabilizing proteins are added. The polyelectrolyte resin was formerly manufactured by National Starch, and Speywood purchased decades-worth of the product prior to its discontinuation. The manufacturing process does not incorporate specific viral inactivation processes, such as heat or the addition of a solvent/detergent mixture. Low levels of porcine parvovirus (PPV) were detected in some batches of the product in late 1996, but Hyate:C has not been shown to transmit any viral illness to its recipients. The product is extensively screened for porcine viruses using a 4-cell line general screen, and the source plasma is screened for porcine parvovirus using a sensitive polymerase chain reaction (PCR; NAT) assay. Dr. C.R. Hay reported in “Porcine factor VIII: current status and future developments.,” Haemophilia 2002 Jan; 8 Suppl 1:24-7, that virus spiking experiments indicate that Hyate:C’s purification and processing are associated with a 6-log viral reduction.”
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19861008; first approval, PLA
Date = 19880000; PLA supplement; Indication = first-line treatment of spontaneous, acquired hemophilia A
Indications: [full text of the "INDICATIONS AND USAGE” section from product insert/labeling]:
Antihemophilic Factor (Porcine)-HYATE:C is indicated for the treatment and prevention of bleeding in congenital hemophilia A patients with antibodies (inhibitors) to human factor VIII and also for previously non-hemophilic patients with spontaneously acquired inhibitors to human factor VIII (acquired hemophilia).
HYATE:C has not been known to transmit any human viruses (i.e., hepatitis, or human immunodeficiency virus). Consideration of HYATE:C concentrate as a primary treatment option in acquired inhibitor patients therefore may be justified.
In patients with acquired hemophilia, porcine factor VIII infusion should be considered as first-line therapy regardless of the initial anti-human inhibitor titer. In hemophilia A patients with an antibody titer of less than 5 Bethesda (B) U/mL against human factor VIII, a human factor VIII concentrate infusion should first be considered. If clinical efficacy is not possible or is judged to be insufficient, HYATE:C is recommended for use in these patients.
In a U.S. multicenter study, patients having antibody titer levels ≤ 20 BU/mL to porcine factor VIII achieved a good to excellent response to therapy with HYATE:C. An antibody titer ≤2 0 BU/mL against porcine factor VIII is therefore a positive indication of the suitability of HYATE:C therapy. Successful HYATE:C therapy is frequently reported in patients with antibody titers in excess of 50 BU/mL against human factor VIII. Due to the wide individual variation in the interaction of anti-human factor VIII antibodies with porcine factor VIII, the patient’s antibody titer should be directly measured against porcine factor VIII.
Status: manufacture was permanently halted effective July 1, 2002. The BLA and approvals in other countries were subsequently withdrawn at the request of the manufacturer. No stocks are available for purchase. However, Speywood holds an IND allowing U.S. distribution of remaining, aging product in extreme life-threatening cases, where no other alternative treatment is available or appropriate.
With no specific viral inactivation processing during manufacture, porcine virus contamination had been a recurring concern. Hyate:C had been in use for about two decades, and there had been no evidence of harm from the product. Porcine parvovirus (PPV) is endemic in pigs worldwide and can frequently be identified in pooled collections of porcine plasma. The virus is highly resistant to inactivation. PPV does not cause clinical or subclinical infection in humans.
U.K. investigators reported in Haemophilia, 8(6):798-801, Nov. 2002, results from a retrospective study of sera from Hyate:C patients, healthy patients, pig abattoir staff, Hyate:C manufacturing staff, and recipients of other porcine products. No antibodies to PPV or porcine respiratory and reproductive syndrome virus (PRRSV) were detected in any subject. Several patients and controls had detectable encephalomyocarditis virus (EMCV) antibodies, but at the same incidence rate as the general population. The study concluded there was no evidence of transmission of PPV or other marker porcine virus associated with the use of Hyate:C.
Investigators from the Centers for Disease Control and Prevention (CDC) reported in Transfusion, 40(6):708-11, June 2000, results from study of samples from 22 stored lots of Hyate:C for the presence of PPV DNA by PCR and nested PCR assays, and testing of 98 Hyate:C patients and 24 controls for PPV antibodies. PPV DNA was detected in 21 of the 22 lots of Hyate:C, primarily by nested PCR testing. However, none of the serum specimens from the 98 Hyate:C recipients tested positive for PPV IgG antibodies. The study concluded the risk of human disease from low levels of PPV in Hyate:C seemed to be low.
Porcine endogenous retroviruses (PERVs) was also a concern. PERVs are retroviruses expressed from DNA elements in the porcine genome, so they can not be eliminated from the source. PERVs are nonpathogenic in pigs and appear non-pathogenic in humans. Investigators from the CBER, FDA, reported in the J. Virol., 75(10):4551-7, May 2001, results from testing six lots of Hyate:C for PERVs. All six lots were positive for PERV RNA and reverse transcriptase. However, infectious virus could not be detected in clinical lots of Hyate:C, indicating that the manufacturing process reduces the load of infectious virus to levels below then detectable limits.
These viral contamination issues and associated liability concerns likely contributed to (or were the sole reason for) removal of Hyate:C from the market.
Medical: Extensive worldwide clinical experience with Hyate:C over the last 20 years, including clinical trials in Europe and the U.S., has confirmed its efficacy and safety for the management of hemophiliacs with inhibitors. The clinical efficiency of Hyate:C has been reported to be as good as that achieved with the administration of human Factor VIII:C in non-inhibitor patients for similar Factor VIII:C levels and similar bleeding episodes.
The general objectives for treatment with Hyate:C – the prevention or control of bleeding, joint mobilization, wound healing and surgical cover – are essentially the same as those employed with the use of human Factor VIII:C concentrates, whether blood-derived or recombinant. Like other Factor VIII products, the dosage of Hyate:C varies for individual patients, but is dependent upon the patient’s weight, the level of circulating antibody, the type and severity of hemorrhage, and the desired plasma Factor VIII:C level. Hyate:C is appropriate for first-line use in inhibitor patients.
The required dose is determined by administering an initial dose of Hyate:C, and assaying the post-infusion level of Factor VIII:C in the patient’s plasma. According to the response, the dosage can then be either increased or decreased for subsequent infusions.
Market: The 2005 Average Wholesale Price (AWP) was $2.15/IU (no change from 2004) (Red Book, 2005). At this AWP, a 600 unit vial would cost about $1,300.
Medicare reimbursement was set at $2.09/IU for inpatient and home care, and $1.52/IU for outpatient care. Estimated Acquisition Costs (for hospitals, treatment centers) was $2.05-$2.15/IU [from NHF].
In some cases, the cost for treatment with Hyate:C could be very high. For example, the lead article in the August 2, 2001, Wall Street Journal discussed the case of a single adult patient having developed acquired hemophilia A, and requiring clotting factors prior to and after surgery. His hospital bill included $2.9 million for Hyate:C (and $1.9 million for NovoSeven). This article cited about $1,000/vial as the wholesale price, and reported that Ipsen’s total U.S. sales of Hyate:C in 2000 were 10,000,000 units used by 163 patients. Based on this, the average Hyate:C recipient in the U.S. in 2000 received about 60,000 units/year. At $2.00/unit, the average cost/patient would be about $120,000, and Ipsen’s 2000 U.S. sales of Hyate:C would be roughly $20 million.
Competition: Other products currently available for use in Factor VIII inhibitor patients are FEIBA VH, Autoplex, Octaplex, and NovoSeven (see related entries).
Ongoing: Octagen Corp., in collaboration with Ipsen S.A., is developing “low immunogenic” recombinant porcine (pig) factor VIII (rpfVIII; OBI-1), based on technology exclusively licensed from Emory University, for treatment of congenital or acquired hemophilia resistant to Factor VIII. OBI-1 is currently in Phase II trials (in early 2006. In Oct. 2005, Octagen was awarded a a three-year, $3 million maximum award, Small Business Innovation Research (SBIR) grant by the National Institutes of Health (NIH) to further fund development of OBI-1.
Companies involvement:
Full monograph
901 Factor VIII, porcine
Nomenclature:
Factor VIII, porcine [BIO]
Hyate:C [TR]
Antihemophilic Factor (Porcine) [FDA]
AHF [SY]
pig-derived Factor VIII [SY]
porcine Factor VIII [SY]
FDA Class: Biologic PLA
Year of approval (FDA) = 1986
Date of 1st FDA approval = 19861008
(in format YYYYMMDD)
Index Terms:
antihemophilic factors
biopharmaceutical products
blood products
porcine endogenous retroviruses (PERV)
porcine parvovirus (PPV)
retroviruses, porcine endogenous
lyophilized (freeze-dried)
polyelectrolyte resin
porcine plasma
Sterile Water for Injection
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
EU011 Approved Formerly in EU/withdrawn
UM999 Not Available/Not Marketed in US
US011 Approved Formerly in US/withdrawn
EM999 Not Available/Not Marketed in EU
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