Coagulation Factor VIIa (Recombinant) - NovoSeven; eptacog alfa (activated); activated Factor VII
Status - approved; marketed
Organizations involved:
ZymoGenetics, Inc. – R&D; Tech.; Former
Novo Nordisk Pharmaceuticals Industries, Inc. – USA mark.
Novo Nordisk A/S – Manuf.; Intl. mark.; Parent
Cross ref.: See the Factor VIII Products entry in the human blood products section for discussion of clotting mechanisms.
Description: Coagulation Factor VIIa (Recombinant) or NovoSeven is a lyophilized (freeze-dried) formulation of recombinant human Factor Vlla (rFVIIa), the activated (zymogen) form of Factor VII, manufactured by culture of a baby hamster kidney (BHK) cell line with purification including immunoaffinity chromatography using matrix-immobilized Factor VII murine monoclonal antibodies. Factor VIIa is a vitamin K-dependent, two-chain (dimer), complex glycoprotein consisting of 406 amino acids and having a molecular weight of ~50 kDa. This dimeric form of recombinant Factor VIIa is composed of a light chain (N terminal) of 20 kDa and a heavy chain (C terminal) of 30 kDa connected by a single disulfide bond. The serine protease enzyme activity of the molecule resides in the heavy chain. Studies of post-translational modifications, e.g., glycosylation, show recombinant Factor VIIa to be similar in structure to human plasma-derived FVIIa, with differences in glycosylation not affecting the product’s safety or efficacy.
rFVIIa has two N- and 2 O-glycosylation sites. The O-glycosylation sites are in the epidermal growth factor (EGF) region of the molecule attached to Ser52 and Ser60. The N-glycosylation sites are Asn145 and Asn322. The O-glycosylation sites are in the epidermal growth factor (EGF) region of the molecule attached to Ser52 and Ser60, while the N-glycosylation sites are Asn145 and Asn322. The O-glycosylation sites consist of one to four monosaccharides, while the N-glycosylations mainly are biantenarry core-fucosylated with one or two sialic acid residues. In the N-terminal region, 10 gamma-carboxylic acid residues have been identified. These post-translational modifications are of importance for the biological function of the molecule, which is why the molecule is expressed by mammalian cells, with transformed CHO cells secreting rFVIIa into the culture medium. rFVII is spontaneously autoactivated to rFVIIa during purification. The glycosylation of rFVII in Novoseven is slightly different than that of human plasma-derived Factor VIIa. The glutamic acid residue at position 35 is only partially carboxylated in rFVIIa. However, the biological activity and potency is the same as for plasma derived FVII.
Factor Vlla facilitates blood clotting (coagulation) by acting upon the blood clotting cascade at a later stage than Factor VIII. NovoSeven is primarily used for treatment of hemophilia A patients with Factor VIII inhibitors (antibodies) and hemophilia B patients with Factor IX inhibitors. NovoSeven is considered a major advancement in hemophilia A treatment because it can ‘bypass’ these inhibitors by its unique mode of action later in the coagulation process. NovoSeven may also be used for those even rarer patients with a deficiency of Factor VII. The activity of NovoSeven is measured with reference to the 1st International Standard of FVIIa 89/688, as KIU or 1,000 IU.
NovoSeven is packaged in single-use vials containing either 1.2, 2.4 or 4.8 mg [dosage strengths of 60,000 (60 KIU) 120,000 (120 KIU) and 240,000 (240 KIU), respectively]. The 1.2 mg (60 KIU) vial contains 1,200 µg of rFVIIa, sodium chloride (5.84 mg), calcium chloride dihydrate (2.94 mg), glycylglycine (2.64 mg), polysorbate 80 (Tween 80; 0.14 mg) and mannitol (60.0 mg). The 4.8 mg (1,200 µg/vial) vials contain proportionately (4-fold) more contents. After reconstitution with Sterile Water for Injection, USP (not supplied), each vial contains approximately 0.6 mg/mL recombinant Factor VIIa (600 µg/mL). The reconstituted vials also contain approximately 5.5 mg sodium chloride (3 mg/mL), calcium chloride dihydrate (1.5 mg/mL), glycylglycine (1.3 mg/mL), polysorbate 80 (0.1 mg/mL), and mannitol (30 mg/mL). Novo Seven contains trace amounts of non-human proteins left over from manufacture and purification, including mouse immunoglobulin G (IgG; max. of 1.2 ng/mg) from immunoaffinity purification, bovine IgG (max. of 30 ng/mg) from the culture medium, and baby hamster kidney (BHK) protein from the host cells (max. of 19 ng/mg). The product contains no preservatives. The dating period is 24 months from the date of manufacture when stored at 2-8˚C (refrigerated), with the date of manufacture defined as the date of the initial sterile filtration of the formulated bulk
In May 2008, NovoSeven RT, a room temperature stable formulation was approved by FDA, allowing the product to be stored at room temperature (up to 77˚F) for up to two years, based on the use of sucrose and L-methionine. NovoSeven RT is supplied as a white lyophilized powder in single-use vials containing 1.0 mg (1000 micrograms), 2.0 mg (2000 micrograms), or 5.0 mg (5000 micrograms) rFVIIa per vial. Each 1.0 mg vial also contains 2.34 mg sodium chloride per mg of rFVIIa; 1.47 mg calcium chloride dihydrate; 1.32 mg glycylglycine; 0.07 mg polysorbate 80 (Tween 80; 25 mg sucrose; and 0.5 mg L-methionine. The diluent for reconstitution of NovoSeven RT is a 10 mmol solution of histidine in water for injection and is supplied as a clear colorless solution. After reconstitution with the histidine diluent, each vial contains ~1.0 mg/mL NovoSeven RT (1000 µg/mL).NovoSeven RT contains trace amounts of proteins derived from the manufacturing and purification processes such as mouse IgG (maximum of 1.2 ng/mg), bovine IgG (maximum of 30 ng/mg), and protein from BHK-cells and media (maximum of 19 ng/mg). In Aug. 2010, FDA approved an 8 mg vial size for NovoSeven RT, making it available in 1, 2, 5 and 8 mg vials.
Novo claims that NovoSeven “poses no risk of human viral transmission through its use,” but does not mention risks from animal viruses or prions.
The NovoSeven Reconstitution Kit, containing all the materials for reconstitution and injection of NovoSeven, was launched in Sept. 2003.
Nomenclature: Factor VIIa, rDNA [BIO]; NovoSeven [TR assigned to Novo Nordisk A/S]; Coagulation Factor VIIa (Recombinant) [FDA]; Coagulation Factor VIIa (Recombinant) Room Temperature Stable, Lyophilized Powder [FDA, for NovoSeven RT]; Coagulation Factor VIIa [Recombinant] Room Temperature Stable [FDA; for NovoSeven RT]; eptacog alfa (activated) [INN]; rFVIIa [SY]; FVIIa, recombinant [SY]; activated Factor VII [SY]; VII25 [SY for room termp. stable formulation]; NDC 0169-7060-01 and NDC 0169-7062-01 [NDC]
Note, it is common, even in technical publications, for these names (e.g., NovoSeven, rFVIIa) to be used imprecisely, e.g., using various names to refer to the active ingredient and the final product.
Biological.: Factor VII is a trace plasma glycoprotein that circulates in blood as a single-chain zymogen (inactive enzyme form). Single-chain Factor VII may be converted to activated (active enzyme) two-chain Factor VIIa by Factor Xa, Factor XIIa, Factor IXa, or thrombin in vitro. Factor Xa is the major physiological activator of Factor VII. The conversion of zymogen Factor VII into the activated two-chain molecule occurs by cleavage of an internal peptide bond located approximately in the middle of the molecule and formation of the disulfide linkage between the two resulting chains. The activation cleavage site is at Arg152-Ile153 for native human Factor VII. Like several other plasma proteins involved in hemostasis, Factor VII is dependent on vitamin K for its activity. Vitamin K is required for the gamma-carboxylation of multiple glutamic acid residues clustered in the amino terminus of the protein, with these residues required for the metal-associated interaction of Factor VII with phospholipids.
Activated Factor X (“Xa”), in complex with other factors, converts prothrombin (Factor II) to thrombin (Factor IIa), which leads to the formation of a hemostatic plug (blood clot) by converting fibrinogen to fibrin as a final stage in forming a fibrin clot. Factor VIIa activates Factor X to Factor Xa, which in turn converts prothrombin to thrombin, thereby initiating the formation of a fibrin clot. Because activation of Factor X is common to both the extrinsic and intrinsic pathways of blood coagulation, Factor VIIa may be used to treat individuals severely deficient in the activities of Factor IX, Factor VIII, or Von Willebrand’s Factor. See the Factor VIII Products entry for further discussion of clotting mechanisms. Also see the Factor IX Products entry (including discussion of Factor IX Complex products which contain some Factor VII).
The “intrinsic pathway” refers to those reactions that lead to thrombin formation through utilization of factors present only in plasma. A series of protease-mediated activations ultimately generates Factor IXa which, in conjunction with Factor VIIIa, cleaves Factor X into Xa. An identical proteolysis is effected by Factor VIIa and its cofactor, tissue factor, in the “extrinsic pathway” of blood coagulation. Tissue factor is a membrane bound protein and does not normally circulate in plasma. Upon blood vessel disruption, however, tissue factor can form a complex with Factor VIIa to catalyze activation of Factor X activation or Factor IX in the presence of calcium ions and phospholipids. Factor VIIa, when complexed with human tissue factor at the site of blood vessel injury, can activate coagulation Factor X to Factor Xa, as well as coagulation Factor IX to Factor IXa.
Native Factor VII is a trace plasma protein. Purification of Factor VII from plasma in sufficient quantities to permit extensive sequence analysis and characterization remains difficult. Degradation of Factor VII occurs during purification, even in the presence of protease inhibitors. Due to these difficulties, Factor VII has been poorly characterized, compared to other more abundant components of the blood coagulation system. Factors VII (and Factor IX, prothrombin, Factor X, Protein C, and Protein S) requires vitamin K for biosynthesis. The amino-terminal portions of these proteins, which contain unique gamma-carboxyglutamic acid residues, are homologous in both amino acid sequence and in biological function. The carboxy-terminal portions of Factor VII, prothrombin, Factor IX, Factor X, and Protein C differ and determine their specific serine protease functions.
Companies.: NovoSeven was developed ZymoGenetics, Inc., then a subsidiary of Novo Nordisk A/S, later an independent company, now part of Bristol-Myers Squib (BMS; acquired in Oct. 2010). ZymoGenetics was spun-off from Novo Nordisk as an independent public company in 2002. It is manufactured by Novo Nordisk A/S, CBER/FDA est. no. 1261, at company facilities in Kalundborg and Gentofte, Denmark. The product is marketed in the U.S. by Novo Nordisk Pharmaceuticals Industries, Inc. and internationally by Novo Nordisk A/S. NovoSeven is marketed in all major pharmaceutical markets.
Manufacture: The gene for human Factor VII was cloned and is expressed in a transformed baby hamster kidney (BHK) cell line (apparently, ATCC CRL 1632 or ATCC CCL 10). The cells are cultured on microcarrier beads in conventional stirred large stainless steel fermenters/tanks in a continuous process, with media replaced/harvested daily and purified. Recombinant Factor VII is secreted into the culture media (which contains newborn calf serum) in its single-chain 406-amino acid form. The glycoprotein is purified by ion exchange and immunoaffinity chromatography using matrix-bound Factor VIIa murine (mouse) monoclonal antibody. During purification, the single-chain Factor VII is proteolytically converted by autocatalysis to the active two-chain form, Factor VIIa (rFVIIa), during chromatography purification. The recombinant Factor VIIa is formulated, filled into vials, lyophilized (freeze-dried), and sealed. The active substance is manufactured at Novo Nordisk facilities in Kalundborg, Denmark, with finishing at facilities in Gentofte, Denmark.
No human serum or other human products are used in the manufacture and formulation of NovoSeven. The final product essentially contains only one protein, rFVII. Bovine materials used in manufacture are sourced from countries not known to have BSE/TSE problems. The purification process has been shown to substantially remove exogenous viruses (MuLV, SV40, pox virus, reovirus, BEV, and IBR virus). Overall, the multiple chromatographic steps and one detergent-based step have been shown to reduce virus titers by ≥ 9.4 log. The chromatographic steps have been validated in scaled-down studies to remove model viruses such as bovine enterovirus (BEV), reovirus type 3, and simian virus 40 (SV40).
Contaminants as a result of the manufacturing process include trace amounts of hamster proteins from host cells; bovine proteins from bovine serum in the fermentation medium; and mouse immune globulin G (IgG) from the Factor VII monoclonal antibody used for purification.
Novo Nordisk was reported in summer 2002 to be undertaking efforts to expand NovoSeven manufacturing capacity and eliminate use of all animal products. This included adding another bioreactor and purification line, decreasing turnover between each culture batch, and reducing maintenance shut-down time. The company was also building a new manufacturing facility, and developing a new host cell line not requiring any animal components in culture media.
In Nov. 2011, to ease EU concerns about viral contamination, an unspecified nanofiltration step was added to the manufacturing process. By adding this layer of protection, Novo Nordisk reassured regulators that a cell-based assay is sufficient for batch testing for virus contamination.
FDA class: Biologic BLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19990325; BLA (no. 96-059); orphan designation (granted 06/06/1988; expired 3/2005)
Date = 20051200; BLA supplement; Indication = addition of warnings of thrombotic and thromboembolic adverse events
Date = 20061016; BLA supplement; Indication = approval for treatment of bleeding episodes in patients with acquired hemophilia, and in the prevention of bleeding in surgical interventions or invasive procedures in patients with acquired hemophilia
Date = 20080509; BLA supplement; Indication = approval of room temperature stable formulation, NovoSeven RT (VII25)
Date: 20100115; BLA supplement; Indication = addition to the product insert of a Black Box Warning concerning serious thrombotic adverse events associated with the use of NovoSeven RT outside labeled indications:.
Date = 20100810; BLA supplement; Indication = approval of NovoSeven RT in 8 mg vials
Indications: [full text of "Indications and Usage” section from product insert/labeling]:
NovoSeven is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX. NovoSeven should be administered to patients only under the direct supervision of a physician experienced in the treatment of hemophilia.
Status: NovoSeven is now marketed in all major pharmaceutical markets.
The BLA was originally filed on May 10, 1996. The FDA delayed approval of NovoSeven due to discussions concerning the underlying production technology. NovoSeven received full approval from FDA on March 25, 1999, after receiving priority review and orphan designation (providing limited approval/marketing exclusivity to March 25, 2005). NovoSeven was launched on April 14, 1999. NovoSeven is exempt from FDA CBER lot release requirements.
NovoSeven was approved by EMEA/European Union (EU) on Feb. 23, 1996. In Jan. 2005, Novo Nordisk filed for supplemental EU approval for control of critical bleeding and reduction of complications and intensive care requirements in severe blunt trauma patients, with approval expected by the end of 2005. In April 2005, Novo Nordisk received preliminary notice from EMEA/EU that additional clinical data would needed before NovoSeven can be approved for blunt trauma indications:. The company had filed for approval based on Phase II studies.. The company is conducting a confirmatory clinical trial.
In Dec. 2005, a warning letter was issued by FDA and the labeling/insert for NovoSeven was modified to warn of thrombotic and thromboembolic adverse events.
On Jan. 18, 2006, a study published in the New England Journal of Medicine reviewed reports of adverse events with NovoSeven in FDA’s Adverse Event Reporting System database from March 25, 1999 to Dec. 31, 2004. Among 431 adverse events, 168 described 185 thromboembolic events. About 151 reports were due to use of NovoSeven for off-label indications: in patients without hemophilia. NovoSeven was linked to 67 deaths since it was approved in 1999. The researchers called for randomized controlled trials in treating bleeding in non-hemophiliacs, the source of most complications, but also the area of largest sales growth potential.
On April 6, 2006, Novo Nordisk withdrew a pending supplemental application in the European Union (EU) for treatment of acute intracerebral hemorrhage (ICH) in adults after EU authorities had requested additional safety and efficacy data. Novo Nordisk planned to resubmit the application upon completion of an ongoing clinical trial. However, as discussed in the Trials section below, the primary endpoint was not attained in the pivotal Phase III ICH trial, and development of NovoSeven for this indication has been abandoned.
With its Oct. 2006 approval for acquired hemophilia, NovoSeven became the only recombinant therapy approved for the treatment of acquired hemophilia.
NovoSeven is being used by the U.S. military to treat critically wounded U.S. troops in Iraq, despite this being an off-label indication and common knowledge that NovoSeven can increase risk for clots that lead to strokes, heart attacks and death in other patients, including FDA issuing a warning letter and the labeling being modified, as discussed above. However, the Army medical command considers NovoSeven a medical breakthrough that gives front-line physicians a way to control deadly bleeding. Physicians in Iraq have used it in more than 1,000 patients (11/2006). Military doctors report patients requiring transfusions of 10 or more units of blood have a 25%-50$% chance of dying from their injuries, and that there is enough evidence of NovoSeven’s effectiveness to continue its use. As noted by one physician, “Patients who are hemorrhaging to death, they get the drug and it stops. Factor VII saves their lives.” However, military physician in Germany and U.S. have reported unusual and sometimes fatal blood clots in soldiers evacuated from Iraq, including unexplained strokes, heart attacks and pulmonary embolisms, or blood clots in the lungs; and some suspect NovoSeven is the cause. Determining the precise cause of blood clots is rarely possible, making it difficult to establish definitively whether NovoSeven is responsible for these adverse events. The U.S. military continues to use NovoSeven in Iraq (and presumably other areas of active combat).
On Aug. 20, 2010, FDA approved NovoSeven RT in an 8 mg vial size, making it available in 1, 2, 5 and 8 mg vials.
Tech. transfer: Patents concerning manufacture of recombinant Factor VII, including U.S. 6,329,176, “Method for the production of factor VII,” assigned to Novo Nordisk; and U.S. patent 4,784,950, “Expression of factor VII activity in mammalian cells,” assigned to Zymogenetics, Inc., than a subsidiary of Novo Nordisk. These describe recombinant Factor VIIa cloning and expression in mammalian host cells. Baby hamster kidney (BHK) cells are transfected with DNA with a nucleotide sequence encoding a calcium binding domain leader peptide and an amino-terminal portion of Factor VII joined to a second nucleotide sequence positioned downstream of the first sequence encoding the catalytic domain for the serine protease activity of Factor VIIa. The nucleotide sequence is followed downstream by a polyadenylation signal.
Because of the difficulty in obtaining a full-length cDNA clone of the Factor VII gene (due to the rarity of the protein and mRNA in humans), three novel approaches were adopted to develop this recombinant construct. First, a partial cDNA clone for Factor VII was joined to a fragment encoding the leader peptide and 5’ portion of Factor IX. This was based on the discovery that the calcium binding activity (and sequence) of Factor IX can substitute for that of Factor VII. The resultant polypeptide retains the biological activity of authentic Factor VII, because the specific serine protease activities of the coagulation factors reside in the carboxy-terminal regions of the molecules. Partial cDNA and amino acid sequences of Factor VII enabled the screening of a genomic DNA or cDNA library for clones comprising the 5’ portion of the Factor VII gene. A partial cDNA clone with a DNA sequence encoding the leader was then combined with the sequence for the amino-terminal regions of Factor VII. The cDNA fragment encoding the leader peptide of Factor IX was then joined with a synthetic gene segment encoding a consensus calcium binding domain or a predicted amino terminal sequence for Factor VII. Upon activation, the resulting recombinant Factor VIIa has substantially the same activity for blood coagulation as native Factor VIIa.
Several U.S. laws, particularly the Hatch-Waxman Act, allow for the extension of the period of patent-based marketing exclusivity for pharmaceuticals for up to five years to compensate for the time during which the product was under regulatory review. The patent office received a patent term restoration application from ZymoGenetics, Inc. for NovoSeven for U.S. Patent No. 4,784,950 to extend this patent for 1,826 days or 5.0 years (maximum allowed). On Jan. 25, 2003, FDA determined the regulatory review period for NovoSeven to be a total of 3,954 days – 2,904 days during the product’s testing period (IND granted May 29, 1988) and 1,050 days during the approval phase (BLA filing to approval). The term of 4,784,950 was presumably extended five years, into 2010. However, patent 6,329,176 appears to provide coverage into 2020.
Trials: The pivotal, double-blind, randomized trial with NovoSeven was conducted in hemophilia A and B patients with and without inhibitors for the treatment of joint, muscle and mucocutaneous hemorrhages. The average number of injections required to achieve hemostasis was 2.8 and 3.2 for the 25 µg/kg and 70 µg/kg groups, respectively. No direct comparison trials of NovoSeven with other coagulation products have been performed. Doses between 35 and 120 µg/kg were used successfully in clinical trials, and NovoSeven patients had fewer complications and spent less time in intensive care units than patients receiving conventional treatment.
In Dec. 2003, Novo Nordisk reported the first results from its Phase II study of the safety and efficacy of NovoSeven in trauma patients, showing that patients receiving treatment with NovoSeven needed significantly less red blood cell transfusion than patients receiving conventional treatment. Results from new analyses were reported in March 2005, with these supporting filing for supplemental approval in the European Union. Among 280 hospitalized patients with life-threatening bleeding and having already received transfusion of ~8 units of blood, patients treated with NovoSeven had fewer complications and spent less time in intensive care units than patients receiving conventional treatment. Overall mortality was lower in the group treated with NovoSeven. NovoSeven patients experienced improved bleeding control, measured by a significant reduction in the requirement of blood transfusions – an average of 2.6 red blood cell (RBC) units less than patients receiving placebo; and were 56% less likely to require massive blood transfusions of >20 units RBC. There were no difference between the two treatment groups in the number or types of serious adverse events, including thromboembolic events. NovoSeven significantly lowered incidences of acute respiratory distress syndrome (ARDS) and multiple organ failure, two common and potentially fatal complications after trauma; a trends were observed towards less Intensive Care Unit (ICU) and ventilator dependency in NovoSeven patients compared to placebo in both blunt and penetrating trauma.
Novo Nordisk is also conducting clinical trials of NovoSeven for bleeding in patients undergoing stem cell transplantation and liver transplantation.
In the Feb. 24, 2005, issue of the New England Journal of Medicine results were published from a study indicating NovoSeven could be a significant advance in treating bleeding stroke (acute intracerebral hemorrhage or ICH). Patients receiving NovoSeven within four hours of a hemorrhagic stroke had a significantly increased chance of survival and suffered less disabling brain damage than those not given the treatment. The primary outcome measure was the percent change in ICH volume (amount of blood entering the brain) at 24 hours. ICH volume growth in the 40, 80, and 160 µg/kg treatment groups (P=0.01, rFVIIa vs. placebo) was reduced by 45%, 52% and 62% compared to the placebo treatment group. Overall, NovoSeven patients had about half the amount of additional bleeding in the brain compared to placebo-treated patients. After 90 days, results found a 38% reduction in mortality and up to three times as many patients surviving with no major neurological deficits, compared to placebo. The proportion of patients treated with the 160 µg/kg dose of rFVIIa with no disability was 24%, compared to 8% in placebo. NovoSeven progressed into Phase III trials for ICH. If approved, it will become only the second emergency treatment for stroke in more than three decades, the first being tissue plasminogen activator (tPA; Activase).
Approval for inherited hemophilia indications: was largely based on pooled data analysis from NovoSeven’s Compassionate Use Programs and the Hemophilia and Thrombosis Research Society (HTRS) registry. NovoSeven demonstrated overall efficacy -- i.e., “effective” and “partially effective” outcomes -- in the majority (78%) of patients treated for bleeding episodes. This translates into 77% efficacy seen in the Compassionate Use Programs and 83% efficacy in the HTRS registry.
In Feb. 2006, it was reported that Novo was experiencing considerable problems, leading to delays, with its Phase III trial for Novoseven for treatment of trauma. Gunshoot wound and other trauma patients have not been in the mood or able to go through the informed consent and forms required to enroll in the clinical trial.
In Feb. 2007, disappointing results were reported from a Phase III trial of NovoSeven for the treatment of stroke-associated intracerebral hemorrhage (ICH). This was a randomized, double-blind, , double-blind, parallel group, placebo-controlled trial to evaluate the efficacy and safety of NovoSeven in severely injured trauma patients with bleeding refractory to standard treatment. Patients received three single doses of NovoSeven (200 µg/kg + 100 µg/kg + 100 µg/kg) or placebo after the transfusion of the fourth unit of red blood cells). The study had the primary endpoint of all cause 30-day mortality to show superiority of NovoSeven compared to placebo in blunt trauma patients. If not superior, the endpoint included an analysis to show non-inferiority of NovoSeven compared to placebo on all cause 30-day mortality and superiority of NovoSeven compared to placebo on pulmonary and/or renal dysfunction requiring ongoing medical intervention at day 30 in blunt trauma patients. NovoSeven significantly reduced intracerebral bleeding compared to placebo treatment. Improvement in clinical outcomes in terms of functional independence and neurological impairment was observed on day 15 after the bleeding. However, the primary endpoint, mortality, was not improved at the end of the study period (day 90). NovoSeven stopped bleeding and patients’ health improved after 15 days, and not after 90 days. With regard to safety, study results were in line with the established safety profile of NovoSeven.
In June 2008, Novo Nordisk discontinued the Phase III trial with NovoSeven for the treatment of bleeding in patients with severe trauma. The decision was made based on the results of an analysis for futility conducted by the independent Data Monitoring Committee. Due to an observed lower mortality than anticipated in the overall study group (around 10% in the trial in total compared to more than 25% in the Phase II trial), a futility analysis predicted a low likelihood of obtaining a positive trial outcome with the planned study population, and as a consequence, Novo Nordisk decided to discontinue the trial. The decision was not due to safety concerns. In its latest review of safety data in March 2008, the independent Data Monitoring Committee had recommended continuation of the study. The study had enrolled more than 550 patients of the planned 1,502 in 24 countries.
Medical: Prior to NovoSeven, the only options available for hemophilia A patients with inhibitors (antibodies) to Factor VIII or IX were high-dose Factor VIII treatment or use of inhibitor bypassing agents such as plasma-derived Factor IX Complex, prothrombin complex concentrates (PCC), porcine Factor VIII, or activated prothrombin complex concentrates (aPCC). See the entries for Hyate:C, Autoplex-T, and Atgam. Hemophilia B patients with inhibitors were usually treated with PCC or aPCC. Use of NovoSeven avoids the risk of severe allergic reactions and viral infection (e.g., HIV, hepatitis B and C viruses) due to human or animal clotting factors. NovoSeven also acts much quicker to achieve hemostasis, and has more predictable efficacy.
Both the dose and administration interval may be adjusted based on the severity of the bleeding and degree of hemostasis achieved. The minimal effective dose for NovoSeven has not been established.
Development of inhibitors (antibodies) to Factor VII is rare. No antibodies were detected in 72 patients followed in three clinical trials.
Disease: Of the estimated 20,000 people in the U.S. with hemophilia, approximately 1,500 have inhibitors (antibodies) to Factors VIII or IX. This restricts their use of human Factor VIII products, both recombinant and plasma-derived, and/or requires higher doses of Factor VIII to overcome (overwhelm) neutralization by antibodies. Prior to NovoSeven, for nearly thirty years, plasma-derived prothrombin complex concentrates (PCC) and porcine Factor VIII (Hyate:C) had been the only treatment options available in the U.S.
Trauma is defined as injury to the body and categorized into two groups. Blunt trauma is internal damage to the body caused by non-penetrating impacts, such as vehicle accidents and falls. Penetrating trauma is damage caused by penetration of the body by external objects, e.g., from stabbings and shootings. Blunt trauma accounts for roughly 80% of trauma cases in Western countries. Trauma is a growing health risk internationally. Trauma is a leading cause of death worldwide, particularly in the young. Roughly half of the five million people who die from trauma each year are aged 15-44. In 2002, road traffic accidents alone were responsible for a similar number of deaths as cancers of the lung, bronchus and trachea (1,239,000). By 2020, an estimated 8.4 million people will die annually as a result of trauma.
Acute intracerebral hemorrhage (ICH) is the third highest cause of death in the U.S, and stroke is the leading source of permanent disability. ICH is the deadliest and most disabling type of stroke, with 35-50% patients dying within one month, and only 20% regaining functional independence. ICH affects 15% of all stroke victims in the U.S., about 70,000 cases a year. In other parts of the world, the incidence of bleeding stroke is even higher--in Asia, ICH affects 30% of all stroke victims.
Acquired hemophilia appears in up to 4 persons per million per year. It disrupts the body’s natural blood clotting process, causing spontaneous, uncontrolled bleeding to occur, most often, in the skin and soft tissues. It is often difficult to recognize and can be fatal in up to 22% of patients. Unlike classical hemophilia, acquired hemophilia is not inherited, with the body producing antibodies against its own Factor VIII or Factor IX blood clotting proteins. The disorder can occur in men or women (median age 64). Often, an underlying medical condition is involved. Associations with autoimmune conditions, cancer, use of certain drugs and pregnancy (although rare) have been recognized. In about half of all cases, there is no identifiable underlying cause.
Market: Total 2007 worldwide sales of NovoSeven were 5.87 billion kroner ($1.12 billion on 9/8/2008); 5.635 billion Danish Kroner (~1.1 billion) in 2006, 5.1 billion Danish kroner (DKK; ~$818 million on 2/9/06) in 2005; $4.395 billion DKK (est. $748.58 million) in 2004, and $511 million in 2002; DKK 2,270 million (est. $415 million) in 2000; and DKK 1,313 million (est. $240 million) in 1999. In Nov. 2006, Novo Nordisk reported, “The worldwide market for recombinant Factor VII was approximately $850 million in 2005, with Novo Nordisk being the only participant.”
The market for NovoSeven could have increased dramatically, if it were approved and widely used for intracerebral hemorrhage (stroke; ICH) and/or trauma, with either indication potentially easily pushing sales over $1 billion/year (blockbuster status). In late 2005, some analysts estimated that worldwide sales of all Factor VIIa products could exceed $2 billion by 2010. However, the market for NovoSeven will not grow dramatically based on approvals for these new indications:, since NovoSeven has been abandoned for stroke/ICH and is experiencing problems with trials for trauma treatment (see the Trials section above).
The 2007 Average Wholesale Price (AWP) is $1.58/µg irrespective of presentation, e.g., $1,896/1.2 mg vial, $3,792/2.4 mg vial, and $7,584/4.8 mg vial (Red Book, 2007). For comparison, the 2005 AWPs were based on $1.48/µg, , e.g., $1,776/1.2 mg vial, $3,552/2.4 mg vial, and $7,104/4.8 mg vial. This is unchanged from 2004. Medicare reimbursement is set at $1,596,00/vial ($1.33/µg) for 1.2 mg vial for inpatient and home care, and at $1.01/IU for outpatient care.
The Estimated Acquisition Costs (for hospitals, treatment centers) is $0.78-0.97/IU [from NHF].
In Nov. 2006, it was reported, in the context of treating severe trauma patients among U.S. military in Iraq, that NovoSeven typically cost $6,000/dose.
In its March 22, 2006 price list, FFF Enterprises, a major biologics distributor, reported its price as $0.98/IU ($0.91 in 2005; $0.89/IU in March 2004).
In Aug. 2010, it was reported that NovoSeven typically costs over $6,000/dose (bulk sales). In late 2005, it was reported that NovoSeven typically costs about $7,500 per dose (unless referring to the 4.8 mg vial). A wholesale cost for NovoSeven of about $6,800/vial (apparently, then referring to the 4.8 mg vial), was reported in an Aug. 2, 2001, front-page article in the Wall Street Journal about a rare case of a hemophilia A patient with acquired Factor VIII inhibitors (antibodies) who needed surgery and had a hospital bill including $1.9 million for NovoSeven (and $2.9 million for Hyate:C).
In the June issue of Annals of Internal Medicine, 2 studies reported problems with Novoseven, with only 3% of Novoseven use used by U.S. patients within the specific indications, with 97% used off-label in hospitals. However, none of these applications was found to make patients any less likely to die than those who didn’t receive Novoseven. The research looked at treatment records in 615 U.S. hospitals from 2000 to 2008 and examined 64 studies of NovoSeven to assess outcomes and side effects.
Companies involvement:
Full monograph
145 Factor VIIa, rDNA
Nomenclature:
Factor VIIa, rDNA [BIO]
NovoSeven [TR assigned to Novo Nordisk A/S]
Coagulation Factor VIIa (Recombinant) [FDA]
Coagulation Factor VIIa [Recombinant] Room Temperature Stable [FDA]
Coagulation Factor VIIa (Recombinant) Room Temperature Stable, Lyophilized Powder [FDA]
eptacog alfa (activated) [INN]
activated Factor VII [SY]
FVIIa, recombinant [SY]
rFVIIa [SY]
VII25 [SY for room termp. stable formulation]
NDC 0169-7060-01 and 0169-7062-01 [NDC]
molecular weight (kDa) = 50
FDA Class: Biologic BLA
Year of approval (FDA) = 1999
Date of 1st FDA approval = 19990325
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2011, as reported by Novo Nordisk); 2019, if process patent 6329176 applies |
U.S. Patent Expiration Year: | 2011 |
U.S. Biosimilars Data Exclusivity Expiration: | 2011 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2006 |
U.S. Biosimilars Launchability Year: | 2011 |
U.S. Biobetters Launchability Year: | 2011 |
Biosimilars/biobetters-related EU Patents: | 2011, as reported by Novo Nordisk
2019, if EP 1127154 process patent applies |
EU Patent Expiration Year: | 2011 |
EU Biosimilars Data Exclusivity Expiration: | 2006 |
EU Biosimilars Orphan Exclusivity Expiration: | 2006 |
EU Biosimilars Launchability Year: | 2011 |
EU Biobetters Launchability Year: | 2011 |
Index Terms:
antihemophilic factors
biopharmaceutical products
blood products
bovine materials used<!-- bovinesource -->
exempt from CBER lot release requirements
hamster source materials
murine (mouse) materials used
recombinant DNA
rodent source materials
baby hamster kidney (BHK) cells
bovine serum
keratinocytes, human
mammalian cell culture
mice, Viral Antigen Free
rodent cells <!-- rodentcells -->
baby hamster kidney proteins
bovine IgG
calcium chloride
Factor VIIa murine monoclonal antibody
glycylglycine
immunoaffinity chromatography
International Standard of Factor VIIa 89/688
lyophilized (freeze-dried)
mannitol
methanol
murine immune globulin
murine monoclonal antibody, Factor VII
polysorbate 80 (Tween 80)
sodium chloride
Sterile Water for Injection
sucrose
virus culture
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
exempt from CBER lot release requirements
orphan status
priority review status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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