Status: approved; marketed

Organizations involved:

CSL Bioplasma, Inc. – USA mark.

CSL Bioplasma AG – Manuf.; R&D; Tech.; Intl. mark.; Parent

CSL Ltd. – Parent

Aventis Behring GmbH – Former

Behringwerke AG – R&D; Tech.; Former

Aventis Behring LLC. – Former

Armour Pharmaceuticals – R&D; Tech.; Former

Cross ref: See the Factor VIII Products entry (#715). See also other Factor VIII:vWF entries, e.g., Koate-DVI (#724) and Alphanate (#725).

Description: Antihemophilic Factor/von Willebrand’s Factor Complex (Human), Dried, Pasteurized or Humate-P is a lyo-phi-lized (freeze-dried) formulation of a natural noncovalently bound complex of Antihemophilic Factor (Human) or Factor VIII with von Willebrand’s factor (vWF), i.e., Factor VIII:vWF, manufactured from pooled Plasma, with manufacture including viral inactivation using a wet heat pasteurization method. The Factor VIII:wWF complex is the major form in which Factor VIII exists in vivo, with the von Willebrand’s factor acting to stabilize Factor VIII against degradation and proteolysis. Unlike most other Factor VIII products, Humate-P also contains vWF multimers, including high molecular weight multimers of vWF essential for treatment of patients with von Willebrand’s disease (hemophilia B) in which patients express insufficient functional vWF. The hemostatic effect of vWF in wWF disease patients is correlated with the content of high molecular weight vWF multimers present in the Factor VIII:vWF preparation. Humate-P is highly purified and contains low amounts of non-coagulation factor proteins. Fibrinogen is present at < 0.1 mg/mL.

After reconstitution (original formulation), each mL of Humate-P contains 20-40 IU Factor VIII activity, 50-100 IU vWF:RCo activity, 15-33 mg of glycine, 3.5-9.3 mg of sodium citrate, 2-5.3 mg of sodium chloride, 4-8 mg of Albumin (Human), 1-7 mg of other proteins, and 5-15 mg of total proteins. Humate-P is supplied in single dose vials along with Sterile Water for Injection, USP diluent, a sterile transfer set for reconstitution, a sterile filter spike for withdrawal, and alcohol swabs. The dating period for the product is 24 months from the date of manufacture when stored at 2-8˚C. Within this period, Humate-P may be stored at room temperature, not to exceed 30˚C, for up to six months. The date of manufacture is the date of first final sterile filtration of the bulk product.

Viral inactivation involves wet heat pasteurization at 60˚C for 10 hours. This processing, combined with a high level of viral inactivation during the overall manufacturing process, provides a mean cumulative total viral reduction capacity of up to 17.0 log or greater for HIV, ≥ 17.8 log for HSV-1 and ≥ 16.3 log for poliovirus.

In Feb. 2006, a new formulation using 50% less diluent (doubling concentration after reconstitution) was launched in the U.S. The new formulation has the same safety and efficacy profile of Humate-P, but offers added convenience to patients, healthcare professionals, and caregivers. The smaller diluent vial size means that patients can spend less time receiving their infusions; and vial and package sizes of the product are now smaller, required less storage space. The new formulation is packaged in 250, 500 and 1,000 IU vials, along with 5, 10 and 15 mL vials of Sterile Water for Injection diluent, respectively. After reconstitution (new formulation), each mL of Humate-P contains 40-80 IU Factor VIII activity, 72-224 IU vWF:RC activity, 15-33 mg of glycine, 3.5-9.3 mg of sodium citrate, 2-5.3 mg of sodium chloride, 8-16 mg of Albumin (Human), 2-14 mg of other proteins, and 10-30 mg of total proteins.

Nomenclature: Factor VIII:vWF/CSL [BIO]; Humate-P [TR]; Antihemophilic Factor/von Willebrand’s Factor Complex (Human), Dried, Pasteurized [FDA]; Antihemophilic Factor (Human) [FDA former, prior to 1999 approval]; Antihemophilic Factor, Human [former USAN]; Blood-coagulation factor VIII, complex [CAS]; 9001-27-8 [CAS RN]; Factor VIII:von Willebrand’s factor complex [SY]; Factor VIII:vWF complex [SY]; Haemate P [TR Foreign]

The proper (FDA) name of the product was only recently changed to describe it as Factor VIII:vWF complex, with the approval of Humate-P for vWF disease, while similar products (lacking vWF multimers and not approved for treatment of von Willebrand’s disease) still retain the proper name Antihemophilic Factor (Human).

Biological.: The content of vWF in Humate-P is determined by von Willebrand’s Factor:Ristocetin Cofactor (vWF:Rcof) activity and vWF-Antigen tests. Each vial contains a labeled amount of Factor VIII in international units (IU), along with a labeled amount of vWF:Rcof expressed in IU. The vWD:Rcof assay is based on the ability of vWF to aggregate platelets in the presence of the antibiotic ristocetin A. This activity reflects a physiological function of vWF and is commonly accepted as a means to quantify the vWF potency of Factor VII:vWF preparations. The vWF-Antigen assay uses an electrophoresis method to detect vWF by formation of wWF antigen-antibody complexes. These two tests were added to lot release specifications with the product’s approval for the von Wille-brand’s disease indication.

Companies.: The product was originally developed and is manufactured by Behringwerke AG, FDA CBER est. no. 0097, which became Centeon Pharma GmbH (subsidiary of Rhone-Poulenc Rorer), which became Aventis Behring GmbH, FDA CBER est. no. 1287, which was merged into CSL Ltd. to form ZLB Behring AG, which was renamed CSL Bioplasma. Humate-P is manufactured by CSL facilities in Marburg, Germany. Humate-P is marketed in the U.S. by CSL Bioplasma LLC. and internationally by CSL Behring AG, both subsidiaries of CSL Ltd..

Manufacture: Humate-P is manufactured from Plasma products obtained from licensed facilities in the U.S. Plasma-derived cryoprecipitate undergoes adsorption with aluminum hydroxide followed by glycine and sodium chloride precipitation. The resultant precipitate is wet heat treated (pasteurized) at 60˚C for 10 hours in the liquid-state in the presence of stabilizers prior to a second sodium chloride precipitation. Albumin (Human) is added before lyophilization.

Overall, the manufacturing process has been shown to have a mean cumulative viral reduction capacity of ≥17.0 log for HIV; ≥17.8 log for HSV-1; and ≥16.3 log for poliovirus. In multiple studies, the heat inactivation process was shown to reduce HIV by ≥ 5.4, 6.3, and 6.8 log to undetectable levels (at the time of the study; protocol not disclosed). Studies of the heat inactivation process using three model enveloped viruses [herpes simplex virus type 1 (HSV-1); bovine viral diarrhea virus (BVDV); and cytomegalovirus (CMV)] and one non-enveloped virus (polio virus) have shown: HSV-1 reduction by ≥ 5.8, 7.2 and 7.3 log to undetectable levels; BVDV reduction by ≥ 4.8 and 5.4 log to undetectable levels; CMV reduction by ≥ 6.0 log to undetectable levels; and poliovirus reduction by ≥ 7.1 and 7.3 log to undetectable levels. The manufacturing processes, exclusive of heat virus inactivation, have been shown to reduce HIV by ≥ 10.8 log, HSV-1 by ≥ 11.1 log, and poliovirus by ≥ 9.1 log. Reduction/inactivation of hepatitis B virus (HBV) was confirmed in two chimpanzee studies; and reduction in hepatitis C virus (HCV) was confirmed in one chimpanzee study (with these in vivo studies apparently done prior to modern PCR/NAT assays).

In May 2000, Aventis Behring, now CSL Bioplasma, was the first North American manufacturer of plasma products to exclusively use plasma released after proprietary investigational polymerase chain reaction (PCR; Nucleic Acid Testing or NAT) screening for HIV-1, hepatitis B virus, and hepatitis C virus. In 2000, Aventis Behring also added PCR screening for parvovirus B19 and hepatitis A viruses, making them then the first company in the world to screen plasma using proprietary investigational PCR screening for five viruses (HIV-1, hepatitis B, hepatitis C, parvovirus B19, and hepatitis A).

FDA class: Biologic PLA

CBER class: Blood And Blood Derivatives

Approvals: Date = 19960824; original PLA granted for Antihemophilic Factor (Human) manufactured by Centeon Pharma GmbH (in addition to Centeon LLC); Indication = hemophilia A

Date = 19990401; licenses (PLA/ELA) for Antihemophilic Factor (Human) revoked and new licenses (PLA/ELA), PLA ref. no. 96-1099, granted to Centeon Pharma GmbH, with addition of a new indication (von Willebrand’s disease) and change to a new FDA proper name, Antihemophilic Factor/von Willebrand’s Factor Complex (Human); orphan designation (granted 10/16/1992 for vWF disease)

Date = 20000411; licenses (PLA/ELA) revoked from Centeon Pharma GmbH and granted (reissued) to new owner, Aventis Behring GmbH

Date = 20000929 (date announced); supplemental approval for adding statement to product insert/labeling; Indication = “The plasma used in the manufacture of this product has been tested and found negative for HBV [hepatitis B virus], HCV [hepatitis C virus], and HIV-1 by an investigational test procedure referred to as Nucleic Acid Testing (NAT) using Polymerase Chain Reaction (PCR) technology. Investigational testing is being performed to determine the effectiveness of NAT to detect low levels of viral material. The significance of a negative result is unknown since the effectiveness of the test has not been established.”

Date = 20050215 [launch, not approval, date]; BLA supplement; Indication = approval of a new formulation with a smaller amount of diluent

Date = 20070427; BLA supplement; Indication = for the second-line prevention of excessive bleeding during and after surgery in certain patients with mild to moderate and severe von Willebrand disease (vWD).

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling; 5/2007]:

Humate-P, Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, is indicated in adult patients for treatment and prevention of bleeding in hemophilia A (classical hemophilia). Humate-P is also indicated in adult and pediatric patients with von Willebrand disease for (1) treatment of spontaneous and trauma-induced bleeding episodes and (2) prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin is known or suspected to be inadequate.

Controlled trials to evaluate the safety and efficacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects. Adequate data are not presently available on which to evaluate or to base dosing recommendations in this setting.

Status: Humate-P (Haemate-P outside of U.S.) has been approved for hemophilia A in over 30 countries.

Tech. transfer: U.S. 4,876,241, “Stabilization of Biological and Pharmaceutical Products During Thermal Inactivation of Viral and Bacterial contaminants,” Oct. 24, 1989, assigned to Armour Pharmaceutical Co. (later Aventis Behring, now CSL Bioplasma), describes the wet heat pasteurization method used for viral inactivation of Humate-P. Solubilized proteins (e.g., Factor VIII:vWF) are stabilized during thermal (heat) viral inacti-vation by mixing the product in an aqueous solution with mono-, di-, or tri-saccharides or sugar alcohol stabilizers (e.g., glucose, sucrose, xylose, fructose and mannitol) and neutral salt stabilizers (e.g., sodium acetate, potassium acetate, lithium acetate, magnesium acetate). This wet (liquid state) heat pasteurization method of viral inactivation has been shown to substantially inactivate cytomegalovirus, Epstein-Barr virus, herpes simplex virus, poliovirus, vaccinia virus, hepatitis B virus, hepatitis C virus, and HIV. Also, neoantigens are not formed during this liquid-state pasteurization.

Trials: In its pivotal Phase III study in von Willebrand’s disease (vWD) patients, approximately 95% of both pediatric and adult patients reported an excellent or good response to Humate-P in regard to the control of bleeding episodes. Currently, not enough evidence exists from clinical trials to evaluate the efficacy of Humate-P in preventing spontaneous or excessive bleeding related to surgery in vWD patients (although the product is used for this indication in patients lacking alternatives).

The April 2007 FDA approval for prevention of excessive bleeding during and after surgery in certain patients with mild to moderate and severe von Willebrand disease (vWD) was primarily based on a study of Humate-P in 35 patients suffering from vWD who underwent a total of 28 major and seven minor surgical procedures. The product was judged excellent or good in 91% of the patients who avoided severe hemorrhage. The most common adverse reaction following surgery was hemorrhage, in 30% of the patients; however, only 9% of the hemorrhages were classified as severe. Other adverse reactions in patients following surgery included nausea (24%) and pain (17%).

Disease: von Willebrand’s disease (vWD) is the most common genetic or hereditary bleeding disorder, affecting approximately 1% of the U.S. population. It is caused by a deficiency or defect in certain plasma proteins (vWF) critical to blood clotting. In persons with von Willebrand’s disease (vWD), the disease is usually mild and treatment is not required to control bleeding. However, approximately 2,000 people in the U.S. each year suffer from severe forms of the disease where bleeding can be excessive if not treated.

Market: The 2007 Average Wholesale Price (AWP) is $1.00/IU for all vial sizes (Red Book, 2007).

Medicare reimbursement is set at $0.95/IU for inpatient and home care, and $1.01/IU for outpatient care. Estimated Acquisition Costs (for hospitals, treatment centers) is $0.67-$0.88/IU (NHF survey).

In its March 22, 2006 price list, FFF Enterprises, a major biologics distributor, reported its price as $0.78/IU ($0.77 in 2005).

In June 2003, Aventis Behring launched the Choice Assurance Program. At the time (and, perhaps, still), there was no other similar program in the U.S. Enrolled patients earn one Assurance Award Certificate for every three consecutive months they use one of Aventis Behring’s Factor VIII or IX products (or IVIG). Each Certificate can be redeemed for one month’s worth of free product, based on the average monthly usage by the patient, in the event of a lapse in insurance. Patients can earn up to four months of free product after only a year in the Program and up to a full year after three years in the Program.

Competition: The market for this product for its von Willebrand’s disease (vWD) indication is very small, apparently at most several thousand patients. The drug desmopressin acetate (DDAVP) is an effective treatment for some forms and patients with vWD and is used by many patients. DDAVP may be administered as a nasal spray (Stimate from Ferring Pharmaceutical) or by injection. However, DDAVP is not fully effective or tolerable for many patients, and about 600 vWD patients in the U.S., require administration of vWF. Humate-P is the only plasma-derived product approved for treatment of von Willebrand’s disease. Other similar Factor VIII:vWF products, e.g., Koate-HP and Alphanate, may sometimes be used off-label for vWD. Cryoprecipitated AHF (entry #716) or crude coagulation factor Plasma precipitates, generally prepared locally by blood banks, have been used for treatment of von Willebrand’s disease, but this is no longer recommended. Highly purified Factor VIII products, e.g., those purified using monoclonal antibodies and recombinant Factor VIII products, do not contain uncomplexed high molecular weight von Willebrand’s Factor and are not useful for treatment of von Willebrand’s disease.