Status - approved by FDA in Feb. 2008; approved in EU in March 2009; replacing (next generation version of) ReFacto

Organizations involved:

Wyeth - Manuf. other; R&D; Tech.; World mark.

Biovitrum AB - Manuf.; R&D; Tech.; Europe mark.

Bayer Corp. - Tech.

Dyax Corp. - Tech.

New York Blood Center, Inc. - Tech.

Behringwerke AG - Tech.; Former

CSL Behring GmbH - Tech.

CSL Ltd. - Parent

Genentech, Inc. - Tech.; Patent dispute

Columbia University - Tech.; Patent dispute

Cross ref: See the entry above for ReFactor, which contains the same active agent (recombinant Factor VIII SQ), which is being replaced by Xyntha. See also the Factor VIII Products entry in the Blood Products, Human section, and the other Factor VIII product entries.

Description: Antihemophilic Factor (Recombinant), Plasma/Albumin-Free or Xyntha is a lyophilized (freeze-dried) formulation of a mutein (modified form) of recombinant Factor VIII glycoprotein (rVIII SQ) expressed by a transformed Chinese hamster ovary (CHO) cell line, with purification including peptide ligand resin (TN8.2)-based affinity chromatography, viral inactivation by a solvent-detergent process, and and manufacture and formulation without addition of Albumin (Human) as a stabilizer or use of any other animal- or human-derived products.  

The active agent (bulk drug substnace) in Xyntha is rVIII SQ, the same active agent in ReFacto, which is being replaced by Xyntha. rVIII SQ is essentially Factor VIII with most of the nonessential B-domain portion of the Factor VIII glycoprotein deleted. rVIII SQ, a 170 kDa glycoprotein, is comparable to the smallest active form of naturally occurring, active, human Factor VIII, with a sequence comparable to the 90+80 kDa form of Factor VIII. See the entries for ReFacto (above) and Factor VIII Products (in the Blood Products, Human section). Removal of the B--domain of the protein facilitates manufacture of a product with a higher specific activity (higher activity per weight) and provides a stable molecule not requiring addition of Albumin (Human) as a stabilizer in the final product. ReFacto and Xyntha are the only hemophilia A therapies indicated for short-term routine prophylaxis.

Note, FDA review documents state that the active bulk drug substance, recombinant Factor VIII SQ, in the former ReFacto and current Xyntha product are the same (for regulatory and all practical purposes). The major (or only) differences between the ReFacto and its follow-on, Xyntha, is that the rVIII-SQ for ReFacto was produced from CHO cells cultured in media containing bovine albumin, while rVIII-SQ for Xyntha involves culture in serum-, albumin- and animal product-free medium; and the immunoaffinity purification of rVIII-SQ for ReFacto used a chromatography medium-bound murine monoclonal antibody with affinity for rVIII-SQ, while that used for Xyntha involves a custom synthetic peptide, TN8.2, with affinity for rVIII-SQ. Manufacture without Albumin (Human) obtained from pooled human blood plasma as a protein/formulation stabilizer and/or cell culture nutrient, and without use of other mammal-derived products, theoretically, reduces risk for transmission of difficult-to-inactivate viruses, such as parvo-virus B19, and possibly prions, including transmissible spongi-form encephalitis (TSE) agents.

Other changes with Xyntha relative to ReFacto are that the potency expressed in International Units (IU) is now determined using the chromogenic assay of the European Pharmacopoeia; and a virus-retaining filtration step was added. The Wyeth manufacturing reference standard for potency has been calibrated against the World Health Organization (WHO) 7th FVIII International Standard (IS) for Factor VIII activity using a one-stage clotting assay. This reference standard replaces the one used with ReFacto that was calibrated against the 6th IS using a chromogenic substrate (CS) assay. Moroctocog alfa (AF-CC), the bulk drug substance, is released for further manufacture using a CS assay performed in accordance with the European Pharmacopoeia Assay of Blood Coagulation Factor VIII. The specific activity of Xyntha is 5,500 to 9,900 IU/mg of protein (numerically lower than that for ReFacto). Xyntha contains trace amounts of hamster proteins.

Xyntha (like ReFacto) is packaged as a lyophilized powder in vials nominally containing 250, 500, 1000 or 2000 IU of rVIII SQ for reconstitution (with 4 ml of 0.9% w/v sodium chloride solution) for intravenous injection, along with a double-ended needle, alcohol swabs, filter needle, infusion set, and disposable diluent-filled syringe. Excipients in Xyntha are sucrose, calcium chloride, L-histidine, polysorbate 80 (Tween 80), and sodium chloride (amounts/concentration not reported). The dating period for Xyntha is 24 months from the date of manufacture when stored at 2-8ûC (refrigerated), and it may be stored at room temperature not to exceed 25 ¡C (77ûF) for up to 3 months. The expiration date for the packaged product plus the diluent in a pre-filled syringe is the shortest expiration date of any component.

Nomenclature: Factor VIII, rDNA, new/Wyeth [BIO]; Xyntha [TR]; Antihemophilic Factor (Recombinant), Plasma/Albumin-Free [FDA]; moroctocog alfa [USAN INN]; moroctocog alfa (AF-CC) [SY; used unofficially by FDA]; recombinant coagulation Factor VIII SQ [SY]; rVIII-SQ [SY]; r-VIIISQ [SY]; B-domain deleted recombinant Factor VIII [SY]; BDDrFVIII [SY]; BDD-rFVIII [SY]

Companies: ReFacto was developed and is marketed worldwide by Wyeth (CBER/FDA est. no. 0003). In 2008, Xyntha is replacing ReFacto in the Wyeth product line (see entry above).

As with ReFacto, Biovitrum AB continues to manufacture Xyntha for Wyeth under contract at its facilities in Stockholm, Sweden, originally Pharmacia AB. Public FDA Xyntha review-related documents redact (censor) this information about the identity and location of Xyntha manufacture. Presumably, as with prior ReFacto, Biovitrum will co-promote ReFacto in the Nordic area and the Middle East.

Manufacture: The transformed CHO cell line is grown in a chemically defined cell culture medium that contains recombinant insulin, and does not contain any materials derived from human or animal sources. The CHO cells are continuously cultivated and harvested. The production cell line for rVIII SQ for ReFacto had been adapted to use defined growth medium containing recombinant human insulin with no Albumin (Human). Presumably, the production cell line for (rVIII SQ for Xyntha is a new one (perhaps, accounting for the full vs. supplemental BLA) adapted for growth in medium without albumin (with recombinant insulin retained as a component).

Cell culture is performed in a 500 L fermentor vessel in a continuous perfusion mode, involving continuous culture and harvesting of culture medium for Factor VIII SQ purification, and reintroduction of fresh medium. Approximately 500 L of culture media is exchanged daily. The original medium (for manufacture of ReFacto) was s well-defined with 60 components and free of antibiotics and serum, but containing Albumin (Human) meeting European Pharmacopeia specifications. The current medium (for manufacture of Xyntha) is well-defined with 60 components and is antibiotic-, serum- and Albumin (Human)-free.

According to the FDA review Chairpeson's Summary of Approval, " There were no major changes to the manufacturing process used to make the ReFacto final drug product (FDP) for moroctocog alfa (AF-CC)," and FDA considers the moroctocog alfa formulated in ReFacto and moroctocog alfa (AF-CC) in Xyntha to be the same.

FDA class: Biologic BLA

Approvals: Date = 20080221; BLA (BL 125264/0)

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

1.1 Control of Bleeding Episodes in Hemophilia A

XYNTHA Antihemophilic Factor (Recombinant), Plasma/Albumin-Free is indicated for the control and prevention of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency or classic hemophilia).

XYNTHA does not contain von Willebrand factor, and therefore is not indicated in von Willebrand's disease.

Status: Wyeth submitted a BLA (or sBLA, with this unclear) under STN 125264 for moroctocog alfa (AF-CC) on 25 April 2007, and received full BLA approval on 6 March 2000. FDA approval documents state that the active agent in Xyntha is moroctocog alfa AF-CC or BDDrFVIII produced by albumin-free cell culture (AF-CC), with the active agent designated moroctocog alfa (AF-CC), which the active agent in ReFacto is moroctocog alfa.

Xyntha received full BLA, not sBLA, approval despite clearing being an updated version of ReFacto. This raises a number of issues related to proposed legislation to enable FDA approvals of biosimilar or follow-on products. Earlier FDA review public documents clearly refer to filing of a sBLA, while later review documents refer to a full BLA, with a full BLA eventually granted. What prompted this change in application type is unclear, including what differences or changes with Xyntha, relative to ReFacto, resulted in its approval with a full vs. supplemental BLA, which traditionally have handled such non-major product manufacture and formulation changes. As recent as Sept. 27, 2007, FDA documents refer to the application for Xyntha as a supplemental BLA for ReFacto, while FDA documentation dated Jan. 1, 2008, shows the application as a full BLA. Much Congressional legislation (in late 2008) concerning enabling biosimilar/FOBs approvals proposes 5-14 years of data/marketing exclusivity granted by FDA to new/reference products, with this defined based on full/original BLA approval. But, as illustrated by Xyntha, with FDA essentially recognizing moroctocog alfa (AF-CC) in Xyntha as being the same as moroctocog alfa in ReFacto, and also illustrated by multiple other recent approvals, including where new/full BLAs were granted to biologics simply for new indication (absolutely no change in the active agent or formulated product), BLAs obviously need not involve what most would consider a substantially new or different product. So, determining current criteria, if any, for what qualifies a follow-on/modified product, e.g., Xyntha, for a full vs. sBLA will be very important.

With Xyntha being so similar or substantially identical to ReFacto and with Factor VIII products presumed to be so well-understood, FDA did not bother to have the BLA considered by the Blood Products Advisory Committee (BPAC).

Xyntha is is exempt from the CBER/FDA lot release requirement of 21 CFR 610.2, i.e., Wyeth can release and market the product without needing final testing of the product and approval by FDA.

Xyntha, upon approval, was the only recombinant factor VIII treatment to utilize an entirely synthetic purification process.

On March 16, 2009, the European Union (EU) granted MAA approval to ReFacto AF for the treatment and prophylaxis of bleeding in adults and children of all ages with haemophilia A.

Tech. transfer: See the Factor VIII Products entry in the Blood Products, Human section (and other Factor VIII entries) for discussion of Factor VIII patents and technology transfer.

The product insert cites U.S. patents 4,868,112; 5,733,873; 5,919,766; 6,005,082; 6,492,105; 5,831,026; 5,378,612.

U.S. 4,868,112, " Novel procoagulant proteins," assigned to Genetics Institute, Inc., now Wyeth, claims Factor VIII molecules with a substantial portion deleted, including the amino acid sequence for Factor VIII SQ.

U.S. 5,733,873 and 5,919,766, "Composition comprising coagulation factor VIII formulation, process for its preparation and use of a surfactant as stabilizer, are assigned to Pharmacia & Upjohn AB, now Biovitrum AB. This concerns Factor VIII formulation containing a non-ionic surfactant e.g., block copolymers, e.g., polyoxamers or polyoxyethylene, e.g., polysorbate 80 as stabilizer. The compositions can also included sodium chloride, calcium chloride, L-histidine and/or sugars or sugar alcohols.

U.S. 6,005,082, "Process for purification of factor VIII," assigned to Genetics Institute, Inc., now Wyeth, includes claims for Factor VIII purification using hydrophobic interaction chromatography (HIC) gels (gel permeation chromatography) in the presense of a surfactant.

U.S. 5,831,026, "Process for purifying factor VIII," assigned to Pharmacia & Upjohn AB, now Biovitrum AB, concerns methods for reducing degradation of recombinant coagulation Factor VIII caused by metal-dependent proteases requiring Zn2+ for activity or containing Zn2+ as an integral part of their structure by adding an inhibitor of Zn2+ dependent proteases to a Factor VIII in solution, including use of L-histidine as a complexing agent. 

In mid-2001, Genetics Inst./Wyeth exclusively licensed from Dyax Corp. proprietary synthetic peptide ligands designed to have high capacity and binding affinity for rVIII SQ. These ligands were identified using phage display technology from Dyax (see the DX-88 entry for further information). These are used for affinity chromatography purification of rVIII SQ (replacing the murine monoclonal antibody originally used for immunoaffinity chromatography purification). U.S. 6,492,105, "Binding molecules for human factor VIII and factor VIII-like proteins," assigned to Dyax, includes claims for polypeptides with binding affinity for Factor VIII. U.S. 6,326,155, "Engineering affinity ligands for macromolecules," assigned to Dyax, includes claims for methods for identifying affinity ligands to purify biological molecules. Under the terms of its license agreement with Wyeth, Dyax receives a milestone payment triggered by the first commercial sale, followed by royalties based on certain pre-determined sales levels

Solvent detergent viral inactivation technology was developed by and nonexclusively licensed from the New York Blood Center. For example, see U.S. 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) for further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).

Genetics Inst./Wyeth in 2000 licensed from Aventis Behring GmbH, now CSL Behring AG, technology for the manufacture of high purity Factor VIII without stabilization using Albumin (Human). This includes U.S. 5,565,427 and other "Freudenberg" patents, origin-ally assigned to Behringwerke AG (later Aventis Pharma, now Sanofi Aventis S.A.) for which CSL also has certain rights through licensing or co-assignment. These patents includes claims use of amino acids, non-ionic detergents and a carbohydrate (e.g., sucrose), to stabilize Factor VIII. For example, U.S. 5,565,427 (EP 508 194) describes Factor VIII preparations containing combinations of detergent and amino acids, specifically arginine and glycine, in addition to excipients such as sodium chloride and sucrose.

Wyeth (originally Genetics Inst.) was a licensee of Columbia University's patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. Presumably, Wyeth paid (or reimbursed) royalties for Factor VIII manufacture by Pharmacia/Biovitrum. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Wyeth and other companies challenged in court. More recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the Tech. transfer section of the Recombinant DNA Products entry (#100) for further information.

Trials: The efficacy of Xyntha was evaluated in a study in which subjects received Xyntha on a prophylaxis treatment regimen, with on-demand treatment administered as clinically indicated. Ninety-four (94) subjects were enrolled and treated with at least one dose, and all were included in the intent-to-treat (ITT) population. Eighty-nine (89) subjects accrued ³ 50 exposure days. From the 94 subjects enrolled, 30 evaluable subjects participated in the PK study (see next paragraph) and received at least 1 PK dose. Twenty-five subjects with FVIII:C ² 1% completed both the first (PK1) and the second (PK2) assessments. All subjects had ³150 previous exposure days with baseline FVIII activity level of ² 2%. In the open-label safety and efficacy period, all 94 subjects received Xyntha for routine prophylaxis at the dose of 30 ± 5 IU/kg 3 times a week with provisions for dose escalation based on pre-specified criteria. Forty-three of 94, i.e. 45.7%, subjects reported no bleeding while on routine prophylaxis. The median annualized bleeding rate (ABR) for all bleeding episodes was 1.9 (mean 3.9, range 0 to 42.1). Fifty-three of 94 subjects received Xyntha for on-demand treatment for a total of 187 bleeding episodes. One hundred ten of 180 bleeds (61.1%) occurred ² 48 hours after the last dose and 38.9% (70 of 180 bleeds) occurred >48 hours after the last dose. The majority of bleeds reported to occur ² 48 hours after the last prophylaxis dose were traumatic (64 of 110 bleeds; 58.2%). Forty-two of 70 bleeds (60%) reported to occur > 48 hours after the last prophylaxis dose were spontaneous. The median dose for on-demand treatment was 30.6 IU/kg (range, 6.4 to 74.4 IU/kg). The majority of bleeding episodes (173/187; 92.5%) resolved with 1 or 2 infusions. One hundred thirty-two of 187 bleeding episodes (70.6%) treated with Xyntha were rated excellent or good in their response to initial treatment, 45 (24.1%) were rated moderate.

The pharmacokinetics of Xyntha were also compared with that of Advate (see related entry) from Baxter containing full, not portion-deleted, recombinant CHO cell-expressed Factor VIII. The pharmacokinetics were found substantially equivalent.  

Medical: Xyntha is administered by intravenous (IV) infusion after reconstitution with the supplied pre-filled diluent (0.9% Sodium Chloride solution, 4 mL) syringe.