Status: approved by FDA in Jan. 2011; marketed in some European and other countries

Organizations involved:

CSL Behring LLC – USA mark.

CSL Ltd. - Manuf.; R&D; Tech.; World mark.; Parent

Description: Factor XIII Concentrate (Human) or Corifact is a lyophilized (freeze-dried) formulation of human plasma-derived Factor XIII containing both its two A- and two B-subunits. Corifact is the first and only Factor XIII product in the U.S. market.

Corifact is available as a single-use vial containing 1000-1600 units of FXIII as a lyophilized concentrate for reconstitution with 20 mL of Sterile Water for Injection, USP. The actual units of potency of FXIII are stated on each Corifact vial label and carton. The dating period is 24 months from the date of manufacture when stored at 2-8 °C (36-46 °F). Within the dating period, the product may be stored at room temperature not to exceed 25°C (77°F) for up to six months. The date of manufacture is defined as the date of final sterile filtration of the formulated drug product. Following the final sterile filtration, no reprocessing/reworking is allowed without prior FDA approval.

Nomenclature: Factor XIII [BIO]; Corifact [TR]; Fibrogammin- P [TR EU]; Factor XIII Concentrate (Human) [FDA]; Antihemophilic factor XIII [SY]; Factor XIII (plasma-derived) [SY]; NDC 63833-528-01 and 63833-518-02

Biological.: Corifact (FXIII) is an endogenous plasma glycoprotein consisting of two A-subunits and two B-subunits. FXIII circulates in blood and is present in platelets, monocytes, and macrophages. FXIII appears in two forms, a heterotetrameric (A2B2) plasma protein with a molecular weight of about 320 kilodaltons and a homodimeric (A2) cellular form.

FXIII is a proenzyme that is activated, in the presence of calcium ion, by thrombin cleavage of the A-subunit to become activated FXIII (FXIIIa). Intracellularly, the homodimeric form of only the A-subunits (A2) is found. The B-subunits in plasma have no enzymatic activity, and function as carrier molecules for the A-subunits. They stabilize the structure of the A-subunits and protect them from proteolysis.

FXIIIa promotes cross-linking of fibrin during coagulation and is essential to the physiological protection of the clot against fibrinolysis. FXIIIa is a transglutaminase enzyme that catalyzes the cross-linking of the fibrin - and -chains for fibrin stabilization and renders fibrin clots more elastic and resistant to fibrinolysis. FXIIIa also cross-links 2-plasmin inhibitor to the -chain of fibrin, resulting in protection of the fibrin clot from degradation by plasmin. Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to primary hemostatic platelet plugs.

Companies.: Developed and manufactured by CSL Ltd., CBER/FDA est. no. 1765, Marburg, Germany. Marketed in the the U.S. by CSL Behring LLC, and internationally by CSL Ltd.

Manufacture: Corifact is manufactured from cryo-depleted plasma into an ethanol precipitate, which is then purified by precipitation/adsorption, ion exchange chromatography and heat-treated for viral inactivation (+60°C for 10 hours in an aqueous solution) steps. The sterile filtered final bulk solution is filled into vials and lyophilized. Besides heat treatment, other processing that contributes to virus removal or inactivation are aluminum hydroxide [Al(OH)3] Adsorption/Vitacel (food plant-derived fiber from J. Rettenmaier & Sohne GmbH and Co.) Defibrination and Ion Exchange Chromatography. Total log10 virus titer reductions for the manufacturing process are: HIV, ≥16.6; bovine viral diarrhea virus, model for HCV, ≥14.3; West Nile virus, ≥7.4; herpes simplex virus type 1, model for large enveloped DNA viruses, ≥15.2; hepatitis A virus, 9.0; and canine parvovirus, model for B19V, 4.7.

FDA class: Biologic BLA

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

Corifact is indicated for routine prophylactic treatment of congenital Factor XIII (FXIII) deficiency. The effectiveness of Corifact is based on maintaining a trough FXIII activity level of approximately 5% to 20%. There are no controlled trials demonstrating a direct benefit on treatment of bleeding episodes with Corifact

Status: Approved by FDA on Feb. 17, 2011 with orphan designation. At the time, Corifact was also approved in 12 other countries (Argentina, Austria, Belgium, Brazil, France, Germany, Great Britain, Indonesia, Israel, Japan, Luxembourg, and Switzerland) under the trade name Fibrogammin- P.

In the approval letter, FDA noted, "We did not refer your application to the Blood Products Advisory Committee because our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion."

Disease: Congenital FXIII deficiency, also known as fibrin-stabilizing factor deficiency, is a rare and potentially life-threatening bleeding disorder in which blood clots normally, but the clots formed are unstable, leading to recurrent bleeding. It is estimated that the condition affects one person in two million, with an incidence in the U.S. of approximately 150 people. The deficiency may lead to soft tissue bruising, mucosal bleeding and fatal intracranial bleeding. Newborns with Factor XIII deficiency may have umbilical cord bleeding. Patients lacking the FXIII protein are also at high-risk for intracranial hemorrhage (ICH), bleeding inside the skull that can be life-threatening. Studies have shown that between 25 and 60 percent of FXIII-deficient patients will experience an ICH at least once during their lifetime.

Trials: In support of FDA approval, 12 clinical studies were conducted and included 187 unique subjects, 90 subjects <16 years of age. These 187 subjects received a total of approximately 3930 infusions of Corifact. The most common side effects observed were hypersensitivity reactions (allergy, rash, pruritus, and erythema), chills, fever, arthralgia, headache, elevated thrombin-antithrombin levels, and an increase in liver (hepatic) enzymes.

There are no controlled trials demonstrating a direct benefit on treatment of bleeding episodes with Corifact. Clinical studies have shown that Corifact immediately increases FXIII levels in the blood.

FDA reported it "approved Corifact based on results of a clinical study of 14 people, including children, with congenital Factor XIII deficiency. In this 12-week prospective, open-label, multicenter, pharmacokinetic and safety study conducted in 7 females and 7 males with congenital FXIII deficiency, ranging in age from 5 to 42 years (3 children, 2 adolescents, and 9 adults), there were no reports of deaths, life-threatening events, or adverse events that led to discontinuation or withdrawal from the study. No breakthrough bleeding episodes were reported in this study.

Medical: Corifact is administered as an intravenous (IV) infusion given approximately every 28 days. The concentrated formula is dosed, depending on the patient's weight, to maintain trough FXIII levels between 5-20% of normal.

Like Factor VIII, Factor XIII can induce "inhibitors" or natural neutralizing antibodies, which may result in a higher dose being required or the patient not being suitable for Corifact treatment.

Corifact has a low infusion volume, which could help reduce administration time.

Market: With an estimated 150 potential patients in the U.S., the market for Corifact is very small.