Catridecacog Coagulation Factor XIII A-Subunit

TRETTEN, Coagulation Factor XIII A-Subunit (Recombinant), is indicated for routine prophylaxis for bleeding in patients with congenital factor XIII A-subunit deficiency.

TRETTEN is not for use in patients with congenital factor XIII B-subunit deficiency

Dosage Forms And Strengths

TRETTEN, Coagulation Factor XIII A-Subunit (Recombinant), is available as a white lyophilized powder in single-use vial containing nominally 2500 IU per vial (2000 – 3125 IU) of recombinant coagulation factor XIII A-subunit. The actual amount of TRETTEN in IU is stated on each carton and vial.

After reconstitution with the provided Sterile Water for Injection, each vial contains 667-1042 IU/mL recombinant coagulation factor XIII A-subunit.

TRETTEN, Coagulation Factor XIII A-Subunit (Recombinant), is supplied as a white, lyophilized powder in single-use vial along with the diluent (Sterile Water for Injection) vial.

The actual amount of TRETTEN in international units (IU) is stated on each carton and vial. TRETTEN and the sterile water vials provided in the package are not made with natural rubber latex.

Storage And Handling

• Store refrigerated at 2°C – 8°C (36°F – 46°F) prior to reconstitution. TRETTEN is stable until the expiration date on the carton and vial label. Do not freeze. Store protected from light.
• Use reconstituted TRETTEN within 3 hours.
• If the reconstituted product is not used immediately, store the solution refrigerated or at room temperature not to exceed 25°C (77°F) for up to 3 hours following reconstitution.

For Information contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark

Mechanism Of Action

FXIII is the terminal enzyme in the blood coagulation cascade. When activated by thrombin at the site of vessel wall injury, FXIII plays an important role in the maintenance of hemostasis through cross-linking of fibrin and other proteins in the fibrin clot.

In plasma, FXIII circulates as a heterotetramer [A2B2] composed of two FXIII A-subunits and two FXIII B-subunits held together by strong non-covalent interactions. The FXIII A is the catalytic subunit and FXIII B-subunit acts as carrier molecule for the FXIII A-subunit in circulation, and is present in excess in plasma. When FXIII A-subunit is bound to FXIII B-subunit [A2B2] the half-life of the FXIII A-subunit [A2] is prolonged. FXIII is a pro-enzyme (pro-transglutaminase), which is activated by thrombin in the presence of Ca2+. The enzymatic activity resides with the FXIII A-subunit. Upon activation, the FXIII A-subunit dissociates from the FXIII B-subunit and thereby exposes the active site of the FXIII A-subunit. The active transglutaminase cross-links fibrin and other proteins resulting in increased mechanical strength and resistance to fibrinolysis of the fibrin clot and contributes to enhance platelet and clot adhesion to injured tissue.

Coagulation Factor XIII A-Subunit (Recombinant) is a protransglutaminase (rFXIII [rA2] homodimer) and binds to free human FXIII B-subunit resulting in a heterotetramer [rA2B2] with a similar half-life to [A2B2]. rFXIII has been shown to be activated by thrombin in the presence of Ca2+. Activated rFXIII has been shown in dose-dependent manner to increase mechanical strength of fibrin clots, retard fibrinolysis, and rFXIII has been shown to enhance platelet adhesion to the site of injury. After combining with available plasma B-subunits, Coagulation Factor XIII A-subunit (Recombinant) has been shown to have the same pharmacodynamic properties in plasma as endogenous FXIII.

Pharmacodynamics

A qualitative assay of clot solubility is widely used as an indicator of FXIII deficiency; when performed correctly the test is positive only when the FXIII activity in the sample is close to zero. The results of standard coagulation tests are normal as it is the quality of the clot that is affected. In addition, at present there are no markers that can quantitatively assess the in vivo pharmacodynamics of FXIII.

Pharmacokinetics

In 23 patients with congenital FXIII A-subunit deficiency, the pharmacokinetics of rFXIII were evaluated over a dosing interval of 28 days during steady state.

The pharmacokinetic parameters based on baseline (trough) adjusted FXIII activity (Berichrom assay) values are shown in Table 3.

Table 3 : Pharmacokinetic parameters based on baseline (trough) adjusted FXIII activity

At steady state, the pharmacokinetics of rFXIII are comparable with the single dose pharmacokinetics of rFXIII.

In a pharmacokinetic trial six children with congenital FXIII A-subunit deficiency were administered a single intravenous dose of 35 IU/kg. The pharmacokinetic parameters based on baseline (trough) adjusted FXIII activity (Berichrom assay) values are shown in Table 4. No dose adjustment is needed for pediatric patients as there is no influence of age on the pharmacokinetics of TRETTEN.  

Table 4 : The pharmacokinetic parameters based on baseline(trough) adjusted FXIII activity

Clinical Studies

To establish the efficacy of TRETTEN for the prevention of bleeding in patients with congenital FXIII A-subunit deficiency, a multi-center, open-label, non-controlled trial was conducted for 52 weeks in forty-one (41) subjects ≥ 6 years. All subjects received monthly doses of TRETTEN at 35 IU/kg. Bleeding episodes that required treatment with a FXIII-containing product were observed to evaluate the efficacy of monthly replacement therapy with TRETTEN on prevention of bleeding episodes.

Subjects with congenital FXIII A-subunit deficiency confirmed by genotyping were included. Subjects who before entering the trial had received regular replacement therapy were to have initiated regular replacement therapy at least 6 months prior to screening and were to have a documented history of at least one treatment-requiring bleeding episode before initiation of regular replacement therapy or a documented family history of FXIII congenital deficiency. Subjects who before entering the trial had only received on-demand treatment were to have a documented history of at least two treatment-requiring bleeding episodes within 12 months of the screening visit. Severe bleeders as defined by a documented history of ≥ 2 treatment requiring bleedings per year during regular FXIII replacement therapy were excluded.

During the prophylaxis treatment period with TRETTEN (434 subject months), five bleeding episodes treated with FXIII-containing products were observed in four subjects. All five were associated with trauma. When calculated for all 41 subjects, this translated into a mean annual rate of bleeding episodes that required treatment of 0.14 [95% CI:0.058- 0.332] per subject year, which was statistically significantly lower than the historic bleeding rate of 1.68 per subject year for on-demand treatment. The age-adjusted rate of bleeding episodes that required treatment during the TRETTEN treatment period was 0.05 [95% CI: 0.0094 - 0.2501] per subject year with a model-based estimate corresponding to the mean age of 26.4 years. The mean annual bleeding rate in patients below 18 years of age was higher compared to that in adults (0.362 versus 0.040 bleeds/subject/year). Table 5 below lists the estimated bleeding rates by age.

Table 5 : Estimated Bleeding Rates by Age

Thirty-four (34) of the 41 subjects and an additional 21 new subjects were enrolled in an ongoing second trial. During a total treatment period of 107.5 subject years (mean of 1.95 years per subject), 5 subjects experienced 6 bleeds that required treatment with a FXIII-containing product. The mean annual rate of bleeding episodes that required treatment was determined to be 0.056 per subject year. The age-adjusted rate of bleeding episodes that required treatment during the TRETTEN treatment period was 0.022 per subject year [95% CI:0.0045; 0.1023] with a model-based estimate corresponding to a mean age of 29.5 years. The annual mean bleeding rate in patients below age 18 was higher compared to that in adults (0.127 versus 0.026 bleeds/subject/year) with some overlap of the respective 95% confidence intervals. Table 6 lists the estimated bleeding rates by age.

Table 6 : Estimated Bleeding Rates by Age

REFERENCES

1. Inbal, A., et.al.:Recombinant factor XIII: a safe and novel treatment for congenital factor XIII deficiency, Blood. 2012;119(22): 5111-5117