NovoThirteen

Pharmacotherapeutic group: Antihaemorrhagics, Blood Coagulation factor, ATC code: B02BD11. Mechanism of action In plasma, FXIII circulates as a heterotetramer [A 2 B 2 ] composed of 2 FXIII A-subunits and 2 FXIII B-subunits held together by strong non-covalent interactions. The FXIII B-subunit acts as a carrier molecule for the FXIII A-subunit in circulation, and is present in excess in plasma. When the FXIII A-subunit is bound to the FXIII B-subunit [A 2 B 2 ], the half-life of the FXIII A-subunit [A 2 ] is prolonged. FXIII is a pro-enzyme (pro-transglutaminase), which is activated by thrombin in the presence of Ca 2 +. 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 enhanced platelet and clot adhesion to the injured tissue. NovoThirteen is a recombinant coagulation factor XIII A-subunit produced in yeast cells ( Saccharomyces cerevisiae ) by recombinant DNA technology. It is structurally identical to the human FXIII A-subunit [A 2 ]. NovoThirteen (A-subunit) binds to free human FXIII B-subunit resulting in a heterotetramer [rA 2 B 2 ] with a similar half-life to endogenous [A 2 B 2 ]. Pharmacodynamic effects At present there are no markers that can quantitatively assess the in vivo pharmacodynamics of FXIII. The results of standard coagulation tests are normal, as it is the quality of the clot that is affected. A clot solubility assay is widely used as an indicator of FXIII deficiency, but the assay is qualitative, and when performed correctly the test is positive only when the FXIII activity in the sample is close to zero. NovoThirteen has been shown to have the same pharmacodynamic properties in plasma as endogenous FXIII. Clinical efficacy and safety A pivotal prospective, open-label, single-arm phase 3 trial (F13CD-1725) including 41 patients with FXIII A-subunit deficiency was conducted to investigate the haemostatic efficacy of rFXIII in patients with congenital FXIII deficiency as reflected by the rate of bleeding episodes requiring treatment with a FXIII-containing product. The dosing scheme used was 35 IU/kg/month (every 28 days ± 2 days). Five bleeding episodes requiring treatment with a FXIII-containing product have been observed in four patients during treatment with rFXIII in the trial. The mean rate of treatment-requiring bleeds was determined to 0.138 per subject year. In the primary endpoint analysis covering the referred period, the age-adjusted rate (number per subject year) of treatment-requiring bleeds during the rFXIII treatment period was 0.048/year (95% CI: 0.009 - 0.250; model-based estimate corresponding to the mean age of 26.4 years for the 41 patients). In the F13CD-1725 extension trial F13CD-3720, the age-adjusted rate of bleeds that required treatment with a FXIII-containing product was estimated to be 0.021 bleeds per subject year with a 95% CI of [0.0062; 0.073] (model-based estimate corresponding to a mean age of the trial population of 31.0 years). The crude bleeding rates in the two trials, F13CD-1725 and F13CD-3720, not adjusted for age, were 0.138 and 0.043 respectively, corresponding to a total of 13 bleeds over 223 subject-years and a pooled rate of 0.058. A 6 year post-authorisation safety study NN1841-3868 including 30 patients with FXIII A-subunit deficiency was conducted to investigate the long term safety of rFXIII. No safety concerns were identified. Five traumatic bleeding episodes in four patients were treated with rFXIII during prophylaxis. The mean rate of bleeding episodes requiring treatment with FXIII was 0.066 bleeds per patient per year (95% CI: 0.029 - 0.150). Minor surgeries Six patients had a total of 9 minor surgeries during the post-authorisation safety study NN1841-3868. Seven of the 9 minor surgery cases took place 0-3 days after last prophylactic dose of rFXIII and rFXIII was given post-surgery in 1 case. In the latter 2 of the 9 cases, the last prohylactic dose was given 12-15 days before surgery, and an extra single dose of rFXIII at 23.2 IU/kg and 21.4 IU/kg respectively was given prior surgery. In 8 of the 9 cases the haemostatic response was reported as good or excellent. Outcome was not reported for the last case. In trial F13CD-3720, extension trial to the pivotal phase 3 trial F13CD-1725, 12 minor surgeries were performed in 9 patients. All surgeries took place within 1-21 days after the last prophylactic dose of rFXIII. No additional doses were given. The outcome in all 12 cases was favourable. Paediatric population Analyses of data from paediatric patients included in clinical trials have not identified differences in treatment response according to age. Twenty-one children between the age of 6 to less than 18 years old and six children less than 6 years old have been treated with NovoThirteen for a total of 986 exposures. Children above 6 years were investigated through the pivotal phase 3 trial (F13CD-1725) and the extension study (F13CD-3720) assessing the safety of monthly replacement therapy with NovoThirteen. The 6 patients below 6 years were investigated through a single dose pharmacokinetic phase 3b trial (F13CD-3760) and then, included in the long-term follow-up trial (F13CD-3835) assessing the safety and the efficacy of monthly replacement therapy with NovoThirteen. No treatment requiring bleeding episodes have been detected in patients below 6 years during 17 years of cumulative follow-up, representing a total of 214 doses. The suggested dose of 35 IU/kg has shown to be appropriate to provide haemostatic coverage in this young population. In the post-authorisation safety study NN1841-3868, 13 children under 18 years were enrolled. Overall, no differences in treatment response or safety profile were seen in the paediatric population compared to the adult population.