To: File (STN 125385)
From: La’Nissa A. Brown-Baker, Ph.D., Pharmacologist, Division of Hematology
Through: Iftekhar Mahmood, Team Lead, Pharm/Tox Group, Division of Hematology/OBRR
Subject: Filing of Midcycle STN 125385/0 - CSL Behring’s BLA Factor XIII Concentrate
(Human), Pasteurized Corifact TM
- Proposed Use and Doses
- List non-clinical Studies in IND
- Summary of non-clinical Studies
Congenital Factor XIII deficiency is a rare autosomal recessive disease usually associated with a severe bleeding diathesis. Factor XIII (FXIII) after activated by thrombin is an enzyme of the coagulation system that cross-links fibrin. Factor XIII deficiency is the rarest of all factor deficiencies and is also known as Fibrin Stabilizing Factor deficiency diagnosed by coagulation screening tests and detailed family history. The incidence of FXIII deficiency is about 1 in 2-5 million people. Historical data demonstrate that FXIII replacement therapy is the most widely utilized and effective therapy with fresh frozen plasma, cryoprecipitate or crude factor XIII concentrate from placenta.
CSL Behring has manufactured a novel plasma derived FXIII called CorifactTM approved for orphan designation for congenital FXIII deficiency. CSL Behring is proposing an indication for the use of its product human FXIII concentrate, pasteurized, also known as Fibrogammin P or P/N, as prophylaxis treatment of FXIII deficiency as a longer acting version than currently marketed FXIII products. Fibrogammin P has a long standing history for clinical use in the EU over a decade. Common side effects following FXIII therapy include anaphylactic reactions, inhibitor development, thromboembolic events, and rarely transmission of disease. Nevertheless, the benefits of replacement FXIII therapy far outweigh the risks.
CSL Behring’s Factor XIII concentrate will be administered intravenously as prophylactic therapy at 10-40 U/kg every 4-6 weeks. The dose and frequency will be determined by treating physician tailored to plasma levels of each patient. The proposed indication is for prophylactic treatment of FXIII deficiency as the half-life is longer than other coagulation factors.
Based on the review of pharmacological and toxicological data presented, I recommend filing of this Biological License Application (BLA) STN 125385 for actor XIII Concentrate (Human), Pasteurized [CorifactTM].
Recommendation for non-clinical studies:
Due to the potential of immunogenicity as associated with all biologics (replacement therapies), I recommend that the sponsor consider continued post-marketing monitoring to address immunogenic concerns as this biological product will be administered as a prophylaxis in clinical setting. I also recommend that the sponsor integrates the existing clinical experience and knowledge to address this major safety concern.
- No teratogenic, reproductive & developmental toxicity, mutagenic, secondary pharmacodynamics, genotoxicity or carcinogenic studies were performed using CorifactTM or its predecessors.
- The immunogenicity of treatment with FXIII is a major concern as with all biologics, especially with a prophylactic indication. The sponsor has drafted a plan to monitor immunogenicity following FXIII administration such as inhibitor and antibody development in clinical trials and a post-marketing commitment.
- There were no substantial or unexpected adverse events in pre-clinical testing following FXIII administration.
Study No. (b)(4) 01-00 The Influence of Factor XIII Substitution on bleeding time and clot strength in a FXIII knockout mouse model
Study No. V-692.1 - Factor FXIII from Human Plasma as component of Fibrin Adhesive Effect on Bursting Strength of Rat Skin Wound
Study No. 154-12 - Acute Toxicity Studies with plasma factor FXIII
Study No. B71368 - Fibrogammin P: 14-day intravenous (Bolus) Toxicity Study in the --(b)(4)-- Rat with an Interim Sacrifice after 5 treatments
Study No. 154.24: Local Toxicity study in rabbits after intravenous, intra-arterial and paravenous injection of BI 71.0123 (plasma factor XIII)
Study No. 154-35 - Safety Pharmacological Investigations with Plasma Factor XIII in --(b)(4)-- Dogs
Study No. 154-11 - Acute Toxicity studies with plasma Factor XIII
Study No. 154-12 - Acute Toxicity studies with plasma factor XIII
Study No. V-211e - Testing for possible formation of antigenic components through modification of production Procedure
Study No. S10844 – In vivo thrombogenicity test
Wound healing (tear off assay w/ adhesives)
K.O. mice vs. WT (----------(b)(4)--)
1.25-200 U/kg; i.v. TEG & bleed time 200 U/kg
Hemophilia A --(b)(4)--
1F/1M; 10, 35, 70 U/kg
Acute (single) dose toxicity
N=10 (5M/5F); i.v. saline, 710, 1775, 3550 IU/kg
Acute (single) dose toxicity
N=10/gr. (5M/5F) i.v. saline, 71,710, 1420 IU/kg
i.v., i.a., p.v. n=3/gr., 250, 71 and 71 IU/kg BW vs. saline
------(b)(4)---- test; passive cutaneous anaphylaxis
Saline, 35, 100, 350 U/kg i.v.
N=26 (13M/13F); Saline, 35, 100, 350 U/kg i.v.
-----------(b)(4)--------------- mouse i.v. = intravenous i.a. =intra-arterial p.v. = paravenous WT = wildtype gr. = group
-----------(b)(4)------------- mouse TEG = thromboelastography BW = body weight
General Comments: Based on the repeat dose and acute dose toxicity, local tolerance, pharmacodynamics, toxicokinetics, antigenicity, thrombogenicity, and efficacy studies in the pre-clinical program submitted for CSL Behring’s FXIII, pasteurized (Corifact) appear adequate to address the safety concerns. The findings presented indicate FXIII (Corifact) is well tolerated with an appropriate safety margin based on proposed dosage. Immunogenicity has been monitored in clinical trials, but continues to be a major concern for prophylaxis indication. Studies have monitored TEG and bleeding time which improved following FXIII administration. Previous clinical experience that has been compiled on FXIII negates necessity for additional toxicity studies in additional higher order animals as component of preclinical program.
There were additional literature submissions to support Factor XIII concentrate administration compared to recombinant FXIII; factor XIII administration in sheep a review article on factor XIII deficiency; and a clinical review on FXIII function.