Developing the First Recombinant Factor XIII for Congenital Factor XIII Deficiency: Clinical Challenges and Successes

Abstract

Congenital factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder with potentially life-threatening consequences. FXIII is composed of two subunits (A and B), and a deficiency or dysfunction of either can result in FXIII deficiency. Traditionally, FXIII deficiency has been managed by infusing plasma-derived products containing FXIII (fresh frozen plasma, cryoprecipitate, and plasma-derived FXIII concentrates), all of which contain both subunits. Despite the increased safety of plasma-derived products, concern remains regarding potential viral safety issues. This review describes the development, from concept to clinical use, of a recombinant FXIII molecule (containing subunit A only; rFXIII-A) for congenital FXIII-A subunit deficiency. Unmet needs and ongoing challenges in congenital FXIII deficiency are also discussed. Despite the challenges in developing a product for a very rare bleeding disorder, the information gathered on efficacy, safety, and pharmacokinetics of FXIII replacement therapy represents the largest dataset on congenital FXIII-A subunit deficiency in the world. It also provides evidence for the safety and efficacy of monthly prophylaxis with 35 IU/kg of rFXIII-A in patients with FXIII-A subunit deficiency. The issues encountered and overcome, along with lessons learned, may be applied to and encourage the development of new recombinant products for other rare bleeding disorders.

Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency

“…This has been reported in several patients treated with pdFXIII-containing products. 26 In the current mentor™2 trial as well as in the entire mentor™ trial programme, no patients have developed inhibitors and in the entire mentor™ trial programme only five individuals, all younger than 18 years, have developed transient, non-neutralizing antibodies to rFXIII-A 2 [reviewed in Carcao et al 21 ]. These antibodies have been shown to have no inhibitory activity and the individuals did not experience any AEs or bleeding as a result of or in association with these antibodies.…”

“…In addition, while limited to 12 procedures in nine patients, initial data from mentor™2 for minor surgeries performed in patients receiving rFXIII-A 2 prophylaxis are favourable, and add to the very limited body of evidence currently available on surgery in FXIII-deficient patients. 21 …”

“… 19 20 In the mentor™ programme to date, no patients treated with rFXIII-A 2 have developed FXIII-neutralizing antibodies (i.e., FXIII inhibitors). 21 …”

Screening cleavage of Factor XIII V34X Activation Peptides by thrombin mutants: A strategy for controlling fibrin architecture

“…The amounts applied would be sufficient to out compete endogenous counterpart levels for a therapeutic period of time. Recombinant WT FXIII A 2 has already been used successfully as a prophylaxis in FXIII A-deficient patients [60–62]. The administered FXIII A becomes readily complexed with endogenous FXIII B-subunits.…”