Improved kinetics of rIX‐FP, a recombinant fusion protein linking factor IX with albumin, in cynomolgus monkeys and hemophilia B dogs

Abstract

Summary. Background: Prophylaxis of hemophilia B, at present, requires multiple infusions of human factor (F)IX concentrates per week. A FIX molecule with a prolonged half‐life has the potential to greatly improve the convenience of, and adherence to, prophylaxis. Objectives: The aim of our studies was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profile of a recombinant fusion protein linking coagulation FIX with albumin (rIX‐FP). Methods: Cynomolgus monkeys and hemophilia B dogs received single intravenous doses of rIX‐FP (50–500 IU kg−1). rIX‐FP plasma levels were determined by an activity‐based assay (dogs only) and anti‐FIX ELISA methods. Additionally, activated partial thromboplastin time (APTT) was determined in hemophilia B dogs. Data were compared with a direct study comparator (recombinant FIX [rFIX]) or previously published data. Results: The terminal half‐life of rIX‐FP was prolonged in both species compared with FIX reference data. In hemophilia B dogs, human FIX antigen levels remained above 0.05 IU mL−1 more than three times longer after rIX‐FP (7.3 days) compared with rFIX (2.3 days), whereas respective calculations based on activity levels confirmed the observed superior profile. Prolonged PDs of rIX‐FP were demonstrated with APTT < 60 s sustained around four times longer with rIX‐FP (5.9 days) than rFIX (1.5 days). Conclusions: These studies indicate that the recombinant albumin fusion technology successfully improves the PK profile of FIX. Clinical studies will test whether the improved kinetics result in a significant half‐life extension in patients with hemophilia B.

The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery

“…After fusion to the Nterminal end of human albumin, separated with a flexible glycine serine linker, the half-life increases up to 4-fold , and the fusion is now in clinical trials for treatment of haemophilia [251][252][253][254][255]. This strategy has also been chosen for coagulation factor IX [248][249][250]. Furthermore, while many albumin-fusions are still in clinical trials, the first (Tanzeum ® ) was approved by FDA in 2014, which is a fusion of glucagon-like peptide-1 (GLP-1) to the Nterminal end.…”

“…Examples include hirudin [256], CD4 [258], insulin [260], growth hormone [259], granulocyte colony stimulating factor [244],  and  interferons [245][246][247], thioredoxin [266,267], coagulation factors [248][249][250][251][252][253][254][255] and antibody fragments [204,[261][262][263]268]. An illustrating example is recombinant interferon 2b used for treatment of chronic hepatitis C with only a half-life of 4 hours in humans, however, upon genetic fusion to human albumin the half-life increases by 35-fold to 141 hours [246].…”

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

“…rIX-FP has demonstrated improved pharmacokinetics (PK) and prolonged pharmacodynamic activity, when compared with rFIX in preclinical studies [9][10][11] and in earlier clinical trials. 12,13 The improved PK profile of rIX-FP may allow patients to be injected less frequently while maintaining a circulating FIX level high enough to minimize the occurrence of spontaneous bleeding episodes.…”

Potential limits of AAV‐based gene therapy with the use of new transgenes expressing factor IX fusion proteins

“…These products raise the possibility of consistently achieving higher trough levels leading to prevention of breakthrough bleeding and subsequent joint disease. Furthermore, animal studies have not suggested an increased inhibitor rate with extended half‐life products . Therefore, these hFIX‐fusion proteins are highly attractive for the next generation of gene therapy vectors, primarily because of the possibility of increasing steady‐state plasma FIX levels due to their extended half‐life, thus improving the potency of gene transfer without having to increase the vector dose and associated toxicity …”