title: PROLONG-9FP clinical development program--phase I results of recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP).
abstract: Hemophilia B is a severe bleeding disorder that is characterized by a deficiency or dysfunction of coagulation factor IX (FIX). Replacement therapy using recombinant or plasma-derived FIX is available, but the relatively short half-life of FIX (approximately 18 hours) necessitates administration every 2-3 days to prevent bleeding episodes. A recombinant fusion protein linking coagulation factor IX with albumin, known as rIX-FP, was developed to extend the half-life of recombinant FIX and allow for less frequent dosing. In a phase I, multicenter, dose-escalation trial (PROLONG-9FP), the safety and pharmacokinetics of rIX-FP were assessed in patients with hemophilia B. At a dose of 25-75 IU/kg, rIX-FP was well tolerated: no serious adverse events were reported and there was no evidence of hypersensitivity or immunogenic reactions. Pharmacokinetic analysis indicated enhanced properties, including a 5-fold increase in half-life, 44% higher recovery, 7-fold greater area under the curve, and 7-fold slower clearance, compared with recombinant FIX. Trough levels were maintained above 5% after 7 days when rIX-FP was administered at 25 IU/kg and after 14 days when given at 50 IU/kg, suggesting that schedules involving weekly dosing or dosing every 2 weeks are feasible. These results represent the first reported experience with rIX-FP in humans, and suggest that rIX-FP therapy is feasible and well tolerated in patients with hemophilia B. Phase II/III studies evaluating rIX-FP are underway.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Ca' Granda Foundation, Maggiore Hospital Policlinico and University of Milan, Milan, Italy. Elena.santagostino@policlinico.mi.it
authors.forename: Elena
authors.initials: E
authors.lastname: Santagostino
mesh_terms: D000293:Adolescent; D000328:Adult; D000418:Albumins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005164:Factor IX / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D002836:Hemophilia B / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000418:Albumins; D011993:Recombinant Fusion Proteins; D005164:Factor IX