Efficacy, PK and Safety Results of Clinical Study Of Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) In Previously Treated Patients With Hemophilia B

The standard of care for patients with severe hemophilia B is replacement treatment with Factor IX (FIX) 2-3 times a week. A fusion protein genetically linking recombinant human coagulation FIX with recombinant human albumin (rIX-FP) was developed with the aim to extend the half-life of FIX. In the completed Phase I pharmacokinetic study, the mean half-life of rIX-FP was found to be over 5 times longer than the subjects’ previous FIX. Thus, rIX-FP has potential to prevent bleedings for longer periods, allowing reduction in the frequency of injections compared to standard FIX and to reduce the number of injections required to treat a single bleed.

This was a Phase I/II open-label, multicenter study of rIX-FP in previously treated patients 12-65 years of age with severe hemophilia B (FIX ≤ 2%). The study evaluated the safety and efficacy of rIX-FP, including prevention of bleeding episodes during weekly prophylaxis of rIX-FP.

After completion of a 14-day rIX-FP pharmacokinetic assessment, 13 subjects in the prophylaxis arm received weekly prophylaxis of rIX-FP for approximately 11 months, and 4 subjects in the on-demand arm received rIX-FP upon occurrence of bleeding events. The treatment doses were initially selected based upon the pharmacokinetic profile of rIX-FP and subject’s bleeding phenotype, and doses could be adjusted at the Investigator’s discretion.

Seventeen subjects were enrolled from hemophilia treatment centers in Israel and Bulgaria; the mean age was 26 years (range 13 to 46 years). Following a single injection of 25 IU/kg rIX-FP (n=13), the mean FIX activity level was 3.75% and 2.67% above baseline at Day 7 and Day 14, respectively, and the mean half-life of rIX-FP was 95 hours (comparable to the previously reported Phase I data).

Over the 11 month treatment period, rIX-FP demonstrated a good safety profile with a total of over 700 EDs. The treatment was well tolerated and no FIX inhibitor formation was observed. There was no AE considered to be related to treatment with rIX-FP. No subject was withdrawn from the study due to safety concerns or lack of hemostatic efficacy.

All 13 prophylaxis subjects were successfully maintained on a weekly routine regimen of rIX-FP for the entire duration of the study, with annualized spontaneous bleeding rates of 1.255 and 1.134 (mean and median respectively). Furthermore, three prophylaxis subjects who received only on-demand treatment prior to study entry had greater than 80% reduction in the annualized bleeding rate compared to their annualized bleeding rate prior to study entry. All bleeding events were treated successfully with ≤ 2 injections of rIX-FP, with approximately 90% of bleeds treated with a single injection of rIX-FP. The mean weekly consumption of rIX-FP was reduced markedly compared to the subjects’ weekly consumption of the previous FIX product.

This Phase I/II study demonstrated the clinical efficacy of rIX-FP for once weekly routine prophylaxis to prevent spontaneous bleeding episodes and for the treatment of bleeding episodes. In addition, rIX-FP showed an excellent safety and an improved PK profile over currently marketed factor IX products.

Lubetsky:CSL Behring: Investigator for CSL clinical trial of rIX-FP Other. Lissitchkov:CSL Behring: Investigator for CSL Behring clinical trial of rIX-FP Other. Santagostino:CSL Behring: Honoraria, Investigator for CSL Behring clinical trial of rIX-FP Other, Research Funding, Speakers Bureau. Jotov:CSL Behring: sub-investigator for CSL Begring trial of rIX-FP Other. Barazani-Brutman:CSL Behring: study coordinator for CSL Behring rIX-FP trials Other. Voigt:CSL Behring: Employment. Moises:CSL Behring: Employment. Jacobs:CSL Behring: Employment. Martinowitz:CSL Behring: Honoraria, Investigator for CSL rIX-FP trials Other, Speakers Bureau.