Hemophilia

Idelvion^® (albutrepenonacog alfa) is a recombinant human factor IX (FIX) genetically fused with recombinant human albumin. Idelvion is indicated for the treatment and control of bleeding episodes in children and adults with hemophilia B. It is also indicated for the perioperative management of these patients and for prophylaxis to decrease the frequency of bleeding episodes.¹ Idelvion was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2016.^1,2

Hemophilia B, also known as Christmas disease, is a genetic blood disorder that results from the deficiency of FIX, a vitamin K-dependent plasma protease involved in the intrinsic blood coagulation cascade.^3,4 This FIX deficiency leads to bleeding in the joints and muscles. People with hemophilia B present with longer bleeding times than those in unaffected individuals.⁵ Spontaneous and recurrent bleeding can occur in patients with the severe form of the disease, leading to the development of long-term disability and a reduced quality of life.⁴

Treatment of hemophilia B involves concentrated FIX products that are infused into the bloodstream.⁵ Replacement therapy is the standard of care in hemophilia B, however, the reduced elimination half-lives of the available plasma-derived FIX and recombinant FIX products require frequent infusions to allow adequate FIX levels to be achieved.⁴ 

How Idelvion Works

Idelvion is the first available recombinant fusion protein that links recombinant FIX (rFIX) with recombinant human albumin (rAlbumin) using a novel cleavable linker peptide.⁴ This peptide is derived from the endogenous activation peptide in native FIX.¹ The genetic fusion of the complementary DNA (cDNA) of albumin to the cDNA of FIX results in the single recombinant protein called rIX-FP.¹ One main advantage of this technological strategy is that albumin has a long half-life of approximately 20 days. Additionally, albumin is present in the human plasma, stable, and not involved in the activation of the immune system. Therefore, the presence of albumin in Idelvion prolongs the half-life of rFIX.⁴

When infused into patients, the rIX-FP protein is kept in the circulation until required for coagulation events. When FIX is activated, rAlbumin is cleaved from rFIX, releasing the factor needed for clot formation and temporarily raising FIX levels.^1,4

Idelvion is available in single-dose vials containing between 250 IU and 3500 IU as a lyophilized powder, and it is manufactured for intravenous administration only. In patients at least 12 years of age, routine prophylaxis may be achieved with 25 to 40 IU/kg injections every 7 days.¹

Safety and Efficacy of Idelvion

The efficacy and safety of Idelvion was evaluated in separate phase 1, phase 2, and phase 3 clinical trials in a program called PROLONG-9FP. A phase 1, multicenter, dose-escalation trial reported the safety and pharmacokinetic profile of rIX-FP in patients with hemophilia B. The results showed an increased half-life for the recombinant protein of approximately 92 hours, with no serious adverse events reported.⁶ 

The safety and efficacy of rIX-FP when used as prophylaxis or as on-demand treatment for bleeding episodes in patients with hemophilia B was studied in a phase 2/3 trial (NCT01496274).⁷ This study enrolled 63 previously treated male patients with severe hemophilia B. The mean half-life of rIX-FP in this study was 102 hours, which was 4.3-fold longer than that of FIX treatment. The median annualized spontaneous bleeding rate decreased by 100%, and a 100% resolution of target joints was also reported. In total, 98.6% of bleeding episodes were successfully treated, and the development of inhibitors or any safety issues were not observed.⁷ In a different phase 3 study involving 27 previously treated children with moderate to severe hemophilia B, the pharmacokinetics, efficacy, and safety of rIX-FP were evaluated (NCT01662531).⁸ The mean half-life of rIX-FP was 91.4 hours, which was 4.3-fold longer than that of FIX treatment. The study also reported that rIX-FP was safe and effective for the prevention and treatment of bleeding episodes in children with hemophilia B when used as a weekly prophylactic.⁸ 

Get full prescribing information for Idelvion at MPR

References

1. Idelvion. Prescribing information. CSL Behring; 2021. Accessed December 24, 2021.

2. Idelvion. European Medicines Agency. Accessed December 24, 2021.

3. Santoro C, Quintavalle G, Castaman G, et al. Inhibitors in hemophilia B. Semin Thromb Hemost. 2018;44(6):578-589. doi:10.1055/s-0038-1660817

4. Lyseng-Williamson KA. Coagulation factor IX (recombinant), albumin fusion protein (albutrepenonacog alfa; Idelvion^®): a review of its use in haemophilia B. Drugs. 2017;77(1):97-106. doi:10.1007/s40265-016-0679-8

5. Hemophilia B. National Hemophilia Foundation. Accessed December 24, 2021.

6. Santagostino E. PROLONG-9FP clinical development program–phase I results of recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP). Thromb Res. 2013;131 Suppl 2:S7-S10. doi:10.1016/S0049-3848(13)70151-8

7. Santagostino E, Martinowitz U, Lissitchkov T, et al; PROLONG-9FP Investigators Study Group. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016;127(14):1761-1769. doi:10.1182/blood-2015-09-669234

8. Kenet G, Chambost H, Male C, et al.; PROLONG-9FP Investigator Study Group. Long-acting recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in children. Results of a phase 3 trial. Thromb Haemost. 2016;116(4):659-668. doi:10.1160/TH16-03-0179

Reviewed by Kyle Habet, MD, on 12/27/2021.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.