Hemophilia

Alprolix^® (coagulation factor IX [recombinant], Fc fusion protein) is a recombinant DNA-derived form of coagulation factor IX (FIX) indicated for the treatment of hemophilia B.¹ Hemophilia B is an X-linked blood disorder characterized by FIX deficiency, resulting in prolonged clotting time.^1,2 Patients with severe hemophilia B experience either spontaneous or post-traumatic bleeding that can affect joints and other tissues. These bleeds may lead to chronic pain and mobility and function issues due to joint degeneration, and they can be life-threatening.²

Managing hemophilia relies on replacement therapy to prevent bleeding episodes. FIX can be delivered intravenously to patients in emergency situations, however, starting FIX prophylaxis early in life can effectively prevent joint degeneration and severe bleeding. Despite the benefits of this therapeutic approach, regular FIX administration is needed and often represents a challenge to treatment adherence.² 

New FIX molecules have been developed with the main focus of increasing plasma half-life and consequently extending the time between each administration.³ The active ingredient in Alprolix is a recombinant fusion protein produced through Fc fusion technology and consists of the human coagulation FIX sequence covalently linked to the Fc domain of the human immunoglobulin G₁ (IgG₁). This production strategy allows Alprolix to use a naturally occurring pathway to delay the degradation of immunoglobulins in the body, which subsequently increases its plasma half-life.¹ 

Alprolix is indicated for adults and children with hemophilia B for episodic treatment and control of bleeding, as well as for perioperative management of bleeding and prophylactic treatment.¹ Alprolix was first developed by Biogen; further development was then continued by Bioverativ Therapeutics, which is now a fully owned subsidiary of Sanofi.^4,5 Alprolix obtained initial approval from the US Food and Drug Administration (FDA) in 2014.^1,4

Mechanism of Action and Use of Alprolix

Alprolix temporarily replaces deficient FIX, allowing hemostasis to occur. The dose of Alprolix required depends on the severity of bleeding and FIX deficiency, as well as on the indication for administration. For routine prophylaxis, the recommended starting dose for patients at least 12 years of age is either 50 IU/kg once a week or 100 IU/kg once every 10 days. Differences in patients’ pharmacokinetic profiles may also affect Alprolix dose and duration of treatment, particularly in patients aged less than 12 years.¹

The administration of Alprolix may result in the formation of neutralizing antibodies (inhibitors), with a possible increased risk of anaphylaxis. The most common adverse reactions in previously untreated patients include the development of inhibitors and erythema at the injection site. In previously treated patients, common adverse reactions include headache and paresthesia.¹

Get full prescribing information for Alprolix at MPR

Efficacy in Clinical Trials

Alprolix approval was based upon the results of the phase 3 trials B-LONG (NCT01027364) and Kids B-LONG (NCT01440946).^6,7 In the B-LONG trial, 123 male patients with hemophilia B aged at least 12 years were enrolled and received on-demand, prophylactic, or perioperative treatment. The open-label and multicenter study showed that participants achieved a reduction in or prevention of bleeding episodes when Alprolix was prophylactically administered at least a week apart. The study also showed that more than 90% of the bleedings were effectively controlled with a single Alprolix administration and that the development of inhibitors did not occur.⁶

Kids B-LONG, an open-label and phase 3 trial, enrolled 30 boys between the ages of 1 and 11 years with severe to moderately severe hemophilia B. Participants were prophylactically infused with Alprolix and followed up for up to 52 weeks. Ten of the trial participants did not experience bleeding during the study.⁷

The phase 3 extension trial, B-YOND (NCT01425723), enrolled 116 participants from the B-LONG and Kids B-LONG trials.⁸ This trial was designed to evaluate the long-term effects and efficacy of Alprolix when used on-demand or for prophylaxis. The results showed that 1 to 2 doses of Alprolix were able to control more than 95% of bleeding events.⁸ An additional phase 3 trial, PUPs B-LONG (NCT02234310), was conducted to determine both the safety and efficacy of Alprolix in previously untreated patients.⁹

Currently, real-world data concerning the use of Alprolix is being reported. A recent study showed that Alprolix was effective in improving the control of bleeding while reducing infusion needs.¹⁰ Other ongoing trials focused on evaluating the real-world effectiveness of Alprolix include the B-SURE (NCT03655340) and B-MORE (NCT03901755) observational studies.

References

1. Alprolix. Package insert. Sanofi; 2020. Accessed December 8, 2021.

2. Mancuso ME, Mahlangu JN, Pipe SW. The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing. Lancet. 2021;397(10274):630-640. doi:10.1016/S0140-6736(20)32722-7

3. Stafford DW. Extravascular FIX and coagulation. Thromb J. 2016;14(Suppl 1):35. doi:10.1186/s12959-016-0104-2

4. FDA approves Biogen Idec’s Alprolix™, the first hemophilia B therapy to reduce bleeding episodes with prophylactic infusions starting at least a week apart. News release. Biogen Idec; March 28, 2014

5. Sanofi completes acquisition of Bioverativ Inc. News release. Sanofi; March 8, 2018.

6. Powell JS, Pasi KJ, Ragni MV, et al.; B-LONG Investigators. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med. 2013;369(24):2313-2323. doi:10.1056/NEJMoa1305074

7. Fischer K, Kulkarni R, Nolan B, et al. Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B-LONG): results from a multicentre, non-randomised phase 3 study. Lancet Haematol. 2017;4(2):e75-e82. doi:10.1016/S2352-3026(16)30193-4

8. Shapiro AD, Pasi KJ, Ozelo MC, et al. Extending recombinant factor IX Fc fusion protein dosing interval to 14 or more days in patients with hemophilia B. Res Pract Thromb Haemost. 2018;3(1):109-113. doi:10.1002/rth2.12163

9. Nolan B, Klukowska A, Shapiro A, et al. Final results of the PUPs B-LONG study: evaluating safety and efficacy of rFIXFc in previously untreated patients with hemophilia B. Blood Adv. 2021;5(13):2732-2739. doi:10.1182/bloodadvances.2020004085

10. Shapiro A, Chaudhury A, Wang M, et al. Real-world data demonstrate improved bleed control and extended dosing intervals for patients with haemophilia B after switching to recombinant factor IX Fc fusion protein (rFIXFc) for up to 5 years. Haemophilia. 2020;26(6):975-983. doi:10.1111/hae.14152

Reviewed by Kyle Habet, MD, on 3/27/2022.

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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.