Hemophilia

Hemophilia therapy Sevenfact^® is a recombinant analog of human factor VIIa (FVIIa).¹ Sevenfact (coagulation factor VIIa [recombinant]-jncw) is indicated for the treatment and control of bleeding episodes in adults and adolescents aged 12 and older who have hemophilia A or B with inhibitors. It utilizes recombinant DNA technology to produce FVII from genetically engineered rabbits. The rabbits are engineered to produce FVII in their mammary glands and secrete it in milk. The milk is processed to isolate FVII, which is then converted enzymatically to FVIIa. Because of this process, Sevenfact is contraindicated in patients who are allergic to rabbits or rabbit proteins.² 

Sevenfact is the most current US Food and Drug Administration (FDA)-approved medication for patients with hemophilia, gaining initial approval on April 1, 2020.​​ Sevenfact is manufactured using the patented and cutting-edge rPRO™ technology from the French company Laboratoire Français du Fractionnement et des Biotechnologies (LFB), resulting in a reliable and secure technique of protein production. HEMA Biologics, LLC is the distributor of Sevenfact. Sevenfact is not authorized for the treatment of congenital factor VII deficiency.^2,3  

Hemophilia is a genetic disease that affects the body’s capacity to form blood clots to stop bleeding. This is caused by deficiencies in clotting factor VIII in hemophilia A and factor IX in hemophilia B.⁴ Sevenfact comes in single-use vials containing 1 or 5 mg of coagulation factor VIIa (recombinant)-jncw as a lyophilized powder. Each mL has 1 mg (1000 mcg) of coagulation factor VIIa (recombinant)-jncw after reconstitution with a specified volume of sterile water for injection.² The Sevenfact treatment dose, frequency, and duration should be determined by the patient’s clinical response and hemostasis assessment. The maximum tolerated doses of Sevenfact are not established, and cumulative daily doses of more than 900 mcg/kg, which could be linked to an increased risk of thromboembolic consequences, have not yet been investigated.¹ 

Mechanism of Action

A recombinant analog of human FVIIa, a vitamin K-dependent coagulation factor, is the active ingredient in Sevenfact. Factor VIIa in a complex with tissue factor (TF) activates factor X to factor Xa in the presence of both calcium and phospholipids, bypassing the processes that require factor VIII or factor IX. Factor X activation to factor Xa starts the common pathway of the coagulation cascade, in which prothrombin is converted to thrombin. This subsequently converts fibrinogen to fibrin to create a hemostatic plug, resulting in clot formation at the hemorrhage site (hemostasis). This mechanism can also happen when there is no TF on the surface of activated platelets.² 

Coagulation testing in the laboratory does not always correspond with or predict the hemostatic efficiency of Sevenfact. Sevenfact has dose- and concentration-dependent pharmacodynamics on the coagulation cascade, including decreases in activated partial thromboplastin time (aPTT) and prothrombin time (PT) and increases in thrombin generation with platelets (TGT) and maximum clot firmness (ROTEM-FIBTEM test).² 

Get full prescribing information on SevenFact at MPR

Efficacy in Trials and Trial Results

Sevenfact was approved based on results from the PERSEPT 1 pivotal phase 3 trial (NCT02020369). In a randomized, multicenter, open-label study design, 468 mild, moderate, and severe bleeding events were assessed in 27 adolescent and adult hemophilia A and B patients with inhibitors. The primary endpoint of bleeding control was achieved by both initial dose regimens (75 mcg/kg and 225 mcg/kg) within 12 hours. Of mild or moderate bleeding episodes treated with an initial 225 mcg/kg dose, 91% achieved hemostatic efficacy after 12 hours, with a median time to hemostatic response of 3 hours. For bleeding episodes managed with an initial dose of 75 mcg/kg, the median time to hemostatic response was 6 hours, with 82% of bleeding episodes attaining hemostatic efficacy at 12 hours. Hemostatic efficacy was maintained in 97.6% of bleeding episodes treated with the 75 mcg/kg dose regimen and in 99.5% of bleeding episodes treated with the 225 mcg/kg dose regimen within 24 hours, without the need for additional treatment.⁵ 

Warnings, Precautions, and Adverse Reactions

Hypersensitivity reactions, including anaphylaxis, can occur with Sevenfact. In such cases, the drug should be discontinued and appropriate treatment should be provided.⁶ 

Adverse events that occurred in at least 1% of patients during clinical trials included headache, dizziness, fever, infusion site reaction, discomfort, and hematoma.² 

Following the use of Sevenfact, fatal arterial and venous thrombotic episodes may develop. Because patients with a history of arterial or venous thromboembolic disease were omitted from the Sevenfact clinical trials, there is minimal evidence regarding the drug’s safety in these patients. Sevenfact is contraindicated in patients with known hypersensitivities or allergies to rabbits or rabbit proteins.⁷ 

Drug-Drug Interactions

When combined with activated prothrombin complex concentrates, FVIIa-containing products can cause an increased risk of major thrombotic events.²  

References

1. Sevenfact [coagulation factor VIIa (recombinant)-jncw]. CenterWatch. Accessed December 27, 2021.
2. Sevenfact. Package insert. HEMA Biologics; 2020. Accessed December 25, 2021.
3. ​​HEMA Biologics™ announces FDA approval of Sevenfact® [coagulation factor VIIa (recombinant)-jncw] for treatment and control of bleeding episodes occurring in adult and adolescent hemophilia A or B patients with inhibitors. News release. HEMA Biologics, LLC; April 6, 2020.
4. Carvalho J. Factor VII treatment approved by FDA for hemophilia A and B with inhibitors. Hemophilia News Today. April 2, 2020. Accessed December 27, 2021.
5. Phase III study of coagulation FVIIa (recombinant) in congenital hemophilia A or B patients with inhibitors. ClinicalTrials.gov. December 24, 2013. Updated June 14, 2017. Accessed December 27, 2021. 
6. Sevenfact- coagulation factor viia recombinant human kit. DailyMed. Updated April 12, 2020. Accessed December 27, 2021.
7. LFB announces FDA approval of Sevenfact®, a recombinant coagulation factor VIIa. News release. Laboratoire Français du Fractionnement et des Biotechnologies (LFB); April 6, 2020.

Reviewed by Kyle Habet, MD, on 12/31/2021.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.