HEMOPHILIA A: TREATMENT LANDSCAPE
ABOUT HEMOPHILIA A
The hemophilia population is predominantly young and male. The median age at diagnosis for infants with severe hemophilia is 2 days.1 The average age of patients with hemophilia in the United States is 23.5 years,2 and there are ~23,800 patients in the United States with hemophilia A.3 Approximately 3,300 of those patients are females, which is an often-overlooked population.3,4 Life expectancy for patients with hemophilia more than tripled from 1960 to 2007, from <20 years to ~70 years.5,6
Hemophilia A is a congenital deficiency of coagulation FVIII7
Factor VIII (FVIII) is a key component of the coagulation cascade, the steps that occur in response to an injury8,9
FVIII activity levels determine disease severity. Disease severity correlates with bleeding frequency.10
| Mild10 | Moderate10 | Severe10 | |
| Factor serum levels | 5% to <40% of normal | 1% to 5% of normal | <1% of normal |
| Bleeding episodes | Spontaneous bleeding is rare; severe bleeding with major trauma or surgery | Occasional spontaneous bleeding; prolonged bleeding with minor trauma or surgery | Spontaneous bleeding into large synovial joints or muscles |
Disease management
Von Willebrand factor (VWF) is responsible for:
Transporting FVIII to sites of injury to participate in forming blood clots11
Protecting FVIII from premature breakdown11
Concentrating FVIII within the forming platelet plug at sites of vascular injury11
VWF limits endogenous FVIII half-life to ~12 hours in adults12
The VWF chaperone effect limits FVIII half-life extension for extended half-lives (EHLs)13
Even with advancements in technology, EHLs were unable to overcome the VWF limitation13
VWF binding sites on the FVIII molecule14
Adapted from Kumar V, et al, eds. Robbins Basic Pathology. 10th ed. 2018.
FVIII prophylaxis is used to increase factor activity levels10,15
Regularly timed infusions are required to maintain factor levels above the bleeding threshold.16 MASAC* defines the goals of prophylaxis as factor activity levels of ≥1% (>3% to 5% if feasible) and minimal to no spontaneous bleeding.17
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PK terminology
Area under the curve (AUC): Relates to the total exposure of the body to the clotting factor over time.16
Trough level (Ctrough): The minimum clotting factor concentration reached following infusion and before the next dose is administered.16
Half-life (t1/2): The length of time required for the concentration of a substance to decrease to half its starting dose in the body.18
Peak level (Cmax): The maximum clotting factor concentration following infusion.16
TAT: Time above threshold.16
Maintaining higher FVIII activity levels through the use of prophylaxis reduces bleeding risk and improves joint health20,21
Seventy percent to 80% of bleeds occur in the joints (hemarthroses), which leads to irreversible joint damage causing pain, discomfort, and disability. Recurrent hemarthroses result in joint damage, which can become permanent and irreversible (hemophilic arthropathy).10,22 Evidence suggests FVIII activity level targets of 1% to 3% are inadequate to prevent all bleeds.10 When FVIII activity levels are between 1% and 10%, every 1% increase in FVIII activity correlates with a 2% rise in patients who experience zero bleeds.23
Treatment challenges in hemophilia A
In a study of a FVIII EHL therapy, researchers investigated a PK-guided regimen for managing severe hemophilia A.27 FVIII levels of ~10% were targeted because studies have shown that annualized joint bleeding rates tend to approach zero in patients with FVIII levels of ≥10%.23,27 Patients were randomly assigned (1:1) to treatment arms targeting FVIII activity levels of either 1% to 3% or 8% to 12% (~10%).27
39% of patients required more
than twice-weekly dosing to achieve
factor activity levels of 1% to 3%27
12.1% of patients required daily
infusions to achieve factor activity
levels of 8% to 12%27
60.3% required infusions
every other day to achieve factor
activity levels of 8% to 12%27
Achieving more protective FVIII activity levels required more frequent dosing than the initial dose recommended in the label.27,28
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F=factor; MASAC=Medical and Scientific Advisory Council; PK=pharmacokinetic.
References: 1. Kulkarni R, Soucie JM, Lusher J, et al. Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention’s (CDC) Universal Data Collection (UDC) project. Haemophilia. 2009;15(6):1281-1290. doi:10.1111/j.1365-2516.2009.02074.x 2. Soucie JM, Miller CH, Dupervil B, Le B, Buckner TW. Occurrence rates of haemophilia among males in the United States based on surveillance conducted in specialized haemophilia treatment centres. Haemophilia. 2020;26(3):487-493. doi:10.1111/hae.13998 3. Factor VIII and factor IX. Centers for Disease Control and Prevention. Reviewed November 28, 2023. Accessed March 21, 2024. https://www.cdc.gov/ncbddd/hemophilia/communitycounts/data-reports/2023-3/table-2-factor.html 4. Women can have hemophilia, too. Centers for Disease Control and Prevention. Reviewed July 25, 2023. Accessed March 21, 2024. https://www.cdc.gov/ncbddd/hemophilia/features/women-and-hemophilia.html 5. Philipp C. The aging patient with hemophilia: complications, comorbidities, and management issues. Hematology Am Soc Hematol Educ Program. 2010;2010:191-196. doi:10.1182/asheducation-2010.1.191 6. History. National Bleeding Disorders Foundation. Accessed April 16, 2024. https://www.hemophilia.org/bleeding-disorders-a-z/overview/history 7. Bauer KA. Current challenges in the management of hemophilia. Am J Manag Care. 2015;21(6)(suppl):S112-S122. 8. Hemophilia A. National Bleeding Disorders Foundation. Accessed April 16, 2024. https://www.hemophilia.org/bleeding-disorders-a-z/types/hemophilia-a 9. Current treatments. National Bleeding Disorders Foundation. Accessed April 16, 2024. https://www.hemophilia.org/bleeding-disorders-a-z/treatment/current-treatments 10. Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition [published correction appears in Haemophilia. 2021;27(4):699]. Haemophilia. 2020;26(suppl 6):1-158. doi:10.1111/hae.14046 11. Franchini M, Lippi G. Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A: a critical literature review. Thromb Haemost. 2010;104(5):931-940. doi:10.1160/TH10-03-0151 12. Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003;361(9371):1801-1809. doi:10.1016/S0140-6736(03)13405-8 13. Lissitchkov T, Willemze A, Jan C, Zilberstein M, Katragadda S. Pharmacokinetics of recombinant factor VIII in adults with severe hemophilia A: fixed-sequence single-dose study of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa. Res Pract Thromb Haemost. 2023;7(4):100176. doi:10.1016/j.rpth.2023.100176 14. Kumar V, Abbas AK, Aster JC, eds. Robbins Basic Pathology. 10th ed. Elsevier; 2018. 15. Mannucci PM. Hemophilia therapy: the future has begun. Haematologica. 2020;105(3):545-553. doi:10.3324/haematol.2019.232132 16. Delavenne X, Dargaud Y. Pharmacokinetics for haemophilia treaters: meaning of PK parameters, interpretation pitfalls, and use in the clinic. Thromb Res. 2020;192:52-60. doi:10.1016/j.thromres.2020.05.005 17. MASAC. National Bleeding Disorders Foundation. Accessed April 16, 2024. https://www.hemophilia.org/who-we-are/our-team/masac 18. Hallare J, Gerriets V. Half Life. In: StatPearls; 2024. Updated June 20, 2023. Accessed April 16, 2024. https://www.ncbi.nlm.nih.gov/books/NBK554498/ 19. MASAC Document 267. National Bleeding Disorders Foundation. April 27, 2022. Accessed April 16, 2024. https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-267-masac-recommendation-concerning-prophylaxis-for-hemophilia-a-and-b-with-and-without-inhibitors 20. Berntorp E, Hermans C, Solms A, Poulsen L, Mancuso ME. Optimising prophylaxis in haemophilia A: the ups and downs of treatment. Blood Rev. 2021;50:100852. doi:10.1016/j.blre.2021.100852 21. Martin AP, Burke T, Asghar S, Noone D, Pedra G, O’Hara J. Understanding minimum and ideal factor levels for participation in physical activities by people with haemophilia: an expert elicitation exercise. Haemophilia. 2020;26(4):711-717. doi:10.1111/hae.13985 22. Carcao M, Moorehead P, Lillicrap D. Hemophilia A and B. In: Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz J, Anastasi J, eds. Hematology: Basic Principles and Practice. 6th ed. Elsevier Saunders; 2013:1940-1960. 23. Chowdary P, Fischer K, Collins PW, et al. Modeling to predict factor VIII levels associated with zero bleeds in patients with severe hemophilia A initiated on tertiary prophylaxis. Thromb Haemost. 2020;120(5):728-736. doi:10.1055/s-0040-1709519 24. Diagnosis of hemophilia. Centers for Disease Control and Prevention. Reviewed October 10, 2023. Accessed April 15, 2024. https://www.cdc.gov/ncbddd/hemophilia/diagnosis.html 25. Kennedy M, O’Gorman P, Monaghan A, et al. A systematic review of physical activity in people with haemophilia and its relationship with bleeding phenotype and treatment regimen. Haemophilia. 2021;27(4):544-562. doi:10.1111/hae.14282 26. Iorio A, Iserman E, Blanchette V, et al. Target plasma factor levels for personalized treatment in haemophilia: a Delphi consensus statement. Haemophilia. 2017;23(3):e170-e179. doi:10.1111/hae.13215 27. Klamroth R, Windyga J, Radulescu V, et al. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study. Blood. 2021;137(13):1818-1827. doi:10.1182/blood.2020005673 28. Adynovate. Prescribing information. Takeda Pharmaceuticals U.S.A., Inc.; 2023.
INDICATION
ALTUVIIIO® [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] is a von Willebrand Factor (VWF) independent recombinant DNA-derived, Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:
- Routine prophylaxis to reduce the frequency of bleeding episodes
- On-demand treatment & control of bleeding episodes
- Perioperative management of bleeding
Limitation of Use
ALTUVIIIO is not indicated for the treatment of von Willebrand disease.
CONTRAINDICATIONS
ALTUVIIIO is contraindicated in patients who have had severe hypersensitivity reactions, including anaphylaxis, to the product or its excipients.
WARNINGS AND PRECAUTIONS
- Allergic-type hypersensitivity reactions, including anaphylaxis, may occur with ALTUVIIIO. Allergic-type hypersensitivity reactions were not reported in the clinical trials. Advise patients to discontinue use of ALTUVIIIO if hypersensitivity symptoms occur and contact a physician and/or seek immediate emergency care.
- Formation of neutralizing antibodies (inhibitors) to Factor VIII is possible following administration of ALTUVIIIO. Neutralizing antibodies were not reported in the clinical trials. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests.
- If assessment of plasma Factor VIII activity is needed, it is recommended to use a validated one-stage clotting assay. The ALTUVIIIO Factor VIII activity level is overestimated by the chromogenic assay and a specific ellagic acid-based aPTT reagent in one-stage clotting assay by approximately 2.5-fold. If these assays are used, divide the result by 2.5 to approximate the patient’s ALTUVIIIO Factor VIII activity level.
ADVERSE REACTIONS
The most common adverse reactions (>10% of subjects) reported in clinical trials were headache and arthralgia.
Please see full Prescribing Information.
Learn more about Sanofi’s commitment to fighting counterfeit drugs.
INDICATION
ALTUVIIIO® [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] is a von Willebrand Factor (VWF) independent recombinant DNA-derived, Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:
- Routine prophylaxis to reduce the frequency of bleeding episodes
- On-demand treatment & control of bleeding episodes
- Perioperative management of bleeding
Limitation of Use
ALTUVIIIO is not indicated for the treatment of von Willebrand disease.
CONTRAINDICATIONS
ALTUVIIIO is contraindicated in patients who have had severe hypersensitivity reactions, including anaphylaxis, to the product or its excipients.
WARNINGS AND PRECAUTIONS
- Allergic-type hypersensitivity reactions, including anaphylaxis, may occur with ALTUVIIIO. Allergic-type hypersensitivity reactions were not reported in the clinical trials. Advise patients to discontinue use of ALTUVIIIO if hypersensitivity symptoms occur and contact a physician and/or seek immediate emergency care.
- Formation of neutralizing antibodies (inhibitors) to Factor VIII is possible following administration of ALTUVIIIO. Neutralizing antibodies were not reported in the clinical trials. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests.
- If assessment of plasma Factor VIII activity is needed, it is recommended to use a validated one-stage clotting assay. The ALTUVIIIO Factor VIII activity level is overestimated by the chromogenic assay and a specific ellagic acid-based aPTT reagent in one-stage clotting assay by approximately 2.5-fold. If these assays are used, divide the result by 2.5 to approximate the patient’s ALTUVIIIO Factor VIII activity level.
ADVERSE REACTIONS
The most common adverse reactions (>10% of subjects) reported in clinical trials were headache and arthralgia.
Please see full Prescribing Information.
Learn more about Sanofi’s commitment to fighting counterfeit drugs.
INDICATION
ALTUVIIIO® [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] is a von Willebrand Factor (VWF) independent recombinant DNA-derived, Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:
- Routine prophylaxis to reduce the frequency of bleeding episodes
- On-demand treatment & control of bleeding episodes
- Perioperative management of bleeding
Limitation of Use
ALTUVIIIO is not indicated for the treatment of von Willebrand disease.
CONTRAINDICATIONS
ALTUVIIIO is contraindicated in patients who have had severe hypersensitivity reactions, including anaphylaxis, to the product or its excipients.
WARNINGS AND PRECAUTIONS
- Allergic-type hypersensitivity reactions, including anaphylaxis, may occur with ALTUVIIIO. Allergic-type hypersensitivity reactions were not reported in the clinical trials. Advise patients to discontinue use of ALTUVIIIO if hypersensitivity symptoms occur and contact a physician and/or seek immediate emergency care.
- Formation of neutralizing antibodies (inhibitors) to Factor VIII is possible following administration of ALTUVIIIO. Neutralizing antibodies were not reported in the clinical trials. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests.
- If assessment of plasma Factor VIII activity is needed, it is recommended to use a validated one-stage clotting assay. The ALTUVIIIO Factor VIII activity level is overestimated by the chromogenic assay and a specific ellagic acid-based aPTT reagent in one-stage clotting assay by approximately 2.5-fold. If these assays are used, divide the result by 2.5 to approximate the patient’s ALTUVIIIO Factor VIII activity level.
ADVERSE REACTIONS
The most common adverse reactions (>10% of subjects) reported in clinical trials were headache and arthralgia.
Please see full Prescribing Information.
Learn more about Sanofi’s commitment to fighting counterfeit drugs.
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