Expert opinion on current and future prophylaxis therapies aimed at improving protection for people with hemophilia A
Language English Country Romania Media print
Document type Journal Article
PubMed
35646171
PubMed Central
PMC9126455
DOI
10.25122/jml-2022-0103
PII: JMedLife-15-570
Knihovny.cz E-resources
- Keywords
- ABR – annualized bleed rate, BPAs – bypassing agents, BU – Bethesda units, EHL – extended half-life, FVIII/IX – factor VIII/IX, ITI – immune tolerance induction, PPX – prophylaxis, QoL – quality of life, SHL – standard half-life, TFPI – tissue factor pathway inhibitor, TGA – thrombin generation assays, WFH – World Federation of Hemophilia, aPCC – activated prothrombin complex concentrates, extended half-life, hemophilia, mHJHS – modified Haemophilia Joint Health Score, pd – plasma-derived, prophylaxis, r – recombinant, rFVIIIFc – recombinant FVIII Fc fusion protein, rFVIIIpeg – recombinant pegylated FVIII, siRNA – small interfering RNA,
- MeSH
- Hemophilia A * drug therapy prevention & control MeSH
- Hemorrhage prevention & control MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Europe MeSH
The next frontier in hemophilia A management has arrived. However, questions remain regarding the broader applicability of new and emerging hemophilia A therapies, such as the long-term safety and efficacy of non-factor therapies and optimal regimens for individual patients. With an ever-evolving clinical landscape, it is imperative for physicians to understand how available and future hemophilia A therapies could potentially be integrated into real-life clinical practice to improve patient outcomes. Against this background, nine hemophilia experts from Central European countries participated in a pre-advisory board meeting survey. The survey comprised 11 multiple-choice questions about current treatment practices and future factor and non-factor replacement therapies. The survey questions were developed to reflect current unmet needs in hemophilia management reflected in the literature. The experts also took part in a follow-up advisory board meeting to discuss the most important unmet needs for hemophilia management as well as the pre-meeting survey results. All experts highlighted the challenge of maintaining optimal trough levels with prophylaxis as their most pressing concern. Targeting trough levels of ≥30-50 IU/L or even higher to achieve less bleeding was highlighted as their preferred strategy. However, the experts had an equal opinion on how this could be achieved (i.e., more efficacious non-factor therapies or factor therapy offering broader personalization possibilities such as targeting trough levels to individual pharmacokinetic data). In summary, our study favors personalized prophylaxis to individual pharmacokinetic data rather than a "one-size-fits-all" approach to hemophilia A management to maintain optimal trough levels for individual patients.
Department of Clinical Haematology University Hospital Brno Brno Czech Republic
Department of Laboratory Methods Faculty of Medicine Masaryk University Brno Czech Republic
Expert Center for Rare Haematological Disorders Sofia Bulgaria
See more in PubMed
Fassel H, McGuinn C. Haemophilia: factoring in new therapies. Br J Haematol. 2021;194(5):835–50. doi: 10.1111/bjh.17580. PubMed DOI
Hermans C, Mancuso ME, Nolan B, Pasi KJ. Recombinant factor VIII Fc for the treatment of haemophilia A. Eur J Haematol. 2021;106(6):745–61. doi: 10.1111/ejh.13610. PubMed DOI PMC
Berntorp E, Fischer K, Hart DP, Mancuso ME, et al. Haemophilia. Nat Rev Dis Primers. 2021;7(1):45. doi: 10.1038/s41572-021-00278-x. PubMed DOI
Mannucci PM. Hemophilia therapy: the future has begun. Haematologica. 2020;105(3):545–53. doi: 10.3324/haematol.2019.232132. PubMed DOI PMC
Srivastava A, Santagostino E, Dougall A, Kitchen S, et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26(S6):1–158. doi: 10.1111/hae.14046. PubMed DOI
Shapiro AD, Mitchell IS, Nasr S. The future of bypassing agents for hemophilia with inhibitors in the era of novel agents. J Thromb Haemost. 2018;16(12):2362–74. doi: 10.1111/jth.14296. PubMed DOI
Okaygoun D, Oliveira DD, Soman S, Williams R. Advances in the management of haemophilia: emerging treatments and their mechanisms. J Biomed Sci. 2021;28(1):64. doi: 10.1186/s12929-021-00760-4. PubMed DOI PMC
Lloyd Jones M, Wight J, Paisley S, Knight C. Control of bleeding in patients with haemophilia A with inhibitors: a systematic review. Haemophilia. 2003;9(4):464–520. doi: 10.1046/j.1365-2516.2003.00782.x. PubMed DOI
European Medicines Agency (EMA). Hemlibra - summary of product characteristics (SmPC); Available from: https://www.ema.europa.eu/en/documents/product-information/hemlibra-epar-product-information_en.pdf.
Krumb E, Fijnvandraat K, Makris M, Peyvandi F, et al. Adoption of emicizumab (Hemlibra®) for hemophilia A in Europe: Data from the 2020 European Association for Haemophilia and Allied Disorders survey. Haemophilia. 2021;27(5):736–43. doi: 10.1111/hae.14372. PubMed DOI
Muto A, Yoshihashi K, Takeda M, Kitazawa T, et al. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost. 2014;12(2):206–13. doi: 10.1111/jth.12474. PubMed DOI
Kizilocak H, Marquez-Casas E, Malvar J, Carmona R, Young G. Determining the approximate factor VIII level equivalency of patients with severe hemophilia A on emicizumab using global hemostasis assays. Blood. 2019;134(Supplement_1):1134-. doi: 10.1182/blood-2019-123820. PubMed DOI
Oldenburg J, Mahlangu JN, Kim B, Schmitt C, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809–18. doi: 10.1056/NEJMoa1703068. PubMed DOI
Carcao M, Mancuso ME, Young G, Jiménez-Yuste V. Key questions in the new hemophilia era: update on concomitant use of FVIII and emicizumab in hemophilia A patients with inhibitors. Expert Rev Hematol. 2021;14(2):143–8. doi: 10.1080/17474086.2021.1875817. PubMed DOI
Banchev A, Batorova A, Faganel Kotnik B, Kiss C, et al. A cross-national survey of people living with hemophilia: impact on daily living and patient education in Central Europe. Patient Prefer Adherence. 2021;15:871–83. doi: 10.2147/ppa.S303822. PubMed DOI PMC
Young G, Liesner R, Chang T, Sidonio R, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019;134(24):2127–38. doi: 10.1182/blood.2019001869. PubMed DOI PMC
Langer AL, Etra A, Aledort L. Evaluating the safety of emicizumab in patients with hemophilia A. Expert Opin Drug Saf. 2018;17(12):1233–7. doi: 10.1080/14740338.2019.1551356. PubMed DOI
Colowick AB, Bohn RL, Avorn J, Ewenstein BM. Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper. Blood. 2000;96(5):1698–702. doi: 10.1182/blood.V96.5.1698. PubMed DOI
Ellsworth P, Ma A. Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates? Hematology. 2021;2021(1):219–25. doi: 10.1182/hematology.2021000253. PubMed DOI PMC
Konkle BA, Shapiro AD, Quon DV, Staber JM, et al. BIVV001 fusion protein as factor VIII replacement therapy for hemophilia A. N Engl J Med. 2020;383(11):1018–27. doi: 10.1056/NEJMoa2002699. PubMed DOI
Drugs.com. Efanesoctocog alfa granted FDA fast track designation for treatment of hemophilia A; Available from: https://www.drugs.com/clinical_trials/efanesoctocog-alfa-granted-fda-fast-track-designation-hemophilia-19233.html?utm_source=ddc&utm_medium=rss&utm_campaign=Efanesoctocog+Alfa+Granted+FDA+Fast+Track+Designation+for+Treatment+of+Hemophilia+A.
Srivastava A, Rangarajan S, Kavakli K, Klamroth R, et al. Fitusiran, an investigational siRNA therapeutic targeting antithrombin for the treatment of hemophilia: first results from a phase 3 study to evaluate efficacy and safety in people with hemophilia A or B without Inhibitors (ATLAS-A/B). Blood. 2021;138(Suppl 2):LBA–3. doi: 10.1182/blood-2021-155018. DOI
Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood. 2019;134(22):1973–82. doi: 10.1182/blood.2019001542. PubMed DOI PMC
Mahlangu J, Lamas JL, Morales JC, Malan DR, et al. Abstract OC 32.4. Presented at the annual ISTH Congress. Philadelphia, PA, USA: 2021. Jul 17-21, Long-term safety and efficacy of the anti-TFPI monoclonal antibody marstacimab in patients with severe haemophilia A or B: results from a phase 2 long-term treatment study.
Ohmori T. Advances in gene therapy for hemophilia: basis, current status, and future perspectives. Int J Hematol. 2020;111(1):31–41. doi: 10.1007/s12185-018-2513-4. PubMed DOI
Kaneda M, Kawasaki R, Matsumoto N, Abe H, et al. Detailed analysis of anti-emicizumab antibody decreasing drug efficacy, using plasma samples from a patient with hemophilia A. J Thromb Haemost. 2021;19(12):2938–46. doi: 10.1111/jth.15506. PubMed DOI PMC
Tripodi A, Santoro RC, Testa S, Molinari AC, et al. Position paper on laboratory testing for patients with haemophilia. A consensus document from SISET, AICE, SIBioC and SIPMeL. Blood Transfus. 2019;17(3):229–36. doi: 10.2450/2019.0241-18. PubMed DOI PMC
Harroche A, Sefiane T, Desvages M, Borgel D, et al. Non-inhibitory antibodies inducing increased emicizumab clearance in a severe haemophilia A inhibitor patient. Haematologica. 2021;106(8):2287–90. doi: 10.3324/haematol.2021.278579. PubMed DOI PMC
Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Int Med. 1992;232(1):25–32. doi: 10.1111/j.1365-2796.1992.tb00546.x. PubMed DOI
Klamroth R, Windyga J, Radulescu V, Collins PW, et al. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study. Blood. 2021;137(13):1818–27. doi: 10.1182/blood.2020005673. PubMed DOI PMC
Klamroth R, Wojciechowski P, Aballéa S, Diamand F, et al. Efficacy of rFVIIIFc versus emicizumab for the treatment of patients with hemophilia A without inhibitors: Matching-adjusted indirect comparison of A-LONG and HAVEN trials. J Blood Med. 2021;12:115–22. doi: 10.2147/jbm.S288283. PubMed DOI PMC
Paz-Priel I, Chang T, Asikanius E, Chebon S, et al. Immunogenicity of emicizumab in people with hemophilia A (PwHA): results from the HAVEN 1-4 studies. Blood. 2018;132(Supplement 1):633-. doi: 10.1182/blood-2018-99-118492. DOI
Young G, Mahlangu JN. Extended half-life clotting factor concentrates: results from published clinical trials. Haemophilia. 2016;22(Suppl 5):25–30. doi: 10.1111/hae.13028. PubMed DOI
Mancuso ME, Santagostino E. Outcome of clinical trials with new extended half-life FVIII/IX concentrates. J Clin Med. 2017;6(4):39–54. doi: 10.3390/jcm6040039. PubMed DOI PMC
Aledort L, Mannucci PM, Schramm W, Tarantino M. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfus. 2019;17(6):479–86. doi: 10.2450/2019.0211-19. PubMed DOI PMC
Dimichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas. Haemophilia. 2002;8(3):280–7. doi: 10.1046/j.1365-2516.2002.00626.x. PubMed DOI
Eckhardt CL, van Velzen AS, Peters M, Astermark J, et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood. 2013;122(11):1954–62. doi: 10.1182/blood-2013-02-483263. PubMed DOI
Meeks SL, Batsuli G. Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches. Hematology Am Soc Hematol Educ Program. 2016;2016(1):657–62. doi: 10.1182/asheducation-2016.1.657. PubMed DOI PMC
Collins P, Chalmers E, Chowdary P, Keeling D, et al. The use of enhanced half-life coagulation factor concentrates in routine clinical practice: guidance from UKHCDO. Haemophilia. 2016;22(4):487–98. doi: 10.1111/hae.13013. PubMed DOI
Lenting PJ. Laboratory monitoring of hemophilia A treatments: new challenges. Blood Adv. 2020;4(9):2111–8. doi: 10.1182/bloodadvances.2019000849. PubMed DOI PMC
Aleman MM, Leksa NC, Peters R, Salas J. Assay challenges (and opportunities) with non-factor VIII therapies for Hemophilia A. Expert Rev Mol Diagn. 2019;19(1):1–3. doi: 10.1080/14737159.2019.1554436. PubMed DOI
Oldenburg J, Kulkarni R, Srivastava A, Mahlangu JN, et al. Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein. Haemophilia. 2018;24(1):77–84. doi: 10.1111/hae.13353. PubMed DOI
Callaghan MU, Negrier C, Paz-Priel I, Chang T, et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood. 2021;137(16):2231–42. doi: 10.1182/blood.2020009217. PubMed DOI PMC
Liel MS, Greenberg DL, Recht M, Vanek C, et al. Decreased bone density and bone strength in a mouse model of severe factor VIII deficiency. Br J Haematol. 2012;158(1):140–3. doi: 10.1111/j.1365-2141.2012.09101.x. PubMed DOI
Lenting PJ, Denis CV, Christophe OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood. 2017;130(23):2463–8. doi: 10.1182/blood-2017-08-801662. PubMed DOI
Hay CRM, Xiang H, Scott M, Collins PW, et al. The haemtrack home therapy reporting system: Design, implementation, strengths and weaknesses: A report from UK Haemophilia Centre Doctors Organisation. Haemophilia. 2017;23(5):728–35. doi: 10.1111/hae.13287. PubMed DOI
Mondorf W, Siegmund B, Mahnel R, Richter H, et al. Haemoassist--a hand-held electronic patient diary for haemophilia home care. Haemophilia. 2009;15(2):464–72. doi: 10.1111/j.1365-2516.2008.01941.x. PubMed DOI
Arvanitakis A, Berntorp E, Astermark J. A comparison of MyPKFiT and WAPPS-Hemo as dosing tools for optimizing prophylaxis in patients with severe haemophilia A treated with Octocog alfa. Haemophilia. 2021;27(3):417–24. doi: 10.1111/hae.14295. PubMed DOI
Mondorf W, Eichler H, Fischer R, Holstein K, et al. Smart Medication™, an electronic diary for surveillance of haemophilia home care and optimization of resource distribution. Hamostaseologie. 2019;39(04):339–46. doi: 10.1055/s-0038-1675575. PubMed DOI