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Thromboembolism

State of Knowledge Summary

  • An increase in factor VIII (FVIII) activity may contribute to a patient’s individual, multifactorial risk for venous and arterial thrombotic events.1,2
  • Patients with histories of arterial or venous thromboembolic events and known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk (e.g., atrial fibrillation), were excluded from clinical trials.3
  • In clinical trials some patients experienced elevations of FVIII activity to levels greater than the upper limit of normal (ULN).3,4
  • No thromboembolic events have been reported in patients treated with valoctocogene roxaparvovec, even when factor VIII (FVIII) levels exceeded 150 IU/dL.3-5
  • FVIII activity levels above ULN were observed in GENEr8-1 and Study 270-201.3,4
  • Four patients in Study 270-201 receiving 6 x 1013 vg/kg exhibited FVIII levels above 150 IU/dL as measured by the one-stage assay (range 201–349 IU/dL) during the first year; no thromboembolic events were reported, and all patients had normal platelet counts, prothrombin time, and activated partial-thromboplastin time.4
  • To date, no patients in GENEr8-1 have experienced a thromboembolic event, including patients with FVIII activity levels >150 IU/dL. 3,7,8 Patients who experienced FVIII activity levels >150 IU/dL had no adverse outcomes related to thromboembolic events.
    • One patient experienced noncardiac chest pain concurrent with an elevated FVIII activity level >300 IU/dL on study day 139 and, per investigator discretion, was initiated on aspirin and enoxaparin.3
    • No other patients with FVIII activity levels >150 IU/dL, including 2 with transient FVIII activity levels >300 IU/dL, required intervention.3 All results were reviewed by the independent Data Monitoring Committee.
  • In GENEr8-1, coagulation parameters were evaluated following the November 2020 data cut as part of laboratory safety assessments.3 In the intent-to-treat (ITT) population, 5.2% (7/134) of patients reported hematology laboratory abnormalities. FVIII increased and fibrin D-dimer increased were reported in 2 (1.5%) patients; activated partial thromboplastin time (aPTT) prolonged, aPTT shortened, coagulation test abnormal, hematocrit decreased, hemoglobin decreased, neutrophil count decreased, prothrombin time shortened, thrombin time prolonged, and von Willebrand’s factor (vWF) antigen decreased were each reported in 1 (0.7%) patient. All adverse events were Grade 1 or 2. Thrombin generation assays were also performed regularly, and results were compared for samples with FVIII activity between 40 and 150 IU/dL (n=349) and with FVIII activity >150 IU/dL (n=47). While samples with FVIII activity >150 IU/dL had slightly lower lag time and time to peak thrombin, they had similar peak height and endogenous thrombin potential as samples with FVIII activity of 40–150 IU/dL.3

Factor VIII Activity Levels Above ULNa

Image of FVIII-Activity-Levels table

aULN of >150 IU/dl for OSA and ULN of >170 IU/dl for CSA.

References:

  1. Jenkins PV, Rawley O, Smith OP, et al. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol. 2012;157(6):653-663.
  2. Algahtani FH, Stuckey R. High factor VIII levels and arterial thrombosis: illustrative case and literature review. Ther Adv Hematol. 2019;10:2040620719886685.
  3. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 2022;386(11):1013-1025.
  4. Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med. 2017;377(26):2519-2530.
  5. Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. N Engl J Med. 2023;388(8):694-705.
  6. EU ROCTAVIAN SmPC
  7. Leavitt AD, Mahlangu J, Raheja P, et al. Efficacy and safety of valoctocogene roxaparvovec 4 years after gene transfer in GENEr8-1 [presentation]. Presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress. June 22-26, 2024; Bangkok, Thailand.
  8. Leavitt AD, Mahlangu J, Raheja P, et al. Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial. Res Pract Thromb Haemost. 2024;8(8):102615.