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FVIII Inhibitor Development

State of Knowledge Summary

  • Patients with prior or active anti-factor VIII neutralizing antibodies (factor VIII [FVIII] inhibitors) were excluded from clinical trials.1,2
  • No FVIII inhibitor responses have been observed in valoctocogene roxaparvovec clinical trials.8-10

FVIII Inhibitor Development

For clinical trial enrollment patients receiving valoctocogene roxaparvovec were required to screen negative for anti-AAV5 antibodies, have no history of FVIII inhibitors, and screen negative (<0.6 BU) for FVIII inhibitors in a Nijmegen modified Bethesda assay with a lifetime minimum of 150 exposure days to FVIII replacement therapy.1,2

Graphic of Factor VIII attaching to antibodies

 

  • No patients have developed a FVIII inhibitor response (Nijmegen modified Bethesda assay)​8-10
  • 12 of 134 (9%) GENEr8-1 participants tested positive at one or more time points for FVIII TAb; no association with ALT elevations or FVIII activity measures ​7
    • A majority of the positive tests were low titer, single positive results that revert to negative at the next ​time point​7
    • No cellular immune response to FVIII (IFN-γELISpot) was detected at those ​time points​7
  • These results are consistent with low titer, transient antibody responses described in the literature for both healthy donors and hemophilia A patients who do not progress to inhibitors3,4

The use of valoctocogene roxaparvovec in patients with active inhibitors or prior history of FVIII inhibitors is under investigation in a Phase 1/2 clinical trial.5

  • Study 270-205 is a 2-part Phase 1/2 open-label, multicenter clinical trial evaluating the safety and efficacy of Valoctocogene roxaparvovec in patients with severe hemophilia A and FVIII inhibitors.5 Patients with active and a prior history of FVIII inhibitors will be included in Parts A and B, respectively.
  • Safety and efficacy outcomes including, change in FVIII activity level and annualized bleeding rate, will be assessed for up to 5 years.5 Additionally, Part A will assess change in FVIII inhibitor titers and Part B the recurrence of FVIII inhibitors.

 

Table including objectives, inclusion criteria, and exlusion criteria

To date, interim data have been collected from 10 patients (3 from Part A and 7 from Part B). Patients have reached 44.7-122.7 weeks of follow-up and none have discontinued the study. 

  • Part A 6
    • All 3 active inhibitor patients had increased FVIII inhibitor titers, suggesting that FVIII is still being produced.  
    • Factor VIII activity was detectable in 1 patient
  • Part B 6
    • Consistent with those observed in GENEr8-1, with patients having mean (standard deviation) FVIII activity levels via chromogenic substrate assay:
      • 50.1 (43.8) IU/dL at Weeks 25-28
      • 25.8 (18.2) IU/dL at Weeks 49-52 
    • No bleed events or use of FVIII infusions were reported

The safety profile was similar to GENEr8-1 with all patients reporting at least 1 adverse event (AE) and most experiencing alanine aminotransferase (ALT) elevations.6 There were no reports of FVIII inhibitor recurrence in Part B patients. 

 

Image of Safety-Outcomes-of-GENEr8-INH-FVIII table

AE, adverse event; ALT, alanine aminotransferase; FVIII, factor VIII; NA, not applicable; SAE, serious adverse event

References:

  1. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 2022;386(11):1013-1025.
  2. Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med. 2020;382(1):29-40.
  3. Reipert BM, Gangadharan B, Hofbauer CJ, et al. The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development. Blood Adv. 2020;4(22):5785-5796.
  4. Whelan SF, Hofbauer CJ, Horling FM, et al. Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients. Blood. 2013;121(6):1039-1048.
  5. BioMarin Pharmaceutical. Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec in Hemophilia A With Active or Prior Inhibitors.
  6. Chavele KM, Chiou S, Chou S, et al. Safety and efficacy of valoctocogene roxaparvovec in participants with active or prior FVIII inhibitors: Results from a phase 1/2 trial [presentation]. Presented at the Bari 13th International Congress (BIC). September 12-14, 2025; Padua, Italy.
  7. Long BR, Robinson TM, Day JRS, et al. Clinical immunogenicity outcomes from GENEr8-1, a phase 3 study of valoctocogene roxaparvovec, an AAV5-vectored gene therapy for hemophilia A. Mol Ther. 2024;32(7):2052-2063.
  8. Symington E, Rangarajan S, Lester W, et al. Valoctocogene roxaparvovec gene therapy provides durable haemostatic control for up to 7 years for haemophilia A. Haemophilia. 2024;30(5):1138-1147.
  9. 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.
  10. 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.