Bleeding Outcomes in Participants with Factor VIII Activity<5 IU/dL post–gene transfer in GENEr8-1

Introduction Valoctocogene roxaparvovec is expected to transfer a functional FVIII coding sequence that would eliminate the need for regular prophylaxis for people with severe hemophilia A (HA). At the same valoctocogene roxaparvovec dose, FVIII levels varied among participants in the phase 3 GENEr8-1 trial. The protective effect of low transgene-derived FVIII is unknown. The aim is to determine clinical outcomes for participants with low FVIII activity 3 years post–gene transfer in GENEr8-1.

Method In the open-label, single-arm, phase 3 GENEr8-1 trial (NCT03370913), 134 adult males (intention-to-treat [ITT] population) with severe HA (FVIII activity<1 IU/dL) previously receiving regular FVIII prophylaxis and with no history of FVIII inhibitors received a single dose of 6x10¹³ vg/kg valoctocogene roxaparvovec. Plasma FVIII activity was measured via chromogenic substrate assay (reported in text; lower limit of quantitation [LLOQ], 1.5 [previously 3.0] IU/dL) or one-stage assay (LLOQ, 1.0 IU/dL). RTP was defined per-protocol as usual FVIII prophylaxis administered≥1 time/week for≥4 consecutive weeks or≥2 emicizumab injections/month. Outcomes are reported for up to 156 weeks.

Results Of 134 ITT participants, 131 completed the week 156 visit. Mean (standard deviation [SD]) FVIII activity at week 156 was 18.2 (30.6) IU/dL in the ITT population. At week 156, 46 of 134 (34.3%) ITT participants had median FVIII activity<5 IU/dL (range, 0 to 4.9 IU/dL). These 46 participants had annualized bleeding rate (ABR) for treated spontaneous and traumatic bleeds at baseline between 0 and 27.5 (mean, 4.8) bleeds/year and from post-prophylaxis to week 156 between 0 and 12.0 (mean, 1.7) bleeds/year.

Of these 46 participants, 8 resumed prophylaxis before week 156 (range, 58–141 weeks; [Fig. 1]) and 38 did not RTP before week 156 ([Fig. 2]).

Fig. 1  ABR for treated bleeds at baseline and post-prophylaxis up to RTP for participants with week 156 FVIII activity<5 IU/dL who resumed prophylaxis before week 156

Fig. 2  ABR for treated bleeds at baseline and during post-prophylaxis up to week 156 for participants with week 156 FVIII activity<5 IU/dL who did not RTP.

For 2 of 8 participants who resumed prophylaxis before week 156, treated ABR was higher during the post-prophylaxis period up to RTP than at baseline; treated ABR was higher post-prophylaxis to week 156 compared with baseline for 5 of 38 participants who did not RTP before week 156. Most of the 38 participants who did not RTP before week 156 had lower ABR for treated bleeds compared with baseline, low post-prophylaxis ABRs for treated bleeds, or no substantial treated spontaneous bleeds.

Conclusion Most participants with low FVIII activity had low bleeding rates, suggesting that low endogenous FVIII expression may provide protective hemostatic benefits. Many participants who resumed prophylaxis had clinical presentation consistent with moderate hemophilia; the individual decision to RTP was multifactorial and influenced by FVIII activity, bleeding rates, desired physical activity levels, and personal preferences.

Conflict of Interest

JM has received research funding from BioMarin Pharmaceutical Inc., Catalyst, Novo Nordisk, Pfizer, Roche, Sandoz, Sanofi, and Spark Therapeutics. MO has participated in advisory boards for Bayer, BioMarin Pharmaceutical Inc., Grifols, Pfizer, Sanofi, and Takeda and received honoraria from BioMarin Pharmaceutical Inc., Biotest, Novo Nordisk, Pfizer, and Roche. AG reports honoraria for service on advisory boards from American Thrombosis and Hemostasis Network, Bayer, BioMarin Pharmaceutical Inc., Genentech, Novo Nordisk, Pfizer, Sanofi Genzyme, and uniQure and travel grants from BioMarin Pharmaceutical Inc. JDW reports consulting fees from Bayer, Chugai, Novo Nordisk, Pfizer, Sanofi, Sobi, and Takeda; speaker fees from Bayer, Behring, Chugai, CSL, Novo Nordisk, Pfizer, Sanofi, and Takeda; and service as a clinical trial investigator for Bayer, BioMarin Pharmaceutical Inc., Novo Nordisk, Pfizer, Roche/Chugai, and Sanofi. DO, HY, and TMR are employees and shareholders of BioMarin Pharmaceutical Inc. CWT has no conflicts to declare.

Publication History

Article published online:
26 February 2024