Real-world factor VIII trough levels of severe-type people with Hemophilia A (PwHA) on efanesoctocog alfa prophylaxis: Interpersonal variation, clinical correlates and predictors

Abstract

Abstract Introduction: Efanesoctocog alfa (EA) is a high-sustained FVIII, designed to decouple FVIII from endogenous von Willebrand factor (VWF). Its half life breaks through the ceiling of VWF half life, achieving to 48 hours in adults in phase 3 EXTEN-1 trial, and provides with trough levels as high as 15%-18%. Trough levels of severe-type people with hemophilia A (PwHA) on EA prophylaxis are important because they are related to the degree of joint protection, suitable strength of exercise, and proper dosing for surgical condition. Although the clinical trial showed good effectiveness with high trough levels for PwHA on EA prophylaxis, real-world reports have been relatively few. Therefore, we aim to investigate real-world trough levels of PwHA on EA prophylaxis and find out its correlate factors. Materials & Methods: This is an observational non-interventional multi-center study. Severe-type PwHA were retrospectively enrolled from hemophilia centers in Taiwan, who switched from rFVIIIFc to Efan after Nov, 2024. The trough levels were checked 1-2 months after switching. Inclusion criteria were non-inhibitor PwHA, being on EA prophylaxis with dosing regimen of 50 iu/kg/dose once weekly as per regulations of National Health Insurance, and having complete data. Exclusion criteria were inhibitor patients, PwHA with on-demand therapy, or incomplete data. Clinical data were retrospectively collected, including age, body weight (BW), body mass index (BMI), body height (BH), ABO blood grouping, inhibitor history, Anti-HCV antibodies, baseline von Willebrand factor (VWF) levels, and pre-switch and post-switch trough levels. The trough levels were checked by one stage assay (OSA), with reagents including Actin-FSL and PTT-A. Results: There were totally 54 PwHA, including 46 adults and 8 boys, with mean age of 36.3 + 16.8 years, ranging from 6.75 to 67.5 years. Mean BW was 72.1 + 19.2 kg. Mean BH was 165.2 + 14 cm. Mean BMI was 25.8 + 4.6. Eighteen (33%) of 54 were O blood group. Nine (20%) of 54 had inhibitor history. Twenty-five (46.3%) of 54 had positive anti-HCV antibodies. Mean baseline VWF:Ag was 114.4% + 47.8%. Mean baseline VWF:activity was 105.3% + 49.7%. Thirty-one PwHA had trough data by OSA with both Actin FSL and PTT-A. Correlation analysis showed trough data by OSA with PTT-A(X) was strongly correlated to that by OSA with Actin FSL(Y) (r=0.91, p<0.05*) and the equation was as: Y=0.61X+0.38. By OSA with Actin FSL, mean post-switch EA trough for 46 adults and 8 boys was 13.3% + 7.3% (range: 1%－39.3%) and 8% + 2.8% (range: 4%－12%), respectively. Five (10.9%) of 46 adults had less than 5%, of whom three had positive inhibitor history. Twenty-nine PwHA had trough levels data of both pre-switch rFVIIIFc prophylaxis and post-switch Efan prophylaxis. Correlation analysis showed there was positively moderately correlated between pre-switch and post-switch trough levels (r=0.501, p<0.01**) Meanwhile, age and BH were significantly weakly correlated to trough level (r=0.37, p<0.01** and r=0.31, p<0.01**, respectively). BW, BMI, ABO grouping, inhibitor history, anti-HCV antibody, and baseline VWF levels were not correlated to trough levels. By multi-variate linear regression analysis, baseline VWF:activity, BH and BW were revealed as predictors for trough levels and baseline VWF:activity was the strongest predictor (p<0.001***). Age was not independent predictor for trough levels. Conclusion:In our study, there were apparent interpersonal variation in trough levels of PwHA on EA prophylaxis in real-world setting. The trough level by OSA with PTT-A might be over-estimated and strongly correlated with that by OSA with Actin FSL. Pre-switching rFVIIIFc trough level was significantly correlated to post-switch EA trough level. Age and BH were found to be positive correlates for trough levels; however, BW, BH, and baseline VWF:activity were revealed as predictors for trough levels.