The Real-World Experience of rFVIII-Fc Used in Hemophilia a Patients in Taiwan: Prophylaxis Rates, Pharmacokinetics and Clinical Correlates, and the Effects on Joint Health

Introduction: Routine prophylaxis (RP) has been a standard therapeutic strategy for person with hemophilia (PWH) since 2007. However, frequent injection resulting in patients' burden decreased rates of RP. Extended half-life (EHL) product rFVIII-Fc can reduce the injection burden of RP compared with standard half-life (SHL) rFVIII and was started to be used in Taiwan since November, 2018. The reports of real-world pharmacokinetics (PK) and clinical experience of rFVIII-Fc in Asian countries were relatively few. We aimed to share our clinical experience of rFVIII-Fc for previously-treated patients (PTP) with hemophilia A iin Taiwan.

Materials & Methods: We reviewed retrospectively the charts of 49 PTP with hemophilia A, including 44 severe type, 3 moderate type, and two mild type disease, who switched from SHL FVIII to rFVIII-Fc from Nov., 2018 to May, 2019 at Taipei Medical University Hospital, a referral center for hemophilia. Among them, 36 severe-type PTP had finished complete recovery rate (RR) and PK study, including 2 with on-demand therapy and 34 with RP having PK coming from blood sampling before and 30 min after infusion, post-infusion 24h, 48h or 72h. The online WAPPS-hemo website was used for calculate individual half life. Other clinical data were also analyzed, including body mass index (BMI), lean body weight (LBW), ABO blood grouping, inhibitor status currently and in the past, times of visiting emergency room (ER) due to bleeding. Many PTP had hemophilic arthropathy with symptoms of morning stiffness, rheumatic joint pain, chronic joint pain, and limited exercise tolerance, we also reviewed their feedbacks of effects on above symptoms after switching.

Results: After switching to rFVIII-Fc, the rates of RP of 40 severe-type elevated from 47.5% (SHL rFVIII) to 90% (rFVIII-Fc). Among the 36 PTP with RP, the patient number of those who receive RP 60-65iu/kg every 5 day (Q5D), 45-50 iu/kg every 4 days (Q4D), and 30-35 iu/kg every 3 days (Q3D) were initially 31, 5 and zero, respectively and then became 27, 7, and 2 respectively. Among the 36 patients completing the PK study, their mean age was 33.8 + 12.9 years (14-62), the mean terminal half life was 19.0 + 4.4 hrs (11-25.75 hrs), the mean recovery rate (RR) was 2.4 + 0.5 (1.55-3.33), and the mean trough level was 3.2 + 1.9% (<1-8.5%). All the 36 PTP had no inhibitors, but six of them had transient inhibitors or had inhibitors eradicated by immunotolerance induction therapy in the past. Eight (23.5%) had still the trough level of 1% or < 1%, despite RP. Compared with the group who had never inhibitors before, the group having inhibitors in the past had significantly lower half life of rFVIII-Fc and marginally significantly smaller RR but trough level. Compared with the group of non-O blood type, the group with O blood type had significantly lower half life and trough level of rFVIII-Fc but RR. By correlation analysis, BMI, body weight, LBW were positively correlated with RR, but not correlated with half life and trough level. Between the group receiving 60-65 iu/kg Q5D and the group receiving 45-50 iu/kg Q4D, there were no significantly differences in half life and trough level of rFVIII-Fc in between the study groups. All our patients had no adverse effects or inhibitors formation after switching. Among the 49 PTP with switching. the frequency of visiting ER due to bleeding during a 6-month period reduced from 6 person-time between Nov., 2017 to May, 2018 with SHL FVIII used before switching to one person-time between Nov., 2018 to May, 2019 with rFVIII-Fc used after switching. Eight (72.7%) of 11 PTP who having morning stiffness, 11 (68.6%) of 16 PTP having rheumatic joint pain, and all 14 PTP having chronic joint pain reported the symptom improved. Twenty-one (63.6%) of 33 PTP reported their exercise tolerance became better after switching.

Conclusion: The rates of RP elevated markedly from 47.5% to 90% after switching from SHL FVIII to rFVIII-Fc. Most (75%) of PTP with RP had received injection Q5D during the study period. O blood type was an associated factor for shorted half life and trough level of rFVIII-Fc. Having inhibitors before was associated factors for shorted half life and smaller RR of rFVIII-Fc. BMI, body weight, and LBW were correlates of RR. The frequency of visiting ER due to bleeding reduced during 6 months after switching. More than 60% of PTP with RP reported improved morning stiffness, rheumatic joint pain, chronic joint pain, and exercise tolerance.