Extension Study With rVIII-SingleChain in Previously Untreated Patients (PUPs) With Severe Haemophilia A

Introduction: Clinical trials and real-world evidence have demonstrated the efficacy and safety of rVIII-SingleChain in previously treated patients with haemophilia A. Aim: To investigate the safety and efficacy of rVIII-SingleChain in previously untreated patients (PUPs). Methods: In an open-label, phase 3, extension study, PUPs with severe haemophilia A (FVIII <1%) received rVIII-SingleChain prophylactically or on-demand. The primary endpoints were incidence of high-titre (HT) inhibitor formation to FVIII, treatment success for major bleeding episodes and annualised spontaneous bleeding rate (AsBR). Results: Twenty-four PUPs (median age 1 year [range 0–5]) were treated with rVIII-SingleChain; median time on study was 35.0 months (range 2.4–54.0). Overall, six PUPs developed a HT inhibitor (>5 BU/mL) and six developed a low-titre (LT) inhibitor (≤5 BU/mL). The median number of exposure days at inhibitor development was 10 (interquartile range [IQR] 5.0–14.0). Of 11 inhibitor-positive PUPs (five HT, six LT) who continued rVIII-SingleChain therapy, nine (81.8%; three HT, six LT) achieved inhibitor eradication (<0.6 BU/mL). Median time to eradication was 14.3 weeks (IQR 9.8–53.8). Seventeen treatment-emergent adverse events in 12 PUPs (50.0%) were related to rVIII-SingleChain, mainly inhibitor development (14/17 events). Treatment was successful (haemostatic efficacy rated excellent or good) for 290/315 bleeding events (92.1%). During prophylactic therapy, inhibitor-negative PUPs had a median (IQR) AsBR of 0.52 (0.00–4.99) and annualised bleeding rate of 1.98 (0.77–11.23). Conclusion: RVIII-SingleChain demonstrated a satisfactory benefit:risk profile in PUPs, with a high treatment success rate and a low AsBR during prophylaxis, and was effective at eradicating inhibitors.