Improvement of Efficacy Outcomes in Patients Who Switched from Sucrose-Formulated rFVIII to BAY 81-8973 Prophylaxis in the LEOPOLD Clinical Trials

Background
BAY 81-8973 (Kovaltry^®) is a full-length, unmodified, recombinant factor VIII (FVIII), indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding and routine prophylaxis to reduce the frequency of bleeding episodes in adults and children with hemophilia A. It has the same amino acid sequence as sucrose formulated FVIII (FVIII-FS; Kogenate^® FS/Helixate^® FS). Pharmacokinetic comparisons confirmed BAY 81-8973 to have a longer half-life and lower clearance than FVIII-FS. The objective of this analysis was to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS prior to enrolling into the LEOPOLD clinical studies receiving BAY 81-8973.

Methods
LEOPOLD I (NCT01029340) Part B and LEOPOLD Kids (NCT01311648) were Phase 3, multinational, open-label studies that included male patients with severe hemophilia A receiving on-demand or prophylactic therapy, with ≥50 exposure days to any FVIII product and no history of FVIII inhibitors. Patients in LEOPOLD I were >12 years old and received 20–50 IU/kg BAY 81-8973 prophylaxis twice-weekly (2×W) or three times a week (3×W) for up to one year. Patients in LEOPOLD Kids were ≤12 years old and received 25–50 IU/kg BAY 81-8973 ≥2×W for six months. Dosing regimens for both studies were assigned by the investigator. In this analysis, efficacy and safety are assessed in the subset of patients in LEOPOLD I Part B and LEOPOLD Kids who were previously treated with FVIII-FS.

Results
In LEOPOLD I, 22 (35.5%) patients were previously treated with FVIII-FS with a median age of 27.0; in LEOPOLD Kids, 24 (47.1%) patients were previously treated with FVIII-FS with a median age of 5.0 (Table 1). In general, these switch cohorts had similar patient demographics to the whole study cohort (Table 1) and any differences did not affect the final analysis. Most patients did not change their dosing frequency when starting treatment with BAY 81-8973 but most increased their dose (FVIII-FS dose is 25 IU/kg 3×W [adults] or every other day [EOD; children]; BAY 81-8973 dose is 25–40 IU/kg 2×W or 3×W [>12 years] or 25–50 IU/kg 2×W, 3×W or EOD [≤12 years]). Switching from FVIII-FS to BAY 81-8973 resulted in lower median annualized bleeding rates (ABRs) in the LEOPOLD studies. In LEOPOLD I, median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) in the 12 months of FVIII-FS treatment prior to study entry, to 1.0 (0.0; 6.8) (Figure 1). In LEOPOLD Kids, median total ABR decreased from 3.0 (1.0; 12.0) to 2.0 (0.0; 6.0) for 0–<6 year old patients (n = 13) and from 4.0 (0.0; 10) to 0.0 (0.0; 2.1) for 6–12 year old patients (n = 11) after switching from FVIII-FS to BAY 81-8973 (Figure 1). Joint and spontaneous median ABRs were zero for <12 year old patients treated with BAY 81-8973. There were no study-drug-related adverse events (AEs) or serious AEs (SAEs) reported in patients switching from FVIII-FS to BAY 81-8973 in either LEOPOLD I Part B or LEOPOLD Kids (Table 2). One patient in the LEOPOLD Kids main study discontinued BAY 81-8973 due to a central venous catheter-related infection after six months of treatment, which was not considered study-drug-related. No FVIII inhibitors developed in any patients in either study.

Conclusions
Switching from FVIII-FS to BAY 81-8973 resulted in improved bleeding control in adults and children with hemophilia A and was well-tolerated.