Patterns of Prior Treatment and Bleeds Among Patients with Severe Hemophilia a: Impact on Frequency of Dosing with Bay 81-8973 in the Leopold I Trial

Background: BAY 81-8973 is an investigational recombinant factor VIII (FVIII) product with recommended prophylactic dosing of 20-40 IU/kg at least 2x or 3x weekly for patients with severe hemophilia A. The frequency of dosing with FVIII is among several decisions made by treating physicians and potentially affects effectiveness and cost. The impact of prior bleeds or prior FVIII treatment on the choice of BAY 81-8973 dosing frequency has not been studied previously and may help clarify the association of dosing frequency with effectiveness. This study examines the association between prior treatment patterns and bleeds with dose frequency assignment in patients from the LEOPOLD I (LEO I) trial.

Methods: Data from part B of the phase II/III randomized, open-label crossover LEO 1 trial were analyzed. The sample consisted of patients who received prophylactic treatment with BAY 81-8973 during the 12-month LEO I study period. At study start, patients were assigned to a dose and a frequency of either 2x/week or 3x/week at the investigator's discretion; once assigned, the dose and frequency were unchanged through the study period. This analysis compared physician-recorded pre-enrollment FVIII treatment frequencies and bleeds during the last 12 months prior to enrollment between the 2x/week and 3x/week groups. Wilcoxon rank sum tests were used to compare average dose per FVIII injection and number of bleeds, and chi-square tests were used for mode of treatment (on-demand or prophylaxis) and FVIII treatment frequencies.

Results: Among 62 patients in the trial, mean age was 31.5 years and 89% were Caucasians. FVIII prophylaxis frequencies ranged from daily to 1x/week prior to enrollment. 11 patients in the 2x/week group had received pre-enrollment FVIII prophylaxis at a frequency of 2x/week (Table 1). 28 patients in the 3x/week group had received FVIII injections at a frequency of 3x/week prior to enrollment. Some of these patients in each group had also received pre-enrollment FVIII prophylaxis at other frequencies. Average FVIII doses per injection in IU/kg were higher in the 2x/week group for prior on-demand and prophylactic therapy, but these differences were not statistically significant. The majority of patients in the 2x/week group (56%) and the 3x/week group (59%) had received Bayer's sucrose-formulated recombinant factor VIII prior to enrollment. Regardless of prior mode of treatment, the average number of bleeds in the last 12 months before enrollment was higher in the 3x/week group (13.4 bleeds) than in the 2x/week group (7.1 bleeds).

Conclusions: Investigator selection of 2x/week or 3x/week dosing frequency was correlated with the regimen patients were on prior to enrollment. Patients receiving FVIII 3x/week had, overall, more frequent bleeding episodes than patients in the 2x/week group in the year prior to enrollment, suggesting that a phenotypic approach can well be used for dosing with Bay 81-8973.

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