Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II)

K Kavakli, R Yang, L Rusen, H Beckmann, D Tseneklidou-Stoeter, M Maas Enriquez, LEOPOLD II Study Investigators, Renchi Yang, Yongqiang Zhao, Jing Sun, Xuefeng Wang, Depei Wu, Antonin Hlusi, Katsuyuki Fukutake, Hideji Hanabusa, Teruhisa Fujii, Oscar Pérez Ramírez, Blanca Salazar Alvarado, Margit Serban, Luminita Rusen, Valentina Uscatescu, Cristina Trucia, Gordana Kostic, Nada Konstantinidis, Zoran Igrutinovic, Farida Perina, Tatiana Andreeva, Kaan Kavakli, Bulent Antmen, Ilgen Sasmaz, Alphan Kupesiz, Mehmet Akif Yesilipek, Ching-Tien Peng, James French 2nd, Miguel Escobar, Johnny Mahlangu, Roger Pool, K Kavakli, R Yang, L Rusen, H Beckmann, D Tseneklidou-Stoeter, M Maas Enriquez, LEOPOLD II Study Investigators, Renchi Yang, Yongqiang Zhao, Jing Sun, Xuefeng Wang, Depei Wu, Antonin Hlusi, Katsuyuki Fukutake, Hideji Hanabusa, Teruhisa Fujii, Oscar Pérez Ramírez, Blanca Salazar Alvarado, Margit Serban, Luminita Rusen, Valentina Uscatescu, Cristina Trucia, Gordana Kostic, Nada Konstantinidis, Zoran Igrutinovic, Farida Perina, Tatiana Andreeva, Kaan Kavakli, Bulent Antmen, Ilgen Sasmaz, Alphan Kupesiz, Mehmet Akif Yesilipek, Ching-Tien Peng, James French 2nd, Miguel Escobar, Johnny Mahlangu, Roger Pool

Abstract

Background: BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance.

Objectives: To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A.

Patients/methods: In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 12–65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed.

Results: Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported.

Conclusions: Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.

Figures

Figure 1
Figure 1
Study design for LEOPOLD II. CS/ADJ = labeled potency adjusted by a predefined factor to mimic results obtained with the one-stage assay; CS/EP = labeled potency determined by the chromogenic substrate assay per European Pharmacopoeia.
Figure 2
Figure 2
Patient disposition. *Reason for termination was noncompliance with documentation of dosing. †Reasons for not being treated were withdrawal of consent (n = 2) and protocol violation (n = 1). CS/ADJ = labeled potency adjusted by a predefined factor to mimic results obtained with the one-stage assay; CS/EP = labeled potency determined by the chromogenic substrate assay per European Pharmacopoeia.
Figure 3
Figure 3
Annualized bleeding rate by time period for the twice-weekly and 3-times-weekly prophylaxis dosing groups.

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