Switching from Sucrose-Formulated rFVIII to Octocog Alfa (BAY 81-8973) Prophylaxis Improves Bleed Outcomes in the LEOPOLD Clinical Trials

Abstract

Introduction

Previous clinical trials established the efficacy and safety of sucrose-formulated recombinant factor (F) VIII (rFVIII-FS/Kogenate FS®/Helixate FS®) and octocog alfa (BAY 81–8973/Kovaltry®; LEOPOLD trials).

Aim

To report the results of a post hoc subgroup analysis assessing efficacy and safety outcomes in patients with hemophilia A who were receiving rFVIII-FS prior to enrolling into the LEOPOLD I Part B and LEOPOLD Kids Part A clinical trials and switching to octocog alfa.

Methods

LEOPOLD I Part B (NCT01029340) and LEOPOLD Kids Part A (NCT01311648) were octocog alfa Phase 3, multinational, open-label studies in patients with severe hemophilia A aged 12–65 years and ≤12 years, respectively. Annualized bleeding rate (ABR) was the efficacy endpoint for both studies. Safety endpoints included adverse events (AEs) and development of FVIII inhibitors.

Results

Of the 113 patients in both LEOPOLD trials, 40 (35.4%) patients received rFVIII-FS prophylaxis pre-study and had data available for pre-study total ABR. In LEOPOLD I Part B (n = 22, 35.5%), median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) pre-study to 1.0 (0.0; 6.8), and from 1.0 (0.0; 6.0) pre-study to 0.0 (0.0; 6.02) in LEOPOLD Kids Part A (n = 18, 35.3%). Octocog alfa was well tolerated, and no patients had drug-related serious AEs or inhibitors.

Conclusion

Treatment with octocog alfa prophylaxis appeared to have a favorable risk–benefit profile compared with rFVIII-FS and thus could be an effective and improved alternative strategy for individualized treatment for children, adolescent and adult patients with severe hemophilia A currently on rFVIII-FS treatment.

Keywords:

• FVIII
• hemophilia A
• prophylaxis
• recombinant proteins
• octocog alfa

Abbreviations

ABR, annualized bleeding rate; AE, adverse event; ED, exposure day; FVIII, factor VIII; PK, pharmacokinetic; rFVIII-FS, sucrose-formulated recombinant FVIII.

Full List of Approving IRBs (TUN)

De Videnskabsetiske Komitéer for Region Midtjylland (35001),

Medizinische Einrichtungen der Universität Bonn Ethikkommission an der Medizinischen Fakultät (10001),

Chaim Sheba Medical Center Helsinki Committee Tel-Hashomer (39001),

Comitato Etico a.o. Pugliese-Ciaccio (22002),

Comitato Etico Per Le Attivita’ Biomediche Carlo Romano Universita’ Studi Federico II (22004),

Comitato Etico Per La Sperimentazione Clinica Della Provincia Di Vicenza (22003),

Comitato Di Etica Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (22001),

Komisja Bioetyczna przy Inst. Hematologii i Transfuzjogii (18001, 18002),

University of Pretoria, Prinshof Campus (37002),

University of Witwatersrand WITS Human Research Ethics Committee (Medical) (37001),

Ciutat Sanitària i Universitaria de la Vall d’Hebron (24001),

Comité Étic d’Investigació Clínica, Complejo Hospitalario Universitario A Coruña

Servicio Galego de Saude – SERGAS Comité Ético de Investigación Clínico de Galicia (24002),

Hospital Central de Asturias Secretaría del Comité Ético de Investigación Clínica (24006),

Hospital Universitari i Politècnic La Fe Comité Etico de Investigación Clínica / Fundación para la investigación (24003),

Regionala Etikprövningsnämnden i Göteborg (34003),

Ege Universitesi Tip FakultesiEge Universitesi Tip Fakultesi Izmir 1 nolu Klinik Arastirmalar Etik Kurulu (47001, 47002, 47003),

East Midlands - Derby Ethics Committee,

Children’s Hospital Boston Committee on Clinical Investigation (14002),

Children’s Mercy Hospital Pediatric Institutional Review Board (14009),

St. Joseph’s Hospital Tampa Florida (14001),

University Hospitals Case Medical Center IRB for Human Investigation (14005),

University of California – Davis IRB Administration (14006).

Data Sharing Statement

Availability of the data underlying this publication will be determined later according to Bayer’s commitment to the EFPIA/PhRMA “Principles for responsible clinical trial data sharing”. This pertains to scope, time point and process of data access. As such, Bayer commits to sharing upon request from qualified scientific and medical researchers, patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the United States (US) and European Union (EU) as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal. Data access will be granted to anonymized patient-level data, protocols and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded.

Acknowledgments

The authors thank Graeme Baldwin of Darwin Healthcare Communications (Oxford, England) for providing medical writing support, which was fully funded by Bayer, in accordance with Good Publication Practice (GPP3) guidelines.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

G. Kenet: is a member of the Board of Directors/advisory committees and has received consultancy fees from ASC therapeutics, Roche, Sobi, Uniquore, Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi, PI Healthcare and CSL Behring; has received research funding from BSF, Opko Biologics, Bayer, Pfizer, Roche, Alnylam (Sanofi) and Shire; has received honoraria for participation in speakers’ bureaus from Bayer, BPL, CSL, Roche, Sanofi-Genzyme, Sobi, Spark, Uniquore, Pfizer, Takeda, BioMarin and Novo Nordisk. T. Moulton: is a Bayer employee. B. M. Wicklund: has received consultancy fees from Bayer, Genentech, Novo Nordisk and Shire. S. P. Ahuja: has received consultancy fees from Genentech, Sanofi Genzyme, CSL Behring and XaTek, Inc.; has received patent royalties and research funding from XaTek, Inc. He also has a patent with royalties for ClotChip and a patent for TraumaChek issued to US Patent office. M. Escobar is a member of the advisory boards and/or has received consultancy fees from Biomarin, Novo Nordisk, CSL Behring, Genentech/Roche, Sanofi, Takeda, Pfizer, Bayer, Kedrion, Hemobiologics/LFB, National Hemophilia Foundation, UniQure. J. Mahlangu is a member of the scientific advisory committee of Amgen, Bayer, Baxalta, Biogen, Biotest, CSL Behring, Catalyst Biosciences, Novo Nordisk, Roche and Spark; has received research grants from Bayer, Biogen, BioMarin, CSL Behring, Novartis, Sanofi, Spark, Takeda, Novo Nordisk, Sobi, Roche, Uniqure; has received honoraria for participation in speakers’ bureaus from Alnylam, Bayer, Biogen, Biotest, ISTH, Novo Nordisk, Pfizer, Roche, Sobi, Shire, and World Federation of Hemophilia. The authors report no other conflicts of interest in this work.

Additional information

Funding

This study and the LEOPOLD studies were funded by Bayer.