Critical Review of the Pivotal Studies of Four rFVIII Products for the Treatment of Hemophilia A Patients: The Role of Octocog Alfa

Abstract

INTRODUCTION: Hemophilia A is a rare congenital bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). The severe form of the disease is characterized by spontaneous bleeds, especially into the joints. Prophylaxis, based on regularly intravenous administration of the missing factor to avoid hemorrhages, represents the gold standard of treatment. In recent years, new products that significantly improve the treatment management options for patients with hemophilia have become available in the market.OBJECTIVE: To critically evaluate the pivotal studies of recombinant FVIII (rFVIII) products, approved in Europe within the first half of 2018 having obtained the indication for a prophylaxis dosing regimen based also on a twice weekly infusion frequency or even less, highlighting their limitations or strengths.METHODS: A systematic literature search was conducted, and several databases (PubMed and Embase) were consulted.RESULTS: Nine clinical trials involving patients with severe hemophilia A without inhibitor were included in this analysis. Four rFVIII products (Elocta®, Biogen, Cambridge, MA, USA; Kovaltry®, Bayer HealthCare Pharmaceuticals, Germany; Afstyla®, CSL Behring GmbH, Germany; Adynovi®, Baxalta Innovation GmbH, Austria) with different pharmacokinetic profiles were evaluated. The trials included in this analysis had different designs and heterogeneous methods were utilized to assess the study outcomes. The baseline characteristics of the patients enrolled in the studies were also often different and sometimes not adequately described. LEOPOLD II, a trial to compare prophylaxis to on-demand therapy with an unmodified rFVIII product (Kovaltry®, octocog alfa), was the only completely randomized trial that enrolled a more critical patient population in terms of compromised joint condition than the other studies. Based on these side-by-side comparison, Octocog alfa reported similar efficacy, in terms of annualized bleeding rate, to the other rFVIII products, including extended half-life.CONCLUSIONS: Even without structural modifications, octocog alfa may be considered a useful treatment option for two times a week prophylaxis in a selected population of haemophilia patients.

Prophylaxis with a recombinant factor VIII Fc in hemophilia A: long-term follow-up on joint health, efficacy, and safety from phase 3 studies in children and adults

“…Notably, at each 6-month efficacy period in A-LONG/Kids A-LONG and ASPIRE, at least 70% of subjects on IP, across all ages, experienced zero spontaneous joint bleeds. It should be noted that comparisons with other EHL FVIII replacement products are limited by heterogenous study designs [ 31 ].…”

Real-World Clinical Outcomes and Replacement Factor VIII Consumption in Patients with Haemophilia A in Italy: A Comparison between Prophylaxis Pre and Post Octocog Alfa (BAY 81-8973)

“…The possibility of personalized therapeutic approaches in haemophilia care has been significantly improved also thanks to the advance in treatment options, such as recent rFVIII products that allow a lower frequency of infusions compared with the usual every other day or three-times-per-week regimen of older standard half-life products [ 4 , 5 , 6 , 7 , 8 , 9 ]. Understanding the impact of these products on the effectiveness and costs in clinical practice has become particularly important to help healthcare decision makers in understanding the real value of these innovations [ 10 ].…”

“…To overcome these difficulties, clinicians moved towards individualized treatment approaches that are defined on the basis of the characteristics of each patient, their lifestyle, bleeding phenotype, preferences, and those of the individual product, including pharmacokinetic properties [ 7 , 8 ]. The possibility of a personalized approach was significantly improved also thanks to the advance in treatment options, as rFVIII products offer the possibility of a lower frequency of infusions compared with the usual every-other-day or three-times-per-week regimen [ 4 , 9 , 10 ]. One of the first rFVIII concentrates available on market that allowed a two-times-a-week prophylaxis regimen was BAY 81-8973 (octocog alfa, Kovaltry ® , Bayer Pharma AG, Berlin, Germany), an unmodified, full-length, standard half-life (SHL) rFVIII concentrate approved in 2016 for on-demand treatment, prophylaxis, and perioperative management of patients with haemophilia A.…”

“…So far, the possible impact of BAY 81-8973 has been assessed with indirect comparisons based on clinical trials results and consumptions as reported in summary of product characteristics [ 9 , 12 ] and only preliminary results of one study on real-world prophylactic treatment with unmodified full-length recombinant FVIII BAY 81-8973 are available [ 13 ]. The aim of this study was to fill this gap, assessing the effectiveness of prophylaxis with BAY 81-8973 in the real-world setting and its impact on FVIII consumption compared with a previous treatment with SHL recombinant product.…”