Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A

Abstract

To cite this article: Mannucci PM, Mancuso ME, Franchini M. Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A. J Thromb Haemost 2016; 14: 1330-6.Summary. After technological progress provided safer therapeutic products for patients with hemophilia A, the development of alloantibodies (inhibitors) neutralizing the coagulant activity of infused factor VIII (FVIII) remains the most serious complication of replacement therapy, predisposing patients to greater morbidity and causing higher treatment costs. The pathogenesis of inhibitors, which develop at a high rate in previously untreated children with severe hemophilia A, is multifactorial, resulting from complex interactions between genetic and environmental factors. Among non-genetic determinants, a key role is played by treatment-related factors, including the source of FVIII product (i.e., plasma derived or recombinant) and the mode of replacement therapy delivery (i.e., intensity, prophylaxis vs. on demand). We review the potential interventions on these modifiable factors that may help to lower the rate of inhibitor development. In addition, interest is currently directed toward the potential for lesser immunogenicity of novel hemostatic agents designed to decrease the dosing frequency or avoid/delay the need of FVIII replacement therapy.

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

“…While on one hand new products with promising features are appearing on the horizon, on the other there is a need to have tools by which clinicians can guide their therapeutic choices. After over 40 years of clinical experience in the field of hemophilia, prophylaxis is now recognized as the only therapeutic approach able to modify the natural course of the disease, preventing joint damage [7]. New drugs have recently become available, and the extent of clinical evidence has grown (and is likely to further increase).…”

“…fusion with the Immunoglobulin Fc fragment, PEGylation and the creation of a single chain) or innovative production techniques (e.g. the co-expression of the Human Heat Shock Protein 70, HSP70), show an improved pharmacokinetic profile which have allowed, in some cases, a reduction in the number of prophylaxis infusions required or to provide more effective protection from bleed while leaving the frequency of administration unchanged [7]. While improved pharmacokinetic properties represent an important advance in the management of hemophilia A patients, they remain secondary to clinical efficacy [8], but represent an additional "piece of the puzzle" to individualize prophylaxis based on the characteristics of the drug and the individual patient's disease course (bleeding phenotype, presence/absence of joint damage, level of physical activity and adherence to prescribed treatment).…”

A Look at the Future Hemophilia A Treatment

“…A purpose of future therapies is to produce novel haemostatic agents with lesser immunogenicity, with the possibility of effective administration in a smaller number of doses, or even making products that avoid the need for substitution therapy with coagulation factors [1]. New therapeutic means for hemophilic patients with inhibitors may therefore consist in the introduction of nonfactor replacement strategies [2].…”

Inhibitors in Patients with Congenital Bleeding Disorders Other Than Hemophilia

“…The most serious complication of treatment with coagulation factor concentrates in patients with congenital hemophilia is development of alloantibodies against the deficient coagulation factor (F), namely, VIII (FVIII; hemophilia A) or IX (FIX; hemophilia B). [1][2][3][4][5] Indeed inhibitory alloantibodies, which develop in up to one-third of previously untreated patients with severe hemophilia A and up to 5 to 6% of patients with severe hemophilia B, neutralize the coagulant effect of factor replacement therapy, therefore requiring a shift toward treatments based on FVIII-and FIX-bypassing agents. [6][7][8] As a consequence, inhibitors preclude the access of persons with hemophilia to safe and effective standards of care, predisposing them to increased risk of morbidity and permanent disability which, ultimately, negatively influences their quality of life.…”