Page 34 - Haematologica March 2020

P.M. Mannucci et al.
IgG1 or albumin;25,26 and (ii) conjugation with chemicals such as polyethylene glycol (PEG).27,28 The mechanism whereby albumin and Fc fusion prolongs the plasma half- life of coagulation factors is through the neonatal Fc recep- tor,25,29 which recycles them in plasma and thereby pro- longs their effective circulation.29 PEG, attached randomly or site-specifically to coagulation factors, acts by slowing their degradation and renal elimination.27,28
Two extended half-life (EHL) recombinant coagulation factors were licensed in 2014: the Fc-fused FIX eftrenonacog alfa and the Fc-fused FVIII efmoroctocog alfa.30,31 Subsequently, other EHL FVIII and FIX products were clinically evaluated, licensed and marketed (Tables 2 and 3), so that three pegylated FVIII products plus an albu- min fusion and a pegylated FIX product, in addition to the two Fc- fusion products, are now available.32-40 FIX prod- ucts can prolong the plasma half-life by from 4- to 5-fold (Table 3), whereas the half-life of FVIII can still be pro- longed by no more than 1.5-1.7 fold (Table 2) due to its dependence on the half-life of its chaperone vWF to which it is complexed in blood. Pivotal clinical studies, conduct- ed in highly selected adults and children, showed that these products were efficacious in stopping or preventing bleeding in the frame of episodic and prophylactic treat- ment regimens, and that they could also be used to safely manage surgical interventions.32-40
The median annualized bleeding rate (ABR), the param- eter most commonly used to evaluate the clinical efficacy
Table 2. Extended half-life factor VIII products.
of antihemophilic products, ranged from 1 to 4 episodes, accumulating all the different prophylactic dosing regi- mens evaluated clinically for FVIII products.41 These ABR values compare favorably with those much higher values obtained with episodic regimens, ranging from 18 to 41.41 For EHL FIX products, the ABR had a similar range of val- ues with different prophylaxis regimens.31,40 In practice, EHL FVIII products can be effectively administered twice instead of thrice weekly, but most patients are not satis- factorily protected from bleeds with weekly dosing regi- mens.41 EHL FIX products are much more satisfactory, because they can be given every 10 or even 15 days,42 and thus allow a lower annual burden of intravenous injec- tions, the average reduction being more prominent (∼60%) than for FVIII products (∼30%) (Figure 2). Furthermore, higher trough levels of both FVIII (2-3%) and FIX (5-10%) could be achieved than with SHL prod- ucts,41,42 and there was, in general, a lower annual con- sumption in units of EHL products.41,42 From a practical clinical standpoint these considerations broadly apply to all the different products, and these may be considered equivalent in terms of efficacy at a time when no face-to- face comparative clinical study is available. The market price of all these products is usually higher, but there are exceptions in countries where the price per unit of EHL FVIII is very close to that of SHL FVIII.
A few limitations warrant our attention. Despite higher trough plasma factor levels, the ideal goal of avoiding all
Engineered protein
Efmoroctocog alfa
Rurioctocog alfa pegol
Danoctocog alfa pegol
Turoctocog alfa pegol
Year of first licensing
2014
2015
2018
2019
Manufacturer
Biogen/Sobi
Baxalta/Takeda
Bayer
Novo Nordisk
Plasma half-life (hours)
19
14.3 19 18.4
Plasma half-life (hours)
82
101
93
Half-life prolongation*
1.5-1.7
1.3-1.5 1.6 1.6
Half-life prolongation*
4.3
5.3
4.9
*Calculated from an average plasma half-life of standard coagulation FVIII of approximately 12 hours.
Table 3. Extended half-life factor IX products.
Engineered protein
Efrenonacog alfa
Albutrepenonacog alfa
Nonacog beta pegol
Year of first licensing
2014
2016
2017
Manufacturer
Biogen/Sobi
CSL Behring
Novo Nordisk
*Calculated from an average plasma half-life of standard FIX products of approximately 19 hours.
Figure 2. Summary features of Factor VIII and Factor IX products with an extended half-life. Comparative main characteristics of the extended half-life coagulation factor products (left FVIII, right FX), including the percentage reduction of the annual infusion number compared with the standard half-life products, trough plasma factor levels that can be achieved, expected changes in the clinical phenotype the range of increase of plasma half-life.
548
haematologica | 2020; 105(3)