Page 35 - Haematologica March 2020

Future of hemophilia therapy
spontaneous bleeds was achieved in no more than 30- 40% of cases in the prophylaxis dosing regimens evaluat- ed in the pivotal studies, even though higher rates of zero bleeding were often obtained in the extension studies through the personalization of the dosing regimens.41 Because these products have only been marketed for six years or less, no evaluation of long-term, real-life experi- ence has yet been made. No theoretical concerns regard- ing a higher rate of inhibitor development with these highly engineered coagulation factors were raised in the pivotal studies,41 although only previously-treated patients at low risk of developing this complication were enrolled. It remains to be seen whether or not this risk is smaller, equal or higher than that of the SHL recombinant or plas- matic products in high-risk patients, i.e. those not previ- ously treated with any source of FVIII and thus with no tolerance of this moiety. Finally, four of the seven current- ly marketed EHL products use an exogenous chemical such as PEG. Pegylation has been safely used to prolong the length of time medication remains in the circulation in several products, e.g. epoietin, interferon, the human growth factor, and many others.28 The amount of PEG used to prolong the half-life of FVIII, present in tiny amounts in plasma, is the smallest among all the pegylated medications, but, as yet, this does not apply for FIX.43 On the other hand, none of the currently licensed pegylated medications is administered lifelong from birth, a unique situation for antihemophilic factors. For the moment, in contrast to the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) has chosen to restrict the use of most pegylated coagulation factors to patients over the age of 12 years.
Non-factor therapies
In spite of the progress made with the availability of EHL factors, unmet needs remained. In HA patients with- out inhibitors, the reduction in the frequency of intra- venous injections was not considered satisfactory,41,42 and therapy still based on the need for a venous access contin- ued to be unattractive. HA patients with FVIII inhibitors remained poor candidates for prophylaxis that could only be provided by bypassing products such as APCC and rFVIIa that are very expensive44 and difficult to administer on a regular preventive basis. With these drawbacks in mind, therapeutic approaches that were not based on the replacement of the deficient factor were developed. This took place in two main ways: (i) for HA, by mimicking the coagulant activity of FVIII; and (ii) for both HA and HB, by increasing defective thrombin formation through the inhi-
bition of the naturally occurring anticoagulants (antithrombin, tissue factor pathway inhibitor, and acti- vated protein C). For the moment, only the monoclonal antibody emicizumab that mimics FVIII activity has been licensed and marketed. The approach of quenching the anticoagulant pathways, potentially applicable not only to both the hemophilias but also to all the inherited coagula- tion disorders, is currently undergoing an advanced stage of clinical development, but since no product has been licensed yet, here this will receive less attention than emi- cizumab.
Emicizumab
This bispecific monoclonal antibody supports the spa- tial interaction between activated FIX (FIXa) and factor X, and thereby promotes thrombin formation by mimicking FVIIIa activity regardless of FVIII deficiency and the pres- ence of FVIII inhibitors.45 Administered subcutaneously, this drug reaches a steady state with a long plasma half- life that allows well-spaced dosing intervals of at least every week or even every two weeks.46,47 It was first licensed in 2017 in the USA, and then in Europe and Japan, for the prophylaxis of bleeding in adults and pediatric patients with HA, with and without inhibitors. The first two pivotal studies were carried out in patients with FVIII inhibitors: HAVEN 1 in adults and adolescents,48 and HAVEN 2 in pediatric patients under 12 years of age.49 Using various dosing regimens and intervals between the subcutaneous injections, both the studies found that the ABR ranged between 0.2 and 2.9, values that compare favorably with those observed in inhibitor patients not on prophylaxis (Table 4). The rate of zero bleeding events ranged between 63% and 90%, the highest rate being obtained in HAVEN 2 when the medication was given at a dosage of 3 mg/Kg of body weight every two weeks (Table 4). These results are impressive if one considers that, until now, HA patients with FVIII inhibitors have been poor candidates for a feasible prophylaxis of bleed- ing, because attempts to use aPCC or rFVIII were jeopard- ized by the need for very frequent intravenous injections, let alone the very high costs.44 Following the striking results obtained in HAVEN 1 and 2, emicizumab has also been evaluated in HA patients without inhibitors.50,51 In the HAVEN 3 study, previously treated adult patients were assigned to subcutaneous emicizumab administered weekly or even every two weeks; study participants had much lower ABR than those not on prophylaxis (1.5 and 1.3 vs. 38.2) and much higher rates of zero bleeds (50% and 40% vs. 0%) (Table 4).
Table 4. Bleeding rates observed with different emicizumab dosing regimen(s) in patients with hemophilia A with and without inhibitors in the context of the HAVEN studies.
STUDY
HAVEN 1
HAVEN 2
HAVEN 3
HAVEN 4
DOSING REGIMEN
1×W prophylaxis (1.5 mg/kg) (n = 35) No prophylaxis (n = 18)
1×W prophylaxis (1.5 mg/kg) (n = 68) E2W prophylaxis (3.0 mg/kg) (n = 10) E4W prophylaxis (6 mg/kg) (n = 10)
1×W prophylaxis (1.5 mg/kg) (n = 36) E2W prophylaxis (3.0 mg/kg) (n = 35) No prophylaxis (n = 18)
E4W prophylaxis (6 mg/kg) (n = 41)
ABR (MEDIAN)
2.9 23.3
0.3 0.2 2.2
1.5 1.3 38.2
4.5a
ZERO BLEEDING RATES
63% 6%
76.9% 90% 60%
50% 40% 0
NR
ABR: annualized bleeding rate; NR: not reported; 1×W: once weekly; E2W: every 2 weeks; E4W: every 4 weeks. aMedian ABR during the expansion phase.
haematologica | 2020; 105(3)
549