At the present time, the development of inhibitors is the most dreaded complication and one that most severely influences the success of treatment and quality of life in hemophilic patients. When confronted with a hemophilic patient, the clinician usually has two goals in mind: one of them immediate, namely treatment and prevention of bleeding episodes, and the other one longer term: permanent eradication of the inhibitor by means of immune tolerance induction therapy.
Patients are classified into high and low responders depending on their inhibitor titer and the nature of their anamnestic response. In low responders, the inhibitor titer will not rise above 5 Bethesda units/dl (BU/dl), although it is repeatedly exposed to the deficient factor.
The presence of an inhibitor does not alter the location or the frequency of bleeding events, but it usually increases the severity of hemophilia as alternative treatments tend to be less effective.
When the inhibitor titer is low, bleeding can be treated or even prevented with high doses of factor VIII (FVIII) or factor IX (FIX) concentrates. For patients with high titers, alternative treatments are available with the so-called bypassing agents. Two bypassing agents are currently available: activated prothrombin complex concentrate (aPCC) (FEIBA) and recombinant activated factor VII (rFVIIa) (Novoseven). The efficacy of these products tends to be lower than substitutive therapy with clotting factors. Their true mechanism of action is not fully understood. No analytical parameters are available to assist clinicians in treatment a response adjustment, which means that the effectiveness of treatment can only be assessed symptomatically. Thrombotic complications have been reported, albeit infrequently, for both products.
aPCC is the result of an in-vitro modification of plasma-derived prothrombin complex concentrates with varying degrees of activation of some of the clotting factors. Factor Xa and prothrombin are the most active components in aPCC. The most usual dose ranges between 50 and 200 U/kg/day, distributed over one to three infusions. The product contains traces of FVIII, which are believed to be responsible for the anamnestic response observed in around 30% of patient with hemophilia, accompanied by an increase in inhibitor titer. The product's half-life is 4–7 h as measured by the thrombin generation test. The product has shown an effectiveness rate of around 82% [1,2].
rFVIIa is a recombinant product. The standard dose range is 90 μg/kg. Half-life is around 2.7 h. As rFVIIa does not contain FVIII, it does not result in an anamnestic response . Effectiveness ranges between 60 and 92% across different studies [4,5].
Publications with high levels of evidence have shown that prophylactic replacement therapy is superior to on-demand treatment in hemophilic patients without inhibitors [6–8].
It is widely known that patients with hemophilia with inhibitors show a more impaired joint status and a poorer quality of life. This was demonstrated scientifically by a study conducted during the past decade in European centers .
aPCC prophylaxis has been sporadically applied in hemophilic patients with inhibitors for over three decades . Over this period, several retrospective studies have shown a bleeding decrease with the administration of prophylactic treatment with bypassing agents. Progression of arthropathy, however, can seldom be halted [11,12]. Nonetheless, it was only in the past decade that better designed prospective randomized trials made it possible to more compellingly demonstrate that prophylactic administration of these bypassing agents can result in a decrease in the number of bleeding episodes, both into the joints and into other organs, and enhance these patients’ quality of life [13–18].
A study on rFVIIa carried out a randomized comparison of two dosing regimens administered daily for 3 months (90 vs. 270 μg/kg). The first regimen led to decreased bleeding in 45% of patients as compared with 59% of patients in the group who received the higher dose. However, as these differences were not significant, the currently recommended dose is 90 μg/kg .
Two randomized trials analyzed prophylactic treatment with aPCC. The ProFEIBA trial treated patients with a three times weekly dose of 85 U/kg for 6 months. Treatment resulted in a 62% reduction in the total number of bleeding episodes and a 61% reduction specifically in joint bleeds. Over 60% of patients were achieved a satisfactory response, that is, a more than 50% reduction in the number of bleeding episodes. Twenty-four percent of patients experienced no bleeds during the 6 months they were on prophylaxis . The second aPCC study compared 17 patients treated prophylactically with 85 U/kg every other day with 19 patients treated on demand over 1 year. The authors observed a 72.5% reduction in the number of bleeds in the group on prophylaxis; factor consumption in this arm was three times higher than in the on-demand arm .
These trials demonstrate that secondary prophylaxis in hemophilic patients with inhibitors can lead to a reduction in the number of bleeding episodes. As these are studies on patients with established joint damage, one would be justified in inferring that outcomes in patients without arthropathy should be even more promising. Nonetheless, follow-up periods were relatively short so no hard-and-fast conclusions can be drawn. At any event, there are series of children where prophylaxis is started at a younger age, which show a decreased annualized bleeding rate (ABR) over a 6-year follow-up period. This seems to suggest that arthropathy may be prevented in these patients.
The choice between aPCC and rFVIIa depends on the stage the patient is at. The variable that is most commonly associated with a satisfactory response to immune tolerance induction (ITI) therapy is a less than 10 BU/dl inhibitor titer at the onset of treatment. This means that patients with inhibitors assigned to ITI should be administered rFVIIa to avoid stimulating the immune system, thus, facilitating a decrease in their inhibitor titer. In other patients on ITI, in those who have failed ITI, or in patients who will not undergo ITI, both treatments can be used indifferently, depending on the efficacy shown in each patient. The characteristics of the products themselves may also influence the clinician's choice. The large doses required for aPCC may complicate infusion in younger children and make the clinician select rFVIIa. Clinicians may resort to the recently published Spanish guidelines for bypassing agent (BPA) prophylaxis in patients with hemophilia, which will assist them in choosing the right .
New promising molecules are currently being investigated for the prevention of bleeding episodes in hemophilia.
One of them is Emicizumab (ACE910; Hoffman-La Roche and Chugai Pharmaceutical), a chimeric bispecific humanized antibody directed against FIXa and FX, which mimics the co-factor function of FVIII. It binds to the enzyme FIXa with one arm and to the FX zymogen with the other, placing both in spatially appropriate positions and thereby promoting FIXa-catalyzed FX activation and tenase formation [20,21].
Compared with traditional factor replacement bypassing agents, emicizumab is currently licensed as a once-weekly 1.5 mg/kg subcutaneously administered prophylactic therapy, offering a reduction in frequency or prevention of bleeds and improved patient convenience.
The phase 1 conduced in healthy male adults, 40 Japanese and 24 Caucasian patients were randomized to receive a single subutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear phrmacokinetic profile and had a half-life of ∼4 to 5 weeks. All adverse events were nonserious. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed . A dose-escalation study was performed in 18 Japanese severe hemophilia A patients (>12 years old; 11 inhibitors and 7 noninhibitors) using once-weekly subutaneous injections of emicizumab at 0.3, 1, and 3 mg/kg for 12 weeks. No serious adverse events (SAEs) were observed. Median ABRs decreased significantly from 32.5 to 4.4 (0.3 mg/kg), 18.3–0.0 (1 mg/kg), and 15.2–0.0 (3 mg/kg). No bleeding events were recorded in eight inhibitor patients or in five noninhibitor patients .
In a phase III open-label, multicenter, randomized HAVEN 1 trial was published. A total of 109 male participants age at least 12 years with hemophilia A with inhibitors were enrolled . In this study, inhibitor patients treated with emicizumab experienced a significant decrease in ABR compared with those receiving an on-demand BPA therapy. Patients who had received BPAs on-demand were assigned to emicizumab prophylaxis (n = 35; group A) and no prophylaxis (n = 18; group B). Patients who had received prophylactic BPA treatment received emicizumab prophylaxis (n = 24; group C). Emicizumab was administered at 3.0 mg/kg for 4 weeks, followed by 1.5 mg/kg weekly. The ABR was 2.9 events [95% confidence interval (CI), 1.7–5.0] among participants who were randomly assigned to emicizumab prophylaxis (group A) versus 23.3 events (95% CI, 12.3–43.9) among those assigned to no prophylaxis (group B), representing a significant difference of 87% in favor of emicizumab prophylaxis (P < 0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous BPA prophylaxis (P < 0.001).
During this study, 3/103 patients experienced thrombotic microangiopathy (TMA) and 2 patients developed thrombosis. The bleeds in these patients were treated with aPCC greater than 100 U/kg/day for greater than 24 h; not noted with lower cumulative doses of aPCC or with a rFVIIa regimen alone. After restricting the dose of aPCC or using only rFVIIa, no cases of TMA have been reported again. A possible explanation of this increased thrombotic incidence lies in the fact that the activity of the bispecific antibody is predominantly dependent on the amount of FIXa that is generated (aPCC contains FIXa) .
The HAVEN 2 study is an open-label, multicenter, safety, efficacy and pharmacokinetic study of emicizumab prophylaxis in pediatric patients, less than 12 years of age and patients 12–17 years old who were less than 40 kg. The study is ongoing; however, an interim analysis was presented in abstract form . There was a very high degree of efficacy with 94.7%% of patients reporting no bleeds requiring treatment. In an intra-patient analysis of patients who were on BPA therapy treatment prior to starting on the emicizumab study similar to what is reported above for HAVEN 1, there was a 99% reduction in treated bleeding events. From the safety standpoint, there were no thrombotic events or TMA; however, only three patients needed BPA therapy such that what caused these events in HAVEN 1 occurred very infrequently in HAVEN 2. The most common adverse event occurring in 17% of patients was mild injection site reaction. The dosing in children is the same as that in adolescents and adults.
In August 2018 was published the study of emicizumab prophylaxis in hemophilia A patients without inhibitors. The participants at least 12 years of age who had been receiving episodic treatment with FVIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg/kg per week (group A) or 3.0 mg/kg every 2 weeks (group B) or no prophylaxis (group C). A total of 152 participants were enrolled. The ABR was 1.5 events (95% CI, 0.9–2.5) in group A and 1.3 events (95% CI, 0.8–2.3) in group B, as compared with 38.2 events (95% CI, 22.9–63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P < 0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events .
This agent received the approval from the US Food and Drug Administration (FDA), under the name of Hemlibra, for hemophilia A patients with FVIII inhibitors in December 2017 and by the European Drug Agency in February 2018. Now it is also approved by the FDA and the European Drug Agency (EMA) for patients without inhibitors.
Another category of agents seeks to cause a coagulation imbalance. Two such agents are concizumab and fitusiran. There are different pharmaceutical companies working with antibodies against tissue factor pathway inhibitor (TFPI), concizumab (Novo Nordisk A/S, Bagsvaerd, Denmark), is the anti-TFPI at the most advanced stage of development .
Concizumab is a recombinant humanized monoclonal antibody (mAb) against tissue factor pathway inhibitor (TFPI). Blocking the action of thrombin activatable fibrinolysis inhibitor (TAFI) could compensate for the limited development of Xa in the absence of FIXa/VIIIa, concizumab also prevents TFPI inhibition of the TF-FVIIa complex and thus promote enough thrombin generation to achieve hemostasis in hemophilic patients [29–31].
In a phase 1 dose escalation, multicenter, randomized, double-blind, placebo-controlled trial escalating single intravenous (0.5–9000 μg/kg) or subcutaneous (50–3000 μg/kg) doses of concizumab were administered in 28 healthy volunteers and 24 hemophilia patients. Plasma concizumab levels were detectable for 43 days, and plasma concentrations of TFPI showing functional activity were decreased for 14 days after administration. There were no serious adverse events and no anticoncizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed because of target-mediated clearance .
A phase I, multicenter, randomized, placebo-controlled, double-blind trial investigating safety, pharmacokinetics and pharmacodynamics of multiple doses (0.25, 0.5, 0.8 mg/kg every fourth day) of concizumab administered subcutaneously to hemophilia A patients (Explorer3) has been recently completed. No safety concerns emerged from this primary analysis, which also confirmed a pharmacokinetics/pharmacodynamics relationship among concizumab dose, TFPI levels and thrombin generation. The estimated exposure response model showed a tight pharmacokinetics/pharmacodynamics relationship between concizumab exposure and free TFPI; free TFPI decreased with the concizumab concentration increase. A strong correlation between concizumab concentration and peak thrombin generation was observed; concizumab at least 100 ng/ml re-established thrombin generation potential to within the normal reference range. Estimated EC50 values for the identified concizumab-free TFPI and concizumab-thrombin generation potential models were very similar, supporting that free TFPI is an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration greater than 100 ng/ml experienced less frequent bleeding. The pharmacokinetic model predicted that once-daily dosing would minimize within-patient concizumab pharmacokinetic variability [33,34]. Two phase II trials evaluating the safety and efficacy of prophylactic administration of concizumab in hemophilia A and B with inhibitors (Explorer 4) and without inhibitors (Explorer 5) are currently ongoing. Explorer 4 is a multicenter, randomized, open-label, controlled trial evaluating the efficacy and safety of prophylactic administration of concizumab in hemophilia A and B patients with inhibitors. A loading dose of 0.5 mg/kg will be given as the first dose, followed by 0.15 mg/kg (with potential stepwise dose escalation to 0.25 mg/kg) administered daily subcutaneous Eptacog alfa administered on-demand during bleeding episodes. Explorer5 is a multicenter trial evaluating efficacy and safety of prophylactic administration of concizumab in patients with severe hemophilia A without inhibitors. A dosage of 0.15 mg/kg (with potential stepwise dose administration to 0.25 mg/kg if the patients have spontaneous bleeding) administered daily subcutameous
PF-06741086 (Pfizer, New York City, New York, USA) is a fully human mAb (IgG1) that targets the K2 domain of TFPI with high affinity. Preclinical studies demonstrated a procoagulant effect as evidenced by thrombin generation and dilute prothrombin time (dPT) with increased thrombin generation and shortened dPT . Animal studies demonstrated the hemostatic efficacy of PF-06741086 .
In a phase 1 study that included 41 healthy male volunteers and subcutaneous and intravenous administration of the drug. Responses were dose-dependent, and interestingly, the change in thrombin generation parameters was modest, indicating a downstream regulation. Antidrug antibodies were detected in 15 volunteers and 3 tested positive for low levels of neutralizing antibody measured with a novel assay .
BAY-1093884 (Bayer AG, Leverkusen, Germany) is a mAb against both K1 and K2. In nonhuman primates, BAY-1093884 administered either subcutaneous or intravenous routes reached lower dPT clotting time, which was correlated with free TFPI levels and BAY1093884 plasma concentrations . BAY-1093884 is currently being investigated in a phase 1 study in humans.
The second agent, fitusiran, causes RNA silencing and results in a deficiency of antithrombin. Fitusiran (Sanofi, Paris, France/Alnylam, Cambridge, Massachusetts, USA) is an siRNA agent designed to reduce transcription of antithrombin in the liver by targeting antithrombin messenger RNA. As antithrombin inactivates thrombin, FVIIa and FXa in plasma, the net result is to enhance thrombin generation and change the hemostatic balance . In a preclinical study in animal models, subcutaneous administration of fitusiran demonstrated a potent, dose-dependent and durable reduction of antithrombin levels, restoring hemostasis and improving the coagulation potential of thrombin generation . A phase I dose-escalation study based upon the subcutaneous administration of ALN-AT3 in 4 healthy volunteers and 25 patients with severe or moderate hemophilia A or B without inhibitors was recently published The healthy participants received a single subcutaneous injection of fitusiran (0.03 mg/kg) or placebo. The hemophilia patients received three injections of fitusiran either once weekly (0.015, 0.045, or 0.075 mg/kg) or once monthly (0.225, 0.45, 0.9, or 1.8 mg/kg, or at a fixed dose of 80 mg). No thromboembolic events were observed during the study. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70––89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants .
Interim results from a phase II study (subcutaneous doses of 50 or 80 mg once monthly) showed a mean antithrombin reduction of approximately 80% from baseline, with mean peak thrombin levels being restored to the lower end of the normal range in nonhemophilia patients. The study showed a median ABR of one event in patients without inhibitors and 0 in those with inhibitors. All intercurrent bleeding events were successfully managed with replacement factor or bypassing agent. No thromboembolic episodes were recorded . A phase III clinical programme (ATLAS) evaluating fitusiran 80 mg once-monthly is under way. The programme is designed to evaluate the safety and efficacy of fitusiran in three separate trials.
After release of the Phase II interim data, one patients on the trial suffered a fatal cerebral sinus thrombosis. This severe adverse event occurred after repeated infusions of high-dose FVIII for greater than 24 h. Following this event, the Food and Drug Administration placed a hold on the Phase II trials, which was subsequently lifted after risk mitigation measures were implemented to reduce risk of bleeding, thrombosis, and liver disease and to standardize management of these potential risks. These included safety precautions for concomitant use of clotting factor with fitusiran as well as the possibility of using antithrombin concentrates if necessary.
These new products are getting a radical change in the prophylaxis of bleeding events in hemophilic patient with inhibitors. Patients with hemophilia and inhibitors can aspire to substantial improvements in their treatment, firstly because with the new treatments, they can reach an ABR close to zero and, secondly, through a more comfortable administration, given that the subcutaneous route is used. All this will mean a great improvement in the quality of life of these patients.
Conflicts of interest
There are no conflicts of interest.
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