Case 360⁰™: Module 2: Managing Joint Health in a Young Adult with Hemophilia B


Significant progress has been made over the past several years towards increasing the use of prophylaxis for hemophilia, yet there is still substantial room for improvement. Prophylaxis has allowed patients to be much more active, but for some this has resulted in an increased risk of injury and bleeding. In certain cases, patients who have been on long-term prophylaxis are not able to easily recognize when bleeds occur, particularly those that are subclinical (ie, microbleeds). Small bleeds into joint spaces can initiate the process of hemophilic arthropathy, causing pain and diminished range of motion.

One important limitation of current prophylaxis is that factors are administered intravenously. This can be especially challenging for toddlers and adolescents who may require administration of factor 2 to 3 times a week, causing stress and inconvenience for patients and their families. Additionally, due to the short half-life and rapid clearance of many recombinant factors, plasma trough levels fall rapidly after infusion, leading to levels that may not provide adequate protection against bleeding. Administration of a 50-U/kg dose of recombinant or plasma-derived factor VIII in a child, for example, will provide a 100% correction of factor levels (Figure 1).1-3 Assuming a typical half-life of 8 to 12 hours, this results in a level of approximately 1% after 48 hours. To maintain factor VIII trough greater than 1% at all times, prophylaxis dosing frequency should be every other day or 3 days per week. There is therefore a need for factors with longer half-lives that could be administered less often but provide similar or improved time spent above the 1% level.

Figure 1. Current Standard Half-Life Factor VIII Challenge in a Child3
figure 1
For some long-acting factors that have a longer pharmacokinetic “tail,” dosing may depend on length of time under a critical trough factor level, which can differ from patient to patient.

To decrease the need for such frequent administration, various methods have been developed to alter the chemical nature of the factor and/or its pharmacokinetics (PK) and improve stability. Bioengineering strategies and fusion protein technologies have resulted in the development of extended half-life (EHL) and next-generation factors that increase factor circulation time, prolong half-life, and extend the duration of time spent above the 1% trough level. These may also reduce the frequency of administration, thus increasing patient convenience. Ideally, such factors should not increase immunogenicity and should be relatively easy to assay for PK monitoring.

To begin, please answer the following polling question about your practice.

What types of extended half-life factors are available for patients with hemophilia, and how do these differ from one another?                         


 Case Challenge

Types of Extended Half-life Clotting Factors

Types of Extended Half-life Factors

Previously, it was fairly straightforward to evaluate the limited number of first-, second-, and third-generation recombinant factors, which were all fairly similar chemically. This is now more challenging given the recent development of new products that have various structural modifications, half-lives, PK, and clinical activity (Table 1).4-10 Advances in recombinant DNA technology and chemical modification have facilitated development of many types of novel recombinant coagulation factor products that can vary with respect to stability, PK, cell lines used for production, and immunogenicity.11 Approaches for generating EHL factors include pegylation, conjugation to albumin or Fc antibody fragments, and development of single-chain factors (Figure 2).6 These can improve factor stability, prolong half-life, and increase binding affinity for von Willebrand factor (VWF).7

figure 2

Figure 2. Approaches to Increase the Half-life of Coagulation Factors6
figure 2

Pegylation (covalent conjugation of polyethylene glycol [PEG] molecules) and polysialylation (addition of polysialic acid molecules) have been used to increase the stability and half-life of other biopharmaceuticals such as antibodies, interferons, and hematopoietic growth factors.12 The resulting increase in molecular mass shields the protein from proteolytic enzymes, thus increasing their half-life. These modifications also slow drug clearance by the liver and kidney and may also reduce immune recognition. Pegylation in particular appears to be safe, with no toxicity observed with long-term treatment of modified proteins.

Fc fusion has been used previously to prolong the half-life of various biologics. The Fc domain of immunoglobulin G (IgG) is fused to a therapeutic protein, which allows the modified protein to bind to the neonatal Fc receptor (FcRn) on the surface of epithelial cells lining the intestine, lung, and kidney, and on endothelial cells lining the vasculature. This effectively removes the protein from circulation and delays its degradation and clearance. The Fc-fusion product is eventually degraded in the lysosome, although some Fc may be released back into the circulation.13 Using this technique, recombinant factor VIII Fc fusion protein (rFVIIIFc) and rFIXFc were developed by fusing B domain-deleted (BDD) rFVIII or rFIX to the dimeric Fc domain of IgG1. In a phase 3 study (A-LONG) of rFVIIIFc in previously treated patients with severe hemophilia A, the terminal half-life of rFVIIIFc was significantly longer compared with rFVIII (geometric mean, 19.0 vs 12.4 hours, respectively; P<0.001) (Figure 3a).14 Similarly, in a phase 3 trial (B-LONG) in patients with severe hemophilia B, the half-life was significantly longer for rFIXFc than rFIX (Figure 3b).15

Figure 3. Terminal Half-life of rFVIIIFc (a) or rFIXFC (b) Versus rVIII or rFIX

A) rFVIII:Fc and rFVIII in boys with severe hemophilia A14
figure 3a
Observed FVIII activity (mean ± standard error) for each treatment group. Dashed lines indicate 1 IU/dL (1%) and 3 IU/dL (3%) trough levels.

B) rFIX:Fc and rFIX in boys with severe hemophilia B15
figure 3b
Dashed lines indicate factor IX trough levels of 1 IU/dL (1%) and 3 IU/dL (3%) trough levels. The terminal half-life of rFIXFc (geometric mean, 82.1 hours) was significantly longer than that of rFIX (geometric mean, 33.8 hours (P<0.001).

Albumin fusion is another means to extend the half-life of coagulation factors. Due to the natural long half-life of albumin, fusion of this carrier molecule to a short-lived factor increases the solubility and stability of therapeutic proteins and peptides, with little impact on the immune response.8 An albumin-modified FIX (rFIX:FP), consisting of a FIX backbone fused to albumin by a linker, resulted in a 5-fold increase in half-life compared to rFIX in a phase 1 study.16

Single-chain factors incorporate both light and heavy chains of a recombinant factor molecule, which are internally stabilized by covalent bonds. These recombinant molecules have increased stability and enhanced VWF binding.7,9,17 In addition, porcine recombinant factor VIII has been used, given its decreased antigenicity.18 Some recombinant factors are produced in Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell lines. Others are made in human cell lines (eg, human embryonic kidney cells) and, while not designed for this purpose, they may also have an extended half-life.19 Clinicians should be familiar with novel factors that are either commercially available or emerging onto the market in order to compare the advantages and disadvantages of each when considering use of a new factor for their patient.

Clinical data from studies of selected agents illustrates their potential to decrease infusion frequency. A phase 3 trial evaluated the efficacy, safety, and PK of a recombinant FVIII Fc fusion protein (rFVIIIFc) in 165 previously treated patients 12 years or older with severe hemophilia A.14 Most bleeding episodes (87%) resolved with 1 injection of rFVIIIFc, and no subjects developed inhibitors. This increase in half-life (1.5- to 1.7-fold longer) suggests that children and adults with severe hemophilia A using this agent could dose just twice weekly. Similarly, a phase 3 trial of rFIXFc in 123 previously treated patients with severe hemophilia B who were at least 12 years of age also found that the terminal half-life of rFIXFc was significantly longer than that of rFIX (geometric mean, 82.1 vs 33.8 hours; P<0.001) (Figure 3b).15 Ninety percent of bleeding episodes resolved after 1 injection of rFIXFc, and no inhibitors were detected in treated patients. Based on the increased half-life, children and adults with severe hemophilia B should be able to dose with rFIXFc just once a week, which could translate into substantially fewer sticks per year for each patient. In general, EHL FVIII products have a 1.4- to 1.7-fold longer half-life compared with the parent factor, while for the increase for EHL FIX products ranges from 4- to 5-fold. Because of this difference, EHL factors may have the greatest impact in patients with hemophilia B.

In addition to these recombinant and EHL factors, novel approaches still in various stages of development include use of a bispecific antibody, peptide inhibitors, DNA and RNA aptamers, and gene therapy.20 These products utilize novel mechanisms of action in an attempt to obviate formation of inhibitors. Fitusiran (ALN-AT3), a small interfering RNA (siRNA) targeting antithrombin, is delivered to the liver, where antithrombin is synthesized. It is designed to lower antithrombin levels and thus promote thrombin generation, restoring hemostasis and preventing bleeding. In a phase 1 study, fitusiran produced durable responses in patients with hemophilia A or B following monthly administration.21 Emicizumab (ACE910) is a recombinant bispecific monoclonal antibody directed against both FIXa and FX, and thus mimics the function of FVIII in promoting coagulation. Promising phase 1 results were seen in patients with severe hemophilia A with or without inhibitors.22 Both of these agents are undergoing additional clinical trials, including in patients with inhibitors.

Can you discuss some of the points prescribers and their patients should consider before changing from their current regimen to an extended half-life factor?                         


Considerations Before Changing to a New Factor

Switching to an Extended Half-life Factor

Following regulatory approval of the initial EHL factors, a significant percentage of patients switched to these agents. Today, this conversion rate is lower and varies substantially among providers and institutions. In some cases, many eligible patients have already switched to EHL products. In contrast, at our institution only 5% to 10% have changed. Given that there are no data yet in previously untreated patients (PUPs), we have insisted that patients either enroll on a PUP trial of an EHL product or initiate treatment with an approved standard half-life product with the option to switch to an EHL product after 50 exposure days (EDs). Given the higher degree of benefit for the EHL FIX products, it is not surprising that a higher percentage of these patients have decided to switch. We have been considering obviation of a central line with the use of the newest approved EHL, recombinant coagulation FIX albumin fusion protein (rFIX-FP), in our PUPs without any PUP data available.

Despite the variety of EHL coagulation factors now available, many patients choose not to change from their current regimen, even if it would mean fewer injections each week. This may be due to a variety of reasons. Some patients feel that if their existing regimen is working, there is no reason to change and try something that may or may not work as well. The hemophilia treatment center team physician should clearly explain that switching factors will necessitate evaluating which agent is best suited for them, determine their PK and extent of coverage, determining how often they would need to infuse, etc. Changing to a newer factor requires frequent initial PK measurements as well as periodic monitoring to ensure that patients are achieving target levels, determine optimal dosing intervals, and avoid the risk of breakthrough bleeding. Some young patients with hemophilia A potentially may require double the adult dose yet still not achieve twice-weekly dosing.

For most pediatric patients, there has not been a major shift away from use of their initial factor to newer formulations, such as recombinant and EHL forms. Many patients and their families become comfortable using one product once their regimen is well established, and they are reluctant to change without a strong rationale, particularly if their annualized bleeding rate is low. This is somewhat surprising given the potential for reduced venous access, particularly in young children. Moreover, about two-thirds of patients have a family history of hemophilia, which may further reinforce old treatment patterns and make families less willing to change to new products.

Cost and insurance coverage may also be considerations, since the price of factor is a key driver in overall treatment costs. In a Canadian study of hemophilia treatment centers, clotting factor concentrates were found to constitute 90% to 95% of total health care costs.23 Primary prophylaxis has been shown to be cost-effective compared with on-demand treatment,24 but the relative and incremental costs and benefits of newer factors remains to be determined. In general, for pediatric patients, the younger the patient the greater the dose required, so the higher cost associated with these newer factors might not outweigh the convenience of less frequent injections. Insurance coverage of EHL factors may also vary. Cost will depend in part on factor pricing (including monthly consumption totals) and dose used, as well as target trough levels. Higher trough levels for prophylaxis (eg, 5% vs 1%) would necessitate increased factor use, although this might be offset by a reduction in bleeds and other complications.25

The potential benefits of EHL regimens (eg, less frequent administration) must be balanced against potential drawbacks. For some patients, changing to a different infusion schedule means departing from an established timetable (typically every Monday, Wednesday, and Friday in the United States), which could result in missed doses. For example, a weekday schedule might improve adherence compared with a more extended schedule that would require shifting the dose during the week to allow for trough evaluation and inhibitor surveillance during the fixed hemophilia clinic time. While EHL factors can provide extended coverage, children metabolize factor differently from adults, so each patient’s PK profile should be assessed to determine their individual kinetics and dosing interval. The increased half-life of these products means they are present in the circulation for longer periods of time, raising potential concerns about the long-term safety of chemically modified rFVIII/IX products in children. Key points that clinicians and their patients should consider before switching to a newer agent are listed in Table 2.

table 2

For patients who choose to switch to an extended half-life factor, what role does pharmacokinetics play in ensuring they are on the appropriate agent?                         


Pharmacokinetics and Management of Prophylaxis

Pharmacokinetically Tailored Factor Prophylaxis

Factor dosing for adolescent patients should be tailored according to the patient’s level of activity and particular coverage needs, and this is also true for EHL and next-generation factors. Children who participate in competitive sports will require increased factor to ensure adequate coverage compared with those with normal activity levels. In some cases, highly active patients may consider more frequent dosing or changing to a longer-acting product. Pharmacokinetically tailored prophylaxis will help ensure optimal factor usage and minimize bleeding episodes, and it may improve bleed prevention and reduce injection frequency.26,27

The focus to date has been on the role of trough factor levels with bleeding, although the association of peak plasma factor levels with bleeding while on prophylaxis has not yet been established.3 Peak levels may be important, for example, in patients participating in competitive sports activities. There is a need to identify the best regimen for each patient to achieve optimal factor levels and suppress bleeds. Some data suggest that peak levels need to be achieved during hemostatic challenges, such as during sports activities. Prophylaxis regimens may therefore need to be tailored to each patient’s PK profile based on specific activities that require coverage at higher levels. Previous PK studies have suggested that a factor level of at least 1% is sufficient, although some investigators have examined whether higher levels (5%-10%) may be more beneficial, albeit at a higher cost.25 The hemophilia team should ensure that parents understand how to interpret these PK results and their practical implications for daily coverage. “Longer-acting” should not be interpreted to mean that the patient can maintain maximal factor levels for a long period, but longer to a targeted trough level. Furthermore, the expected duration and level of coverage based on the patient’s PK profile must be clearly explained, since with the currently available products there is more time spent below 15-20%.
Prescribers should recognize certain caveats regarding PK assays for these newer factors and how they can impact treatment decisions. Measurement of PK levels varies significantly between laboratories, depending on the reagents and methods used. Moreover, PK assays for certain EHL factors often require optimization with respect to the particular product used, since some chemical modifications can reduce factor assay reactivity and lead to erroneous results.28-30 For example, a pegylated form of FVIII displayed significantly prolonged clotting time and reduced precision when silica activated partial thromboplastin time (aPTT) reagents were used compared with ellagic acid reagents.28 A field study evaluating the accuracy of global laboratories found a difference of approximately 30% in quantification of a B-domain-deleted recombinant FVIII using the one-stage clotting assay compared with a chromogenic assay.31 Most laboratories are not currently equipped to monitor levels of a next-generation EHL factor using unique methods and/or reagents, so PK monitoring of such factors may be inaccurate. Furthermore, the majority of US coagulation laboratories do not employ the chromogenic assay for routine clinical use. Clinicians who are using such factors in their patients should inform the testing center which type of product is being used and discuss optimizing detection of the factor (where possible) with the laboratory director.

Does the use of recombinant factors, including extended half-life factors, increase the risk of inhibitor formation compared with plasma-derived concentrates?                        


Recombinant Factors and Inhibitors

Inhibitor Formation

A substantial proportion of patients undergoing hemophilia treatment develop inhibitors (neutralizing antibodies) to factor VIII and less so to factor IX that reduce their hemostatic activity. This results in hard-to-manage bleeding, increased morbidity, and higher health care costs. Inhibitors are thought to occur in more than 30% of patients with severe hemophilia A, 13% of those with non-severe hemophilia A, and 3% of those with severe hemophilia B.18 Many children with hemophilia are now started on prophylaxis at a very young age due to concerns about bleeding and development of arthropathy. A study by Kurnik et al in 26 previously untreated pediatric patients suggested that initiation of prophylaxis during the first 20 EDs (when the risk of developing inhibitors was highest) could reduce the risk of inhibitor formation.32 These investigators developed a prophylaxis regimen for the first 20 to 50 EDs designed to induce tolerance to FVIII and minimize inhibitor development by avoiding immunological “danger signals,” by not administering the first dose of FVIII during a bleeding situation or with a vaccination. However, this approach may require a central line, which can increase risk of infection. It also exposes the child to large doses of factor early in life, which may in itself increase the inhibitor risk. In our clinic we usually start patients on prophylaxis at around 18 months of age, in part due to venous access issues in infants and toddlers.

The increasing use of recombinant factor products that seems to have corresponded with a rise in inhibitor prevalence has led some investigators to question whether these agents might enhance the risk of inhibitor development compared with plasma-derived products. Some studies have not found a significant difference in risk between these 2 classes of factors.33 In a landmark prospective study, the rate of FVIII inhibitor formation was compared for recombinant factors and plasma-derived products in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) study (Figure 4).34

More than 250 children younger than 6 years with severe hemophilia A who had been minimally treated or untreated were randomized to VWF-containing plasma-derived factor concentrates or recombinant factor VIII.34 The risk of developing inhibitors within the first 50 EDs was approximately 1.7-fold higher with recombinant factor products (cumulative incidence of all inhibitors 44.5% vs 26.8%; high-titer inhibitors 28.4% vs 18.6%). The inhibitor was persistent in 73% of patients in whom inhibitors developed, and results were not affected when second-generation full-length recombinant factor VIII was excluded from the analysis. The implications are quite significant, as there may be a beneficial role of pdFVIII products in PUPs during the first 50 EDs to reduce risk of inhibitor formation. The clinical significance of these results is unclear, however, since the SIPPET study included only PUPs, evaluated intermediate-purity pdFVIII products that contained VWF as the comparator and not all pdFVIII products, and did not include any of the EHL factors commonly in use today. Furthermore, this study did not address inhibitor risk in hemophilia B patients.

figure 3b

Cumulative incidence of inhibitor development for all inhibitors (≥0.4 Bethesda units) in the SIPPET study. Patients treated with recombinant factor VIII had a higher incidence of inhibitors than those treated with plasma-derived factor VIII containing von Willebrand factor. (Patients who did not complete 50 exposure days before the trial ended are indicated by tick marks.)

There have been no studies completed to date evaluating these new EHL products in PUPs, but there are hypothetical reasons why some of the modifications could result in decreased immunogenicity. We do know that newer products do not have a significantly increased risk of inhibitor formation when given to PUPs. Other clinical trials in PUPS are ongoing, but in the absence of any data on their efficacy and safety, we do not currently use these factors in such patients. Other hematologists are waiting for more data in PUPs before suggesting a change to newer EHLs, so the immediate impact of the SIPPET results on treatment strategies in this patient population remains to be determined.

What do health care professionals and their patients need to know about these new EHL factors, and how can nurses assist in this process?


Education of HCPs and Patients


There is a significant need for further education of health care providers, as well as patients and their families, regarding new factors for hemophilia. The increasing number and variety of products now available or in late-stage clinical development make it challenging to remain well informed about the various options.10 Health care professionals should be knowledgeable about differences in methods of production, efficacy, safety and immunogenicity, dosing, PK, and cost in order to better assess their potential. Continuing education regarding recently approved factors and emerging therapies is essential so practitioners can better assess these options and make rational recommendations to their patients.    

Nurses in particular play an important role in providing education on various aspects of hemophilia care, since they often have the initial and most extensive contact with patients and their families. Topics can include how to administer factor, maintaining adherence, identifying treatment-related side effects with new factors, and modifying infusion schedules to address activities. Patients should also be aware of the signs and symptoms of inhibitor development when changing to a new factor, such as breakthrough bleeds in a patient on prophylaxis or one who stops responding to factor replacement for an acute bleed, in order to facilitate early interventions.