Practical aspects of extended half-life products for the treatment of haemophilia

Abstract

Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients’ quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5–1.8 times that of standard products for FVIII and 3–5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.

Introduction

Haemophilia A and haemophilia B are bleeding disorders caused by deficiencies of factor VIII (FVIII) or factor IX (FIX), respectively.¹ Haemophilia treatment has advanced considerably since the early 20th century, when whole blood and fresh frozen plasma were the only treatments available for bleeding episodes.² Nowadays, the cornerstone of treatment in many countries is replacement FVIII or FIX concentrates, respectively.^1,3 Prophylaxis is the treatment regimen of choice for patients with severe haemophilia,^4,5 and the introduction and large-scale production of plasma-derived and recombinant factor concentrates has enabled increased implementation of prophylactic regimens in many parts of the world.² Prophylaxis with factor concentrates aims to prevent joint and other spontaneous bleeds by changing the bleeding phenotype from severe to a milder form,⁶ and has been shown to reduce the progression of joint damage significantly, reduce the frequency of joint and other bleeds, and to improve physical and social health in patients with severe haemophilia.^7,8

While prophylaxis is very effective in terms of preventing bleeds, there are still challenges associated with these regimens when standard factor replacement, such as recombinant FVIII (rFVIII) and recombinant FIX (rFIX) products, are used. Foremost among these challenges is the high infusion frequency required: as standard rFVIII and rFIX products have relatively short half-lives (for example, 8–12 h for rFVIII),⁹ intravenous (IV) infusion is usually required up to every 2 days for patients with severe haemophilia A and often at least twice weekly for those with severe haemophilia B.^10,11 The inconvenience of such frequent IV infusions is a challenge and may lead to adherence problems, particularly in adolescents.^12–14 Frequent infusion may be particularly difficult in patients with poor venous access, which is often the case in children; in such instances, injections can be distressing for both the child and the caregiver.^12,15

Another challenge associated with current prophylaxis regimens is that they do not completely prevent long-term joint disease: while a long-term (median 25 years) prophylaxis regimen virtually eliminated joint bleeds, lifetime joint arthropathy was still apparent.^7,16 This is likely due to breakthrough bleeds or subclinical or microbleeds that eventually lead to haemophilic arthropathy.^7,8,17 This inability to deliver completely effective prophylaxis for all patients may reflect reduced compliance or difficulty in maintaining an adequate trough level, particularly in individuals with a relatively short factor half-life.

Factor preparations with an extended half-life (EHL) hold the potential to improve the management of severe haemophilia by allowing less frequent dosing.⁶ This may encourage patients to switch from on-demand treatment to prophylaxis, improve patient quality of life (QoL), promote adherence, and reduce the need for central venous lines in children.¹⁴ EHL products may also offer further benefits to patients if the goal of treatment focuses on increasing the plasma trough levels as a key outcome, rather than only reducing infusion frequency.⁶ EHL products increase factor trough levels when infused at the same dosing schedule as standard factor concentrates; this may allow a more active lifestyle and help to improve outcomes by preventing spontaneous and subclinical bleeds so that long-term joint health can be maintained.^6,14

However, there are currently few evidence-based guidelines, such as those published by the UK Haemophilia Centres Doctors’ Organization,¹⁸ to help physicians identify those patients who will benefit from prophylaxis with EHL products. With the increasing availability of such products, members of the Zürich Haemophilia Forum convened for their 19th meeting in May 2017 to discuss the practicalities of incorporating these new treatments into the management of people with haemophilia. The Zürich Haemophilia Forum is an expert forum of European haematologists involved in haemophilia care who gather at least annually for roundtable meetings, sponsored by Novo Nordisk, to discuss current relevant topics in haemophilia and its management. The forum has largely comprised the same participants since its first meeting in May 2008.¹⁹ The current report summarizes this expert panel’s perspectives on the new EHL products recently licensed or in development, focusing on the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.

Extended half-life factor VIII and factor IX products

Several new rFVIII and rFIX preparations that are engineered to have an extended plasma half-life are available for clinical use and others are in development (Table 1).

Table 1.

Extended half-life recombinant factor VIII and recombinant factor IX preparations.^2,14

Disease	Molecule name	Brand/generic name	Structure	Mean terminal half-life	Company	Status
Haemophilia A (FVIII replacement therapy)	rFVIIIFc20,21	Eloctate®/Elocta	rBDD-FVIII Fc fusion	19 h	Biogen, Inc. and Sobi	Approved in USA, Canada, Europe, Australia, New Zealand, Japan
	BAX85522	Adynovate®/Adynovi	PEGylated rFVIII (20 kDa)	14–16 h	Shire	Approved in USA, Japan, Canada, Switzerland, Colombia, Europe
	BAY94-902723	Damoctocog alfa pegol	PEGylated rBDD-FVIII (60 kDa)	19 h	Bayer HealthCare Pharmaceuticals	Under development
	N8-GP24,25	Turoctocog alfa pegol	GlycoPEGylated rBDT-FVIII (40 kDa)	18–19 h	Novo Nordisk	Under development
Haemophilia B (FIX replacement therapy)	rFIXFc26	Alprolix®	rFIX–Fc fusion	82 h	Biogen, Inc. and Sobi	Approved in USA, Canada, Europe, Japan, Australia, New Zealand, and other countries
	CSL654 (rIX-FP)27	Idelvion®	rFIX–albumin fusion	102 h	CSL Behring	Approved in USA, Europe, Canada, Japan
	N9-GP28,29	Refixia®/Rebinyn®	GlycoPEGylated rFIX	93 h	Novo Nordisk	Approved in Europe, USA (on-demand treatment)

Fc, fragment crystallizable; FIX, factor IX; FVIII, factor VIII; PEG, polyethylene glycol; rBDD, recombinant B-domain deleted; rBDT, recombinant B-domain truncated; rFVIII, recombinant factor VIII; rFIX, recombinant factor IX; Sobi, Swedish Orphan Biovitrum AB (publ) (Sobi™).

Various technologies have been used to extend the half-life of rFVIII and rFIX. These include the attachment of a polyethylene glycol (PEG) group to the protein (PEGylation) for rFVIII and rFIX^22,24,28 and fusion with other recombinant proteins, such as albumin (rFIX) or the fragment-crystallizable (Fc) part of immunoglobulin G1 (both rFVIII and rFIX)^20,26,27 (Table 1). Due to the differences in structure and manufacturing techniques required for these different molecules, safety and effectiveness must be established for individual products. A number of clinical trials have been conducted to assess these products, and data from these trials are reported elsewhere.^{20,22,24,26–28,30} It is worth noting that trials of EHL–rFVIII and –rFIX preparations frequently report mean half-life rather than median or actual half-life.^{20–23,26,28,31,32} Median half-life, where equal numbers of patients have a half-life below and above this value, would be a more meaningful measure with which to compare the half-life in an individual patient. A median is less presumptive about the underlying distribution of this parameter within a study group than are means and standard deviations.

When compared with the half-life commonly reported for standard FIX concentrates (18–30 h),^9,33 EHL–rFIX preparations extend the FIX half-life by three to five times (Table 1), resulting in maintenance of higher plasma FIX trough levels that may allow patients to achieve effective prophylaxis with once-weekly or even once-fortnightly infusions (in adults).¹⁴ For EHL–rFVIII products, the extension in half-life is more modest (1.5–1.8 times that of standard FVIII products, which have a half-life of 8–12 h)^9,14 (Table 1). However, these EHL–rFVIII products may also allow a reduced infusion frequency.¹⁴

For the sake of completeness, it is also appropriate to mention lonoctocog alfa, a single-chain FVIII molecule (rFVIII-single chain, Afstyla®) in which the light and heavy chains are covalently linked, providing a twofold higher affinity for von Willebrand factor (vWF) and improved structural stability.³⁴ These alterations may also offer a slight prolongation of half-life when compared with standard FVIII.^35,36 However, as the modifications made to lonoctocog alfa were not intended to extend half-life and as half-life extension is minimal compared with that of standard FVIII,³⁷ we conclude that it cannot really be considered an EHL factor. Therefore, lonoctocog alfa has not been discussed further in this article.

The following sections will briefly summarize some dosing considerations for EHL products and how to monitor factor levels. Due to the large difference in half-life extension observed between the EHL–FVIII and EHL–FIX preparations, they are discussed separately.

Dosing extended half-life products

Currently, there is no consensus around the optimal prophylactic treatment regimens with EHL products. Weight-based regimens are effective for standard and EHL–rFVIII and –rFIX preparations;^14,38 whatever the dosing schedule, however, two considerations should be noted. First, dosing should always be based upon the needs and clinical scenario [including the pharmacokinetics (PK)] of each individual patient. Second, factor levels should always be monitored during treatment and the dose or frequency of injections adjusted based on joint status, observed individual bleed pattern, measured factor levels, and anticipated physical activity.³⁸

Extended half-life recombinant factor VIII

Generally, the aim of FVIII prophylaxis in haemophilia A is to keep plasma FVIII levels above a target threshold. It has been shown that the time spent with a FVIII trough level below 1% is proportional to the incidence of breakthrough bleeds,³⁹ and that trough levels higher than 1% provide increased protection against joint bleeds.⁴⁰ A FVIII level of 1% may not be sufficient for all patients in all circumstances, and many patients will require a higher trough level to prevent bleeding. Furthermore, the ability of an individual laboratory to measure low levels of FVIII and FIX must be carefully monitored. FVIII activity level alone is not the only component of an effective prophylaxis regimen: activity, lifestyle, joint status, and body build are all important variables.

For EHL–rFVIII products, typical recommended initial regimens for weight-based prophylaxis in adults are dosing twice weekly or every third or fourth day (versus every 2 days with standard FVIII products¹¹). It has been suggested that, based on bleeding pattern, well-controlled adult and adolescent patients may be able to modify their prophylaxis regimen to enable longer dosing intervals^18,21 according to their individual PK outcomes; but this is unlikely to be appropriate for most patients. It is also important to note that the half-life of many EHL–rFVIII products is shorter in young children than in adults; therefore, it is likely that the time between infusions will need to be shorter for children.¹⁸

An alternative option for prophylaxis with some standard FVIII replacement therapies is individualized PK-based dosing, based on the patient’s own PK profile, to determine the dose and schedule needed to maintain a predetermined factor trough level.⁴¹ However, the frequent blood sampling required for personalized PK assessment is burdensome and costly; additionally, a personal PK assessment may be too inconvenient for some patients, and not all patients have ready access to the expertise required for such evaluations. Repeated blood sampling may also be particularly challenging in very young children.³⁸ Therefore, current prescribing information for the available EHL–FVIII products does not follow individualized PK-based dosing,^42,43 although in some cases the recommended fixed dose is based on individualized PK-guided dosing in clinical trials.^21,42 A more convenient and less costly PK-based estimate of factor requirements can be carried out using population-based PK estimation with reduced sampling.^44–47

Extended half-life recombinant factor IX

In adults with haemophilia B on weight-based prophylactic schedules using EHL–rFIX, the initial recommended dosing frequency is once weekly¹⁸ (in contrast with twice-weekly dosing using standard FIX products¹⁰). However, well-controlled patients with haemophilia B might be able to extend their dosing interval to once every 10–14 days.^18,26,27 As has been noted for haemophilia A and EHL–rFVIII products, the half-life of many EHL–rFIX preparations is shorter in young children,^18,48 and so the dosing interval is usually once weekly in these young patients.

Evidence for the clinical significance of maintaining a 1% FIX trough level does not exist, and the relevance of FIX trough levels, which are usually much higher (10–20 IU/dl) than those maintained with EHL–rFVIII, is widely debated.^14,49 Also, unlike haemophilia A, the value of PK-guided prophylaxis in most adult patients with haemophilia B on standard FIX products is limited,^49,50 and PK-guided dosing strategies for EHL–rFIX products will likely be complicated, due to the interpatient variability and complexity of FIX PK, the need for a multicompartmental approach, and uncertainty regarding the optimal sampling time that best accounts for a prolonged half-life.⁵¹ As with haemophilia A, population PK may be more useful than an individualized approach.⁵¹

Monitoring extended half-life products

Optimal dosing of replacement FVIII or FIX relies on monitoring plasma factor levels using accurate coagulation factor assays. Two assays used to assess factor activity are the one-stage clotting assay and the chromogenic assay. However, it is widely recognized that these assays provide discrepant results for some of the standard factor replacement products currently in use, and the availability of multiple reagent/instrument combinations in laboratories contributes to that variability.⁵² Likewise, there is evidence that assays routinely used in laboratories may under- or overestimate factor levels of EHL products. It is therefore recommended that laboratories use an assay that accurately measures the activity of a specific EHL product and that laboratory protocols and assays are adapted in light of further evidence.¹⁸ It is also possible that a product-specific standard should be used when monitoring factor replacement therapy with some EHL factor concentrates.¹⁸ Healthcare professionals who treat patients with haemophilia and laboratory personnel should be aware of how each assay performs under their conditions;⁵² however, general considerations on the use of different assays for EHL products are briefly summarized below.

Extended half-life recombinant factor VIII

Three PEGylated EHL–FVIII preparations are currently under development [N8-GP (Novo Nordisk, Bagsvaerd, Denmark), BAY94-9027 (Bayer HealthCare Pharmaceuticals, Berlin, Germany)] and approved for use in some markets [BAX855 (Shire, Dublin, Republic of Ireland)] (Table 1). The one-stage assay using ellagic-acid- and kaolin-based activators has been shown to measure FVIII activity for N8-GP accurately, while the one-stage assay using an ellagic-acid-based reagent accurately reflects the activity of BAY94-9027.⁵² However, for BAY94-9027, one-stage assays using silica-based activators tend to underestimate FVIII activity; for N8-GP, this can be the case for some, but not all, of these assays.⁵² In contrast, chromogenic assays reliably estimate PEGylated FVIII levels for both products.⁵² For BAX855, while acceptable recovery has been reported for one-stage assays (using silica, ellagic acid or kaolin as activators) and the chromogenic FVIII assay,⁵³ the Swiss Multicentre Field Study found that accurate measurement required a product-specific reference for both one-stage and chromogenic assays.⁵⁴

One EHL–FVIII product developed through fusion of rFVIII with the Fc fragment of immunoglobulin G is commercially available [rFVIIIFc (Biogen, Inc., Cambridge, MA, USA and Swedish Orphan Biovitrum AB) (publ) (Sobi™, Stockholm, Sweden)] (Table 1). Data suggest that the activity of rFVIIIFc can be measured accurately with the one-stage assay using silica, ellagic acid or kaolin as activators; however, the chromogenic FVIII assay overestimates FVIII recovery.^2,52

Extended half-life of recombinant factor IX

One PEGylated FIX product is currently approved for use [N9-GP (Novo Nordisk)]. One-stage assays using ellagic-acid-based activators measure the FIX activity of N9-GP with differing degrees of accuracy; some provide reliable measurements, while some underestimate FIX activity. Silica-based activators tend to overestimate potency, while kaolin-based reagents tend to underestimate potency.⁵² Chromogenic assays have been shown to be reliable for measuring PEGylated rFIX activity levels.^2,52

For the one rFIX–Fc fusion protein product currently available [rFIXFc (Biogen, Inc. and Sobi)], one-stage clotting assays that use ellagic-acid- or silica-based reagents measure rFIXFc activity levels accurately, but those involving kaolin as activator do not.^2,52 The chromogenic FIX assay accurately measures rFIXFc activity levels.⁵⁵

Finally, one EHL–rFIX product has been developed by fusion with albumin [rFIX-FP (CLS Behring, King of Prussia, PA, U.S.)] and approved for use. Plasma activity of rFIX-FP can be measured reliably using the one-stage assay with a variety of reagents, except kaolin, which tends to underestimate FIX levels.⁵⁶ Results for the use of chromogenic assays with rFIX-FP are not currently available.

Introducing extended half-life products into the management of patients with haemophilia

Patient selection

Evidence-based guidelines advising which patients may benefit from prophylaxis with EHL factor concentrates are currently lacking. However, some general considerations can be noted. Foremost among these is the need to assess patients individually: bleeding phenotype during treatment with standard factor concentrates, severity of haemophilia (note, this may include moderate haemophilia), PK outcomes, level of physical activity, venous access, joint status, lifestyle, compliance, comorbidities that may affect bleeding status, and therapy preference/convenience should all be taken into account.

Patients with severe forms of the disease, particularly children, are the optimal candidates for prophylaxis with EHL products.² Patients with severe disease are more likely to have frequent, spontaneous, severe bleeds and are therefore likely to derive the greatest benefit from prophylactic schedules.² However, it is increasingly recognized that some patients with moderate haemophilia may also benefit from prophylaxis. Patients with a significant bleeding phenotype, such as joint bleeds, or evidence of early joint damage or high levels of activity may also be suitable candidates for prophylaxis and will face the same challenges of treatment burden.⁵⁷ It is therefore important to carefully evaluate and monitor individuals with moderate haemophilia and those with the features described above to consider whether prophylaxis with an EHL product might be beneficial.

In terms of therapy preference and treatment convenience, patients with haemophilia B are more likely to experience greater benefit from EHL products than those with haemophilia A, due to the longer half-life of EHL–rFIX preparations, the higher trough levels that can be maintained, and the longer dosing intervals this allows. Moreover, any patients who previously chose to remain on an on-demand regimen from a desire to avoid the frequent infusions required for prophylaxis may be more likely to consider a prophylactic regimen with a less onerous infusion schedule.

On a related note, EHL factor products might be of particular benefit to patients who struggle with adherence to prophylactic therapy. Loss of adherence is typically seen in adolescents, largely because they tend to focus primarily on short-term goals; as they have no experience of long-term joint damage, they often do not prioritize the prevention of future joint disease.¹³ Lack of adherence is not limited to adolescents, however: in a review of the impact of treatment regimen on adherence in patients of all ages with chronic conditions (e.g. diabetes, hypertension/cardiovascular disease, pain, human immunodeficiency virus/acquired immunodeficiency syndrome), higher dose frequency was found to be associated with poorer adherence.⁵⁸ Given these findings, it is unsurprising that reducing the frequency of infusions has been proposed as a key factor in improving adherence to prophylaxis in patients with haemophilia.^12,50

Other patients who may receive significant benefit from EHL factor products are those with difficult venous access requiring less frequent dosing. Venous access is particularly difficult in young children who have very small veins; in such cases, IV infusions can cause anxiety in both the child and their parents.^2,15 A reduction in dose frequency might help preserve a patient’s veins and decrease the need for central venous lines in young children, with the attendant benefits such as reduced risk of infection and thrombosis,¹⁵ as well as relieving the inconvenience of frequent dosing for both patients and their caregivers.^12,14 This potential reduction in dose frequency in young children, as for adult patients, might be a more realistic goal for patients with haemophilia B than for those with haemophilia A, due to the longer extension of half-life for EHL–rFIX versus EHL–rFVIII.

In addition to these individual patient factors, one other consideration is previous exposure to factor concentrate. To date, published experience with EHL factor products has been derived from previously treated patients (PTPs) with a minimum of 50 exposure days (EDs) to another factor concentrate and no history of inhibitors.^14,18 The rationale behind this is that the highest risk of inhibitor development occurs within the first 50 EDs; therefore, before data are available for previously untreated patients (PUPs), it seems reasonable to avoid switching patients to an EHL factor product until they have reached 50 EDs.¹⁸ However, there is no evidence to suggest that patients in whom inhibitors have been eradicated using immune tolerance induction (ITI) could not receive EHL products after an appropriate length of time has elapsed since tolerization. Studies evaluating the use of EHL products in PUPs are ongoing, and it will be some time before outcome data are available.¹⁸ If the use of an EHL product for a PUP is considered, then entry into a PUP study should be offered.¹⁸

Finally, a patient’s suitability for treatment with EHL–rFVIII concentrates might be influenced by endogenous levels of vWF. The half-life of endogenous FVIII and standard rFVIII products increases with higher vWF levels, and this relationship has also been demonstrated for an EHL–rFVIII product.⁵⁹ This suggests that patients with higher levels of endogenous vWF may experience better outcomes following treatment with EHL–FVIII concentrates than those with low vWF levels.⁵⁹

Based on the above points, we recommend that patients who would most benefit from EHL products are those with the following characteristics: poor adherence to standard factor regimens, especially adolescents; difficult venous access (e.g. young children); individuals who are physically active/involved in sporting activities (depending on the frequency of injections); or those with a severe bleeding phenotype.

Considerations when introducing patients to extended half-life products

Several factors should be considered when introducing patients to an EHL factor product. A primary consideration is that, as with standard factor replacement therapy, patients receiving EHL products will benefit from evaluation of their plasma factor levels; they also require physical monitoring to detect bleeds that might otherwise be missed, especially those that could contribute to joint damage.

Switching products may lead to ‘teething issues’ in terms of defining the right dose and prophylactic regimen for the individual patient; there may be longer periods at low factor concentrations before an effective regimen is established, and this may lead to breakthrough bleeds. It is important that physicians discuss this possibility with patients ahead of switching, to ensure that patients’ expectations are managed appropriately.

After switching to prophylaxis with an EHL product, reductions in the dose or infusion frequency could potentially be considered in patients who do not experience bleeding episodes:¹⁸ low doses of an EHL factor would achieve the same steady-state factor concentrations as standard factor concentrates, without increasing factor consumption. For patients with haemophilia A who require higher FVIII trough levels because of frequent bleeding or the presence of target joints,^18,57 providing prophylactic coverage with an EHL–rFVIII product administered at the regular dose interval used for standard half-life products may be suitable. This strategy could also be used for patients with haemophilia A who do not achieve FVIII trough levels > 1% with prophylaxis regimens that use standard FVIII products.⁵⁷

The potentially higher trough levels offered by EHL products may also enhance the efficacy of prophylaxis by reducing the incidence of breakthrough or subclinical bleeds. Patients receiving EHL products who experience breakthrough (episodic) bleeds can treat themselves with the same EHL product.^21,26,28

To date, evidence on the use of EHL products in ITI protocols is limited in haemophilia A.^60,61 While this limited evidence shows favourable results for the safety and efficacy of ITI using EHL–rFVIII, further studies are warranted and ongoing. For example, the Haemophilia Inhibitor Response to Eloctate (HIRE) Study, a prospective observational study evaluating ITI in children with inhibitors, is currently underway and will add valuable data to the current evidence base on EHL factor use in ITI schedules.

Finally, it is important to emphasize that patient empowerment is a crucial factor in facilitating a switch to, and maintenance of, prophylaxis with an EHL product. Management strategies that involve the patient, allowing them to adjust their lifestyle and physical activity appropriately, may have a large positive impact on the acceptance of EHL therapies. It should be noted that if patients, particularly those previously treated on-demand, do derive benefit from switching to an EHL, their confidence may improve, leading to increased activity levels and thus necessitating further adaptation of their prophylaxis regimen.

Safety concerns related to switching to extended half-life products

Some patients may be hesitant to switch to EHL products. Patients and parents alike may be wary of changing a successful prophylaxis regimen that uses a standard half-life product; however, the fear of developing an inhibitor may also play a part in their reluctance to switch. Surveys among patients and physicians showed that 57% and 20%, respectively, believed that there was an increased risk of inhibitor development when switching standard factor replacement product.^62,63 These surveys provide evidence of a discrepancy between patient knowledge and physician experience. More importantly, their worries do not appear to be evidence based: studies do not show an increased risk of developing inhibitors when switching from plasma-derived FVIII to rFVIII, or from one rFVIII to another (including full-length to B-domain-deleted rFVIII).^62,64 However, these survey results do imply that fear of inhibitor development may cause patients, and some physicians, to be reluctant about switching from standard factor to EHL products. These fears seem unfounded: indications of the risk of inhibitor development on switching from standard half-life to EHL products can be gleaned from clinical trials in PTPs, and these have reported no inhibitor development or a very low risk of an inhibitor.^{20–25,28,31,32} Clinical studies in PUPs are underway; these data will be important to assess inhibitor development following exposure to EHL products.

Consideration should also be given to any potential safety issues associated with switching to an EHL product in patients with a history of inhibitors who have undergone ITI. Pivotal clinical trials described here exclude patients with a history of inhibitors, and thus there are no published safety data on these patients. Two patient groups are key here: those who achieved successful tolerization and a normal PK profile, and those who achieved undetectable inhibitor levels through ITI, but who still present with impaired PK characteristics. For the former group, where numerous patients have already had one or more product switches since tolerization, the risk of inhibitor relapse may be deemed very low. For the latter group, the question remains open, and patients who switch to an EHL product should be closely monitored for inhibitor development.

No major safety issues have been identified as yet for any of the technologies used to extend the half-life of rFVIII and rFIX.¹⁴ There are, however, theoretical concerns that should be briefly addressed here. First, possible accumulation of the PEG moiety with long-term exposure to some PEGylated EHL products is one such area of concern.^14,18 PEGylation is an established technique for extending the half-life of proteins and is used in the production of therapeutic proteins for other diseases.^65,66 Since the early 1990s, more than 10 PEGylated therapeutic drugs have become available, with proven safety; it must be noted, however, that the data are derived mainly from adults and only from a limited period of treatment (whereas haemophilia treatment is usually lifelong).^66,67 It should also be noted that the PEGylated EHL–rFVIII and –rFIX products use different methods for PEGylation, and different PEGylated products have PEG molecules of different sizes.¹⁴ Another theoretical safety concern associated with EHL factor products is vacuolation of some cell types, including epithelial cells in the choroid plexus, which has been observed in toxicological studies with some PEGylated agents.^68,69 This vacuolation is considered to be the result of an adaptive PEG removal process and, while vacuole formation has not been linked to any signs of toxicity, it is important to note that toxicology studies in animals showed no vacuolation with N8-GP, N9-GP, BAY 94-9027 or BAX855.^70–73 Furthermore, there is a theoretical increase in the risk of thromboembolism if replacement factor products produce supraphysiological factor levels; however, factor levels in patients with haemophilia are unlikely to be augmented to such a degree.

As a final note on safety issues, long-term post-marketing safety monitoring will be important to establish the long-term safety of EHL products.

Outcome measures for assessing response to extended half-life products

Assessing real-world outcomes associated with EHL factor products is complicated by the fact that comprehensive outcome assessment is rare outside of clinical trials.⁷⁴ In clinical practice, assessing outcomes tends to be limited to clinical outcomes such as bleeding frequency, QoL and joint status.² However, additional measures may be needed for EHL products. Monitoring treatment, for instance, might be a useful short-term outcome measure: data to be collected would include the number of infusions and dose required to resolve a bleed, time from the last infusion to a bleeding episode, and total annualized consumption for prevention and treatment of bleeding episodes.

The most relevant outcomes that can be performed in clinical practice for the long-term follow up of patients receiving EHL factor products need to be clearly defined, and are likely to be more challenging to evaluate than any short-term assessments that are implemented. Depending on the dose and frequency of infusions, EHL products may maintain factor levels above critical thresholds for longer than standard factor concentrates; therefore, outcome assessment should focus on joints, and include functional and radiographic joint outcomes.⁷⁵ Ultrasound or magnetic resonance assessment of ankle joints may serve as a good indicator of early joint disease, as they are considered to be the first affected joints in patients with haemophilia.¹⁶ Additionally, the long-term consequences of using EHL products for physically active patients need to be investigated to help ascertain whether these patients can increase or maintain their physical activity without experiencing bleeds. Whether or not QoL represents a useful long-term outcome measure in patients receiving EHL products remains to be seen: both QoL and annualized bleeding rate (ABR) tend to be low in patients who adhere to primary prophylaxis with standard factor concentrates prior to switching to an EHL product, and it may be difficult to achieve statistically significant improvements in these measures.² In addition, QoL assessment tools are often less sensitive to smaller differences in outcome measures⁷⁶ and there is the risk of a low response rate if patients are overburdened with repeated requests to complete questionnaires. However, in the short term at least, QoL might be a more sensitive outcome measure than ABR.

Economics of introducing extended half-life products into treatment regimens

Many patients will already be on satisfactory treatment regimens, and so the potential advantages of EHL products must be demonstrated in order to encourage and justify switching from standard products. These advantages include clinical benefits, such as superior efficacy and reduced treatment burden, but also improved cost effectiveness.

The significantly greater impact of EHL–rFIX products on reducing infusion frequency and raising trough levels, compared with EHL–rFVIII products, will likely mean that cost may play a greater role in switching decisions for patients with haemophilia A than for those with haemophilia B. However, even if clinical, rather than cost, considerations are the main driving force behind switching to EHL–rFIX products for patients with haemophilia B, cost effectiveness will still be a key consideration. Importantly, EHL–rFIX products may result in long-term cost savings in haemophilia B by reducing bleeding into joints and postponing or eliminating the need for joint replacement.^6,77 Pharmacoeconomic analysis of the use of EHL factor products in various clinical scenarios is warranted.

With both haemophilia A and haemophilia B, the pricing of EHL factor products will be important in influencing whether they will be available to all patients who choose them, or whether their use will be restricted to those deemed likely to derive the most benefit and in whom the use of such products is considered cost effective. In some European countries, certain EHL products have been introduced at a price that results in the same annual treatment cost as standard products.¹⁴ As with standard factor replacement therapy, authorities may not approve the use of therapies with higher acquisition costs in patients with moderate disease, particularly those where the benefits could be less certain.

A final consideration to note is that, as more novel products become available, there will be an increase in competition. The extent to which this may reduce acquisition costs is not yet known.

Conclusion

EHL factor products may encourage patients to switch from on-demand treatment to prophylaxis, reduce the burden of frequent IV injections, reduce the need for central venous lines in children, promote adherence, improve outcomes, and potentially allow for more active lifestyles.^14,20,28,31 For patients with haemophilia B, EHL–rFIX products have the potential to reduce infusion frequency significantly and raise trough levels with a consequent increase in effectiveness. For haemophilia A, EHL–rFVIII products extend the half-life of FVIII to a lesser extent and the impact on dosing frequency is less dramatic than for EHL–rFIX products; as such, discussions among physicians and conversations with patients regarding the use of EHL–rFVIII products will be more complex.

We recommend that patients who would most benefit from EHL products are those with poor adherence to standard factor regimens with or without difficult venous access, those who are physically active/involved in sporting activities, patients with a severe bleeding phenotype, and (for haemophilia A) those with high levels of endogenous vWF. Although there is currently no consensus regarding an optimal prophylactic treatment schedule with EHL products, the recommended initial regimens are twice weekly or every third or fourth day for EHL–rFVIII and once weekly for EHL–rFIX. Children usually require a shorter dosing interval than adults, as the half-life of many EHL–rFVIII and EHL–rFIX preparations is shorter in these young patients.

Factor levels should always be monitored during treatment. EHL factor products should ideally be monitored using an assay that accurately measures the activity of a specific EHL product, within the context of ongoing adaptation of existing laboratory protocols and assays as new evidence accrues. Use of a product-specific standard may also be advantageous when monitoring some EHL factor concentrates. Regarding the monitoring of EHL–rFIX products, the chromogenic assay has shown reliability in measuring the FIX activity of N9-GP and rFIXFc; the one-stage assay may also be helpful if specific reagents are used. However, the one-stage assay using a variety of reagents can be used to reliably measure rFIX-FP.

Typically, FVIII prophylaxis in haemophilia A aims to keep plasma FVIII levels above a target threshold; however, factor activity alone is not the only component of effective treatment, and the relevance of target FIX levels in haemophilia B is not currently known. Therefore, the dosing schedule of EHL factor products should be adjusted as necessary according not only to measured factor levels, but also to joint status, individual bleed pattern, lifestyle and physical activity.

Although challenges associated with introducing EHL products remain (including cost, long-term safety and long-term patient follow up), the new EHL factor products that are currently available and in development have the potential to bring about significant changes to the treatment of haemophilia. Their ultimate role will be dependent on how the treatment landscape evolves.