Haemophilia: An overview and emerging treatments

Haemophilia is an inherited X-linked bleeding disorder which affects approximately 1,125,000 individuals globally.¹ Haemophilia A results from a deficiency of factor VIII (FVIII) and haemophilia B from deficiency of factor IX (FIX), both of which lead to diminished thrombin generation resulting in spontaneous bleeding in joints, muscles, and soft tissue.² Haemophilia A is caused by an array of mutations of the FVIII gene, the commonest being intron 22 inversion, which brings about severe haemophilia A.³ Haemophilia A is commoner than B and accounts for approximately 85 per cent of all haemophilia cases.⁴

Classification and symptomatology

The increased risk of excessive bleeding associated with haemophilia A relates to the severity of disease, which in turn depends on the baseline level of FVIII.⁴ (Table 1)

Individuals with mild FVIII deficiency may bleed upon trauma or surgical interventions, while those with the severe form of haemophilia A not on prophylactic treatment may experience spontaneous bleeding, most commonly in the joints and muscles.⁶ Those with moderate FVIII deficiency generally have an intermediate bleeding phenotype, however, these individuals may have a clinical phenotype similar to severe haemophilia.⁷

Diagnosis

Diagnostic investigations for haemophilia A include screening tests and clotting factor tests. Screening tests aim to check whether clotting is normal and these include a full blood count (FBC), a coagulation profile including activated partial thromboplastin time (APTT) and prothrombin time (PT), and fibrinogen (also known as clotting factor I) levels.⁵ (Table 2)

Clotting factor tests, also known as factor assays, are used to measure FVIII activity.⁹ When it comes to measuring plasma FVIII activity, there are two main strategies which are applied, these being, the one-stage clotting assay (OSCA), and the chromogenic substrate assay (CSA), which are both calibrated against plasma FVIII standards.¹⁰

Differential diagnoses include von Willebrand disease, acquired haemophilia A, haemophilia B or C, factor XI deficiency, Ehler-Danlos syndrome, platelet disorders, and Glanzmann thrombasthenia.⁵

Management

Irrespective of disease severity, studies have shown that this condition causes significant physical, social, and mental burdens.¹¹ A multidisciplinary approach is required for the management of patients with haemophilia, including the need for mental health and genetic counselling to address psychosocial issues and mode of inheritance respectively.¹²

Preventive measures

Recommended immunisations should be given at age-appropriate intervals to people with haemophilia. Modifications in order to reduce the risk of bleeding, especially in intramuscular vaccines, include limiting the number of injections per limb, using the smallest gauge needle, and application of pressure and/or ice to the injection site for approximately five minutes post-administration.¹³

Regular dental care and appropriate oral hygiene is also of the utmost importance in order to prevent dental and gingival disease, both of which increase the risk of bleeding.¹³ The avoidance of medications such as anticoagulants, aspirin, and other nonsteroidal anti-inflammatory drugs, also aims to reduce the bleeding risk in such patients.¹³

An adequate exercise regimen should be encouraged as part of the individual’s routine, and is beneficial for maintaining a healthy weight, decreasing cardiovascular risk, and positively affecting strength, balance, flexibility, and bone density, all of which aid to minimise stress on joints.¹³

Obstetric care in women who are carriers for haemophilia A is very complex and considerations should include the management of bleeding risks which are associated with invasive prenatal procedures along with regional anaesthesia, and also the increased risk of having postpartum haemorrhage.¹⁴ Obstetric care should be implemented by an appropriate multidisciplinary team.

Regardless of disease severity, appropriate planning for travelling should occur in all individuals with haemophilia A. An emergency supply of haemostatic replacement therapy should be kept with the patient during travel and the use of a medic alert bracelet is advised.¹³

Preparing for elective surgery

For haemophilia A patients undergoing elective surgery, there must be a collaboration between the surgeon, haematologist, anaesthesiologist, and laboratory and transfusion medicine, allowing for a sufficient amount of time for optimisation of FVIII levels with timely replacement therapy if needed.¹³ The desired factor level and duration of therapy depend on the type of procedure, with longer durations for greater bleeding risk procedures or procedures where healing requires a longer duration of coverage.

For patients who require perioperative factor administration, the dose should be administered at the time of greatest bleeding risk (typically 30-to-60 minutes before the operation). The dose is based on the patient’s weight, baseline factor (assumed to be 0 per cent for the first dose), desired factor level, volume of distribution, and presence of inhibitors. Should any postoperative bleeding develop, a factor level is taken and if this is adequate, it is important to consider the possibility that bleeding may be due to an anatomic or mechanical cause.¹⁵

The efficacy and safety of extended half-life (EHL) FVIII products (recombinant factor VIII-Fc fusion or PEGylated recombinant factor VIII) have been proven in small studies, in which haemophilia A patients were managed peri-operatively for both major and minor operations. Such patients had excellent haemostasis without serious adverse events.^16,17

For patients with mild haemophilia A, a DDAVP test dose can be given at least one week before a planned procedure. DDAVP is a synthetic analogue of vasopressin (also known as antidiuretic hormone) which promotes release of FVIII and its carrier protein von Willebrand factor from storage pools within platelet granules and endothelial cells.

Giving a test dose of DDAVP in these individuals determines whether DDAVP is effective in that patient, and if so, whether it can be used in order to increase FVIII level in the setting of mild bleeding or more invasive procedures. DDAVP may be administered subcutaneously (SC), intravenously (IV), or intranasally, and measurement of FVIII should be taken before and after DDAVP administration.¹³

Prophylaxis

Observational studies have shown that routine prophylaxis is associated with reduced joint bleeding and chronic arthropathy, especially when initiated earlier and targeted to individuals having the severe form of the condition.^18,19,20 The choice of prophylactic therapy must be individualised based on the patient’s needs and circumstances.¹³ Prophylactic therapy options for haemophilia A include factor replacement products and emicizumab, both of which are able to produce adequate haemostasis.¹³ However, these vary in patient responses; safety profile, including burdens and costs and risk for inhibitor development; and product characteristics such as monitoring needs and half-life.²¹

For administration, most of the clotting factor replacement products require reconstitution and all of them are administered IV.²² The age at initiation of prophylactic therapy has varied throughout the years by various working groups; however, routine prophylactic treatment for patients with severe haemophilia A initiated before two years of age appears to prevent spontaneous bleeding and development of arthropathy.²³

A typical starting schedule may consist of either 25-to-40 units/kg of body weight given three times per week or 15-to-30 units/kg given three times per week.¹³

FVIII replacement products include concentrates from plasma, recombinant products, and recombinant products with an EHL. Emicizumab, on the other hand, is a humanised bispecific monoclonal antibody which binds to both factor IXa and X, acting as a substitute for the role of FVIII in haeomstasis.²⁴

The most serious complication when it comes to replacement therapy in haemophilia A and those with severe disease is the development of inhibitors (both low and high titre), that is, antibodies directed against infused concentrates after this therapy.²⁵ Inhibitor development can profoundly interfere with the ability to treat bleeding and achieve sufficient haemostasis. High titre inhibitors bind to exogenously administered replacement FVIII and prevent it from exerting its effect. In cases where there is inhibitor development, emicizumab is effective.¹³

Emergency treatment

If the patient presents with serious bleeding such as bleeding in the central nervous system, airway, eye, hip, or
muscle, then treatment should be initiated immediately, even before all diagnostic assessment is completed.
– If the patient has the appropriate replacement therapy, this should be administered as soon as possible.
– If the patient’s own product is not available, then recombinant FVIII is administered.
– Plasma-derived concentrate can be administered should recombinant factor not be available as well.
– Cryoprecipitate and fresh frozen plasma are no longer recommended for treatment of individuals with haemophilia A.

Around 15-to-25 per cent of haemophilia A patients have FVIII inhibitors. In patients with high titre inhibitors (>5 Bethesda units at any point during their medical history, regardless of titre level at the time of major bleeding), require the use of recombinant activated FVII (rFVIIa) at a dose of 90mcg/kg or activated prothrombin complex concentrate (aPCC) at a dose of 75-to-100 units/kg.

In patients without inhibitors, factor activity level needs to be maintained above 50 per cent at all times. Therefore, guidelines recommend administering FVIII at a dose of 40-to-50 units/kg, leading to FVIII level of 80-to-100 per cent. Subsequent doses need to be administered so as to ensure that the patient’s circulating factor level does not drop below 50 per cent.

It is important to remember that while emicizumab is used as prophylaxis to prevent bleeds, it is ineffective in the setting of an acute bleed. Therefore, in patients receiving emicizumab who present with acute bleeding, FVIII should be given nonetheless. For patients receiving efanesoctocog alfa, which has a half-life of around 48 hours, additional factor should generally not be given if it has been less than two days since the patient’s prophylaxis infusion.

Patients who have mild haemophilia A (baseline FVIII >5 per cent and <50 per cent), and presenting with non-life threatening bleeding, may be given desmopressin. This treatment should only be used if there is documentation that a previous haemostatic response was achieved when administering this drug. Otherwise, treatment is the same as for other patients with haemophilia A.

Desmopressin can be administered SC at a dose of 0.3 mcg/kg, IV at a dose of 0.3 mcg/kg in 30ml normal saline over 15-to-30 minutes. It can also be administered intranasally, at a dose of one spray in one nostril for individuals <50 kg and one spray in each nostril for individuals >50 kg.¹²

Emerging treatment

Significant developments have been undertaken with regards to gene therapy in haemophilia in recent years, with several ongoing trials. The first adeno-associated viral (AAV)-based haemophilia A gene therapy clinical trial involved the administration of valoctocogene roxaparvovec. The latter is an AAV5 vector, expressing the B domain–deleted (BDD) FVIII-SQ variant. In this trial, 15 male patients with severe haemophilia A, lacking a history of FVIII inhibitors and without detectable anti-AAV5 antibodies, were enrolled.²⁶

The trial spanned a dosage range from 6e12 to 6e13 vector genomes per kilogram (vg/kg) body weight. Seven patients received one dose of 6e13 vg/kg body weight. After one year, the median FVIII activity was 60 IU/dL, as assessed by a CSA. Six years after the gene transfer, the median FVIII activity, determined by CSA, declined to 5.6 IU/dL.²⁷ In addition, a discrepancy was noted between different assays, specifically CSA and OSCA.²⁸

In a separate trial, 134 men with severe haemophilia received a single dose of 6e13 vg/kg of valoctocogene roxaparvovec. At one year following the infusion, median CSA FVIII activity levels measured at 23.9 IU/dL.29 Once again, median FVIII activity levels declined to 8.3 IU/dL by the end of the third year. Seventeen patients also resumed prophylactic treatment.³⁰ Nonetheless, clinical benefits were noted from such trials, leading to conditional approval in Europe and full approval in the US for valoctocogene roxaparvovec.³¹

During the initial phases in trials involving giroctocogene fitelparvovec, an AAV6 encoding BDD-FVIII-SQ, median FVIII expression of 40.1IU/dL was noted by CSA in patients receiving the highest dose of 3e13vg/kg after 1.5 years of infusion. This declined to 11.8IU/dL at the end of a three-year post-infusion period. Trials are now in phase 3, with data still not published yet.³²

In a trial involving dirloctocogene samoparvovec, FVIII activity levels measured by OSA ranged from 4-22IU/dL for 16 patients out of 18. Such patients received vector doses between 5e11vg/kg and 2e12vg/kg. Two out of the nine participants who received the highest dose had loss of FVIII expression, leading to a rapid decline in FVIII levels within 26 weeks after the infusion, along with raised alanine aminotransferase (ALT) levels.³³ A further study involving AAVhu37 encoding BDD-FVIII given to nine patients at a dose of 5e12 to 2e13vg/kg showed a sustained FVIII expression for over 23 months.³⁴

The commonest adverse event associated with AAV vector administration is transaminitis, with raised levels of ALT. This could be due to the cellular immune response triggered by the AAV vector. In view of this, more frequent and prolonged high dose immunosuppressive regimens are required.²⁶ Moreover, the degree of factor expression in all AAV-based clinical trials was noted to be highly variable, with a decline in FVIII expression over the years raising concerns with regards to efficacy of such treatment.³¹

Limitations of the current AAV gene therapy may be overcome by alternative gene transfer systems. Three phase 1 studies collect and transduce hematopoietic stem cells (HSC) ex-vivo with lentiviral vectors encoding FVIII and these are transferred back to participants.³⁵

Two ongoing trials are utilising the FVIII-ET3 variant under the CD68 promoter. In this way, FVIII expression is localised in monocytes.³⁵ In a particular study, utilising a platelet-specific promoter FVIII-BDD expression was induced in megakaryocytes, leading to FVIII expression and storage in platelet α-granules.

This approach led to the correction of haemostasis in animal models, whilst neutralising anti-FVIII antibodies, meaning that individuals with a history of FVIII inhibitor could also be recruited in this clinical trial. Twelve months after treatment, one patient showed sustained expression in platelets, with no episodes of bleeding for nine months, even after discontinuation of prophylaxis.³⁶ A major drawback of HSC-based approaches is that the bone marrow requires toxic pre-conditioning.

Several systemically-delivered gene therapy approaches involve targeted or random transgene insertion in the genome. In haemophilia A, this approach has been tested by delivery of the transgene and the CRISPR/Cas9 machinery using a combination of two AAV vectors.³⁷ Since these approaches involve AAV, pre-post treatment anti-AAV antibodies, variability of responses, and inability to redose will likely occur, just as in current gene therapies. Non-viral gene transfer systems are being developed to overcome these adverse events.

A gene-editing approach for haemophilia A utilises a combination of two lipid nanoparticles (LNPs), whereby one carries a FVIII-encoding transposon (DNA) and the other delivers mRNA that encodes Super piggyBac transposase. The latter excises the FVIII transgene from the transposon and integrates it with the genome. This approach allows for repeat dosing, thereby enabling achievement of the desired factor expression as LNPs do not trigger the neutralising immune responses that prevent AAV dose titration.³⁸

Concizumab

Inhibition of endogenous anticoagulant pathways has gained attention in the management of haemophilia. One pathway which has been targeted is through tissue factor pathway inhibitor (TFPI). The latter is a serine protease inhibitor that inhibits activated FX (FXa) and the tissue factor (TF)–activated FVII (FVIIa) complex in an FXa-dependent manner, as well as early forms of the activated FV (FVa)–FXa (prothrombinase) complex.³⁹

A new drug which has been developed to target this pathway is concizumab, a high-affinity, humanised monoclonal immunoglobin G4 antibody against the TFPI-K2 domain that prevents TFPI binding to, and its inhibition of, FXa 14. This drug has shown to reduce cuticle bleeding in a rabbit model of haemophilia A. Following this, the safety and efficacy of concizumab has been explored in humans. Several studies have been carried out, with phase 3 trials also finding that daily SC treatment is safe and effective.⁴⁰

It has been shown that concizumab can rescue thrombin generation in haemophilia A plasma in closed systems without flow in a concentration-dependent manner. However, clots formed under flow in an open system with concizumab. A study was carried out to measure the effect of concizumab on clot formation in whole blood under physiologic flow conditions.

Samples of blood were collected from patients with haemophilia and normal controls. An anti-FVIII antibody was added to the latter so as to simulate haemophilia A with inhibitory antibodies to FVIII. Following this, concizumab or whole blood and recombinant activated FVIII were perfused over a surface micropatterned with tissue factor and collagen-related peptide.²

Platelet and fibrin(ogen) accumulation were measured, with results showing rescued total platelet accumulation of 93-to-101 per cent and partial rescued fibrin(ogen) accumulation of 53-to-63 per cent for both concizumab and recombinant activated FVIII. Both drugs had similar effects on clot formation under flow; however, concizumab was associated with enhanced thrombin generation under static conditions, to a greater extent than recombinant activated FVIII.²

From this study it was concluded that concizumab’s effect on TFPI inhibition with enhanced activation and aggregation of platelets and fibrin clot formation in haemophilia A was comparable to recombinant activated FVIII.²

Treatment options in Ireland

Access to treatment and healthcare services for haemophilia patients in the Republic of Ireland ranks highly by international standards when it comes to contemporary haemophilia management.⁴¹ The current predominant specific therapies for haemophilia A patients in Ireland are EHL FVIII (elocta) and emicizumab (hemlibra). The current national licensed therapies are listed in Table 3.

Other treatment options which are currently under development in clinical trials for use in the Irish healthcare system include clotting factor concentrates such as recombinant EHL, prophylactic non-factor replacements including bi-specific antibodies and rebalancing therapies, and gene therapy.

References