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Individualizing Hemophilia A Treatment: Strategies for Implementing Pharmacokinetic-Based Dosing

Introduction

Hemophilia A is an X-linked congenital bleeding disorder resulting from a deficiency of Factor VIII (FVIII), a coagulation factor critical to the normal process of coagulation. As a result, persons with hemophilia A (PWHA) may experience spontaneous bleeding into soft tissue, joints, and internal organs or excessive bleeding following injury or trauma. [Bauer 2015] Because the hemophilia mutation is located on the X chromosome, this disorder affects males primarily, whereas females who inherit the affected X chromosome are carriers. [Bauer 2015] Females can develop hemophilia A in rare instances. [Bauer 2015] This condition affects 1 in 5,000 male births; approximately 400 babies are born with hemophilia A each year in the United States. [Soucie 1998, CDC 2017]

Persons with hemophilia A experience a range of bleeding manifestations that vary in severity from mild to life-threatening. [Carcao 2015, Peyvandi 2016] The severity of hemophilia A is defined by the level of endogeneous FVIII: mild disease is defined as FVIII levels >5%; moderate disease is defined as FVIII levels between 1% and 5%; and severe disease is defined as FVIII levels <1%. [Lieuw 2017] A significant percentage of individuals with hemophilia A have severe disease (43% -65%). [Soucie 1998, Mazepa 2016] Compared to those with mild hemophilia A, these individuals suffer from greatly increased rates of spontaneous bleeds, complications of recurrent bleeds, limitations in physical function, disability, and mortality. [Bauer 2015, Mazepa 2016, Zhou 2015]

The diagnosis and management of PWHA is a complicated task that requires the efforts of a multidisciplinary team of specialists. [Ruiz-Sáez 2012] This team, which may include hematologists, orthopedic specialists, nurses, pharmacists, and laboratory specialists, is responsible for the ongoing supervision of all medical and psychological aspects that affect the patient and caregivers. [Ruiz-Sáez 2012] These teams must work with patients and caregivers to ensure adequate inpatient, outpatient, and supervised home treatment. [Ruiz- Sáez 2012] Thus, clinicians who treat and manage PWHA must understand how to provide optimal care within a multidisciplinary framework.

FVIII Pathophysiology and Replacement Mechanisms

Coagulation FVIII is a 2332-amino acid glycoprotein that is produced in the liver and circulates throughout the plasma in an inactive heterodimer form. [Castaman 2018] This form is non-covalently bound to the glycoprotein von Willebrand factor (VWF) until vascular damage and bleeding occurs, at which point FVIII undergoes proteolytic activation by thrombin or activated factor X (FXa) to dissociate from VWF as a heterotrimer and bind to the activated platelet surfaces. [Castaman 2018] Serving as a cofactor for the activated Factor IX (FIXa), this complex converts FX to FXa; the binding to VWF prevents early degradation of FVIII by the activated protein C system and early elimination by the receptor-mediated clearance mechanism. [Castaman 2018] Thus, the plasma half-life of FVIII is significantly influenced by its interaction with VWF. [Castaman 2018] Although the severity of bleeding generally correlates with FVIII level, significant heterogeneity has been observed in this relationship. [Carcao 2015]

Current therapy for hemophilia A is based on the infusion of FVIII concentrates either at the time of bleeding (ie, on-demand therapy) or at regular intervals to prevent bleeding episodes from occurring (ie, prophylaxis). [Peyvandi 2013] When administered in PWHA, FVIII rapidly binds to endogenous VWF, with only a small fraction of this complex being distributed outside the plasma compartment. [Castaman 2018] As a result, to achieve a peak plasma level of 1.0-1.3 U/mL when basal level of pro-coagulant activity of FVIII (FVIII:C) is <0.01 U/mL, an infusion of 50 IU/kg is typically needed. Peak levels are usually reached within 10-15 minutes following the end of infusion, but can occur as late as 1-2 hours post-infusion. [Castaman 2018]

FVIII clearance can be affected by individual patient factors, including the patient's activity level, bleeding type, blood level, etc, all of which affect the pharmacokinetic (PK) properties of these agents.

Acute bleeding episodes in those with mild/moderate hemophilia A are typically managed with the synthetic vasopressin analog desmopressin acetate (DDAVP), which can increase FVIII levels three- to six-fold at one hour post-administration, although the response rate is variable and each individual must be give a test dose to monitor FVIII levels post-treatment. [Peyvandi 2016] Among those with moderate or severe hemophilia A, FVIII replacement therapy using a prophylactic regimen is considered standard care. [Peyvandi 2016] However, this approach has significant challenges. The efficacy of prophylactic FVIII replacement products is limited by a relatively short half-life (mean 12.9-14.8 hours) and the development of FVIII antibodies. FVIII clearance can be affected by individual patient factors, including the patient's activity level, bleeding type, blood level, etc, all of which affect the pharmacokinetic (PK) properties of these agents. [Barnes 2013, Carcao 2015] In addition, the availability of extended half-life (EHL) FVIII products, which have been manipulated to produce different PK and pharmacodynamic (PD) effects through half-life prolongation, offer alternative treatment options that require individualized dosing strategies. [Barnes 2013, Carcao 2015] Thus, prophylactic protocols must be modified according to the patient's specific PK profile and further tailored to each individual patient. [Srivastava 2013] Fortunately, methods to overcome these challenges are being developed, and clinicians can be equipped to provide essential prophylaxis to their patients with hemophilia A now more than ever.

Prophylaxis with FVIII Replacement Therapies

Prophylactic Therapy: Rationale and Evolution

FVIII replacement prophylaxis works to correct the deficiency in FVIII such that trough levels are maintained at >1%. This goal is based on observations that individuals with moderate hemophilia experience lower rates of hemophilic arthropathy compared with those with severe hemophilia. [Manco-Johnson 2007, Cheng 2018, Fischer 2002] Approximately 90% of those with FVIII <1% experience arthropathies by young adulthood. [Cheng 2018, Ljung 2016] Therefore, by achieving and maintaining ideal peak and trough FVIII levels through regular prophylactic dosing, PWHA can reduce their risk of bleeding related to repetitive physical activity and breakthrough bleeding events. [Cheng 2018]

Modern treatment of hemophilia A with replacement of FVIII began with the use of fresh frozen plasma (FFP) in the 1950s, followed by cryoprecipitate in the 1960s. [Lieuw 2017] The development of lyophilized FVIII derived from pooled plasma revolutionized treatment for hemophilia A, although the contamination of blood used for factor concentrate manufactured with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in the 1980s was a significant setback. [Lieuw 2017] During this time, approximately 90% of individuals with severe hemophilia were infected with HCV, and more than half were co- infected with HIV. [Bauer 2015] Fortunately, the generation of safer plasma-derived FVIII through multiple different viral inactivation methods rendered such treatments safe again. The cloning of the gene for FVIII in 1984 and resultant development of recombinant FVIII (rFVIII) agents was another technological advancement in the concentrate used for the prevention and treatment of hemophilia-associated bleeding. [Lieuw 2017] More recently, the development of EHL products and non-replacement therapies have expanded options for PHWA.

Effectiveness of FVIII prophylaxis

The use of prophylaxis in hemophilia A is supported by numerous studies which revealed the benefits of prophylaxis versus on-demand (episodic) therapy. [Barnes 2013, Manco-Johnson 2007, Gringeri 2011, Manco-Johnson 2013, Royal 2002, Oladapo 2015] In 2007, a landmark randomized, controlled study of 65 boys with severe hemophilia A was performed by Manco-Johnson et al. [Manco-Johnson 2007] The aim of this study was to determine the effect of routine prophylactic infusions of FVIII on the incidence of bone or cartilage damage in index joints (ankles, knees, and elbows) compared with enhanced episodic FVIII replacement therapy. At endpoint, 93% of those in the prophylaxis group were considered to have normal index-joint structure on magnetic resonance imaging (MRI) compared with 55% of the episodic-therapy group (P=0.006). In addition, the mean annual numbers of joint and total hemorrhages were higher in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). [Manco-Johnson 2007]

Several years later, the 2011 ESPRIT study was conducted to compare the efficacy of prophylaxis in preventing hemarthroses and image-confirmed joint damage in children with severe hemophilia A over a 10-year period. [Gringeri 2011] Forty-five children were consecutively randomized to prophylaxis with rFVIII or episodic therapy until complete clinical bleeding resolution. Over the study period, the children on prophylaxis had fewer hemarthroses than children on episodic therapy (0.20 vs. 0.52 events per patient month, P<0.02). Plain-film radiology also showed signs of arthropathy in 29% of the prophylaxis group versus 74% of the episodic treatment group (P<0.05). The study also confirmed that prophylaxis was more effective when started early in life (≤36 months), in individuals with fewer joint bleeds, and in those with no radiologic signs of arthropathy. [Gringeri 2011]

More recently, a 2013 study confirmed the efficacy of prophylactic therapy in older PWHA. [Manco-Johnson 2013] In the 3-year Severe Prophylaxis In Adults, a Randomized Trial (SPINART) study, routine prophylaxis was compared with on-demand treatment with sucrose-formulated rFVIII in a randomized controlled trial of 84 males aged 12-50 years with severe hemophilia A. At endpoint, the median number of total bleeding episodes and total bleeding episodes per year were both significantly lower in the prophylaxis group than in the on-demand treatment group (0 vs. 54.4 total; 0 vs. 27.9 total per year; P<0.0001 for both). In addition, there were no treatment-related adverse events and no incidences of FVIII inhibitor development. [Manco-Johnson 2013]

Prophylaxis also appears to be positively associated with health-related quality of life (HR- QOL) dimensions. [Oladapo 2015] A recent international systematic literature review evaluating the impact of prophylaxis on HR-QOL in adults with severe or moderately severe hemophilia A and B revealed that this form of treatment is associated with reduced pain, fewer restrictions on physical activities, and better general health. Those who previously received on-demand treatment only and those who experienced marked reductions in bleeding frequency on prophylaxis reported the greatest improvements in HR-QOL. [Oladapo 2015] A similar US study on QOL in PWHA conducted by the Hemophilia Utilization Study Group VA (HUGS-VA) found that the physical aspects of HR-QOL decreased with increasing severity of illness. [Poon 2012]

Limitations of prophylactic therapy

Extended half-life (EHL) products offer numerous theoretical benefits, including reduced dosing frequency, improved adherence, and increased time spent in target peak/trough range.

One of the most significant challenges associated with modern FVIII replacement therapies has been the half-life of these products, which necessitate frequent infusions in order to maintain adequate FVIII trough levels. [Lieuw 2017] The mean half-lives of standard rFVIII therapies range from 12.9 to 14.8 hours [Castaman 2018] As a result, prophylactic therapy with these agents, while effective, is also burdensome, requiring multiple infusions per week, which often results in decreased adherence among PWHA. [Castaman 2018] Treatment adherence can be defined as 'the active, voluntary, and collaborative involvement of a patient in a mutually acceptable course of behavior to produce a desired preventive or therapeutic result.'[Thornburg 2017] Adequate adherence to FVIII replacement prophylaxis is generally poor, although it is significantly higher in young children compared with adults (VERITAS-Pro scores of 38-40 versus 46-51, respectively). In general, patient-reported rates of adherence to hemophilia prophylaxis range from 30% to 96%, while healthcare provider- reported rates of patient adherence range from 42% to 54%. [Thornburg 2017] Inadequate patient adherence to standard FVIII replacement therapies has been directly associated with greater numbers of bleeding episodes, greater numbers of missed days of work or school, and lower physical health status scores. [Krishnan 2015] It has been cited by physicians as a primary reason for withholding or discontinuing prophylactic therapy. [Thornburg 2012]

To improve the management of PWHA, researchers are now focusing on newer generations of rFVIII concentrates with extended half-lives. [Castaman 2018] Extended half-life (EHL) products offer numerous theoretical benefits, including reduced dosing frequency, improved adherence, and increased time spent in target peak/trough range. [Castaman
2018] Efforts to extend product half-lives have been met with moderate success through the conjugation of FVIII with larger molecules such as polyethylene glycol (PEG), albumin, or the human immunoglobulin (Ig) FC. [Tiede 2015, Lieuw 2017] A novel single-chain construct formulation was also developed in 2016 called recombinant factor VIII single chain (rFVIII- SC) that works through increased stability and affinity for VWF. [Lieuw 2017, Cafuir 2017] To date, available EHL FVIII products produce a 1.4- to 1.6-fold increase in half life (mean 14 to 19 hours) compared with standard half-life FVIII products. [Tiede 2015, Cafuir 2017]

There are currently two EHL FVIII products approved by the FDA: efmoroctocog alfa, a BDD FVIII-fusion protein (rFVIIIFc) and rurioctacog alfa pegol, a PEG-coupled rFVIII product. Efmoroctocog alfa was evaluated in the Phase 3 A-LONG trial, which included 165 previously treated males aged ≥12 years with severe hemophilia A who received individualized prophylaxis, weekly prophylaxis, or episodic treatment. [Mahalangu 2014] The median annualized bleed rates (ABRs) were 1.6, 3.6, and 33.5, respectively, and the agent was found to be well-tolerated and had a prolonged half-life compared with rFVIII when dosed 1 to 2 times per week. This agent was also evaluated in children with hemophilia A in the Phase 3 Kids A-LONG study. [Young 2015] Seventy-one children who were previously treated (≥50 exposure days with any recombinant or plasma-derived FVIII product) received rFVIIIFc twice weekly, and at endpoint, the median ABR was 1.96 overall, and 90% were infusing twice weekly; no reports of inhibitor development were reported. [Young 2015] Rurioctocog alfa pegol was evaluated in a phase 3 trial of 137 previously treated individuals with severe hemophilia A aged 12-65 years. [Konkle 2015] In this trial, the median ABR associated with this prophylaxis was 1.9, and no inhibitors were detected. This agent was also studied in a phase 3 pediatric trial, which included 66 previously treated children with severe hemophilia A aged >12 years. [Mullins 2017] At endpoint, the total mean ABR was 3.04 and the mean joint ABR was 1.10. [Mullins 2017] Again, no inhibitors were detected, and significant improvement in HR-QOL, pain, and physical activity were also observed. [Mullins 2017]

A second challenge associated with FVIII replacement therapy is the development of neutralizing anti-FVIII antibodies (ie, 'inhibitors'). [Liauw 2017] Inhibitors develop in up to 25%-30% of PWHA, and results in the need for new treatment with bypassing agents and immune tolerance induction. Although factors including ethnicity, genetic mutations, and environment all appear to play a role in the development of inhibitors, treatment-associated patterns have emerged as well. Several studies have found that second-generation FVIII products have higher rates of inhibitor development compared with third-generation products. [Liauw 2017, Gouw 2013, Calvez 2014] Differences in the cell lines utilized for the production of these products may be responsible for this phenomenon. [Liauw 2017] Another observation has been made that EHL products may confer lower rates of immunogenicity. [Liauw 2017] Although this hypothesis requires additional study, case reports of successful immune tolerance induction using rFVIIIFc have supported this claim. [Liauw 2017, Groomes 2016, Malec 2016] Recently, the Survey of Inhibitors in Plasma- Product Exposed Toddlers (SIPPET) trial found that plasma-derived FVIII products had lower rates of inhibitor formation compared with recombinant FVIII products. [Peyvandi 2016²] However, the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) have warned that other notable trials have not reported similar findings, and that the different ethnicities involved in the SIPPET trial may not translate to the US population. [MASAC 2016]

In response to the crisis of inhibitor development, emicizumab-kxwh was approved in November 2017 to prevent or reduce the frequency of bleeding episodes in PWHA who have developed inhibitors. [FDA 2017] This agent is a bispecific humanized monoclonal antibody therapy with Orphan Drug designation. The approval was based on a phase 3 clinical trial in which emicizumab-kxwh was associated with 2.9 bleeding episodes per year compared with 23.3 bleeding episodes per year among PWHA with inhibitors who did not receive prophylactic therapy. [Oldenburg 2017]

The Future of Prophylactic Therapy

Although the ongoing challenges associated with prophylactic therapy complicate optimal treatment selection, it is important to note that there are yet more treatments on the horizon for hemophilia A. Turoctocog alfa pegol (N8-GP) is a novel EHL FVIII that was shown in a Phase 1 clinical trial to have a mean half-life of 19.0 hours, representing a 1.6-fold prolongation as compared with the individuals' previous FVIII products (mean half-life 11.7 hours). [Tiede 2013] This agent was recently evaluated in a Phase 3 trial in previously treated adolescents and adults with severe hemophilia A and found to produce a median ABR of 1.33 and low rates of new inhibitor development. [Giangrande 2017] Among those receiving this therapy, 83.6% of bleeds were resolved with one injection and 95.5% with up to two injections; the agent had a favorable safety profile and was well-tolerated, although one patient developed an inhibitor. [Giangrande 2017]

BAY 94-9021 is another BDD rFVIII in development. Pharmacokinetic studies of this agent demonstrated non-inferiority to rFVIII-FS in both children (≤12 years of age) and adolescents/adults (12-62 years of age), with a half-life that is significantly higher versus plasma or albumin-free rFVIII (14.5 hours vs. 11.7 hours, P<0.0001). [Shah 2015, Shah 2017] In a phase 2/3 trial among previously treated subjects with severe hemophilia A, this agent demonstrated a median ABR of 1.9 and 3.9 when given as prophylaxis every 5 and 7 days, respectively. [Reding 2017] 90.6% of bleeding episodes were controlled with up to 2 infusions, and no patient developed inhibitors. [Reding 2017]

There are also adeno-associated virus (AAV)-based gene therapy products in development for severe hemophilia A. BMN 270 was designated as an orphan drug by the FDA in February 2016 when this therapy was shown to be well tolerated in a Phase 1/2 trial. [Pas 2016] In addition, data presented at the American Society of Hematology (ASH) 2017 Annual Meeting confirmed the safety and efficacy of SPK-8011, an alternative AAV-based gene therapy, in a Phase 1/2 trial. [George 2017]