New directions to develop therapies for people with hemophilia

ABSTRACT

Introduction

The past few decades have seen a tremendous advancement in the management of hemophilia. Whether it is improved methods to attenuate critical viruses, recombinant bioengineering with decreased immunogenicity, extended half-life replacement therapies to mitigate the burden of repeated infusion treatments, novel nonreplacement products to avoid the drawback of inhibitor development with its attractive subcutaneous administration and then the introduction of gene therapy, the management has trodden a long way.

Areas covered

This expert review describes the progress in the treatment of hemophilia over the years. We discuss, in detail, the past and current therapies, their benefits, drawbacks, along with relevant studies leading to approval, efficacy and safety profile, ongoing trials, and future prospects.

Expert opinion

The technological advances in the treatment of hemophilia with convenient modes of administration and innovative modalities offer a chance for a normal existence of the patients living with this disease. However, it is imperative for clinicians to be aware of the potential adverse effects and the need for further studies to establish causality or chance association of these events with novel agents. Thus, it is crucial for clinicians to engage patients and their families in informed decision-making and tailor individual concerns and necessities.

KEYWORDS:

• Hemophilia
• replacement factor VIII
• replacement factor IX
• extended halflife factor VIII
• extended halflife factor IX
• gene therapy
• inhibitor

1. Introduction

Hemophilia A (HA) and B (HB) are X linked recessively inherited monogenic bleeding disorders caused by quantitative or qualitative abnormalities of coagulation factor VIII (FVIII) and factor IX (FIX), respectively [1]. The first inscriptional account of hemophilia dates back to the 2^nd century AD described in the Talmud, Jewish rabbinical writings that mentions to avoid circumcision in children if two of their brothers had previously died due to hemorrhage following the procedure [2]. The modern-day accounts materialized only in the 19th century suggests that the only available treatment during that time was whole blood transfusion. Subsequently, in the middle of the 20^th century, the discovery of “antihemophilic globulin” lined the way to the invention of cryoprecipitate and then of FVIII and FIX concentrates [3]. Sadly, in 1980s, calamitous infection with human immunodeficiency virus and hepatitis C virus was reported in hemophiliacs due to contamination of factor concentrate supply thus necessitating development of improved methods to attenuate viruses. Dry-heat, pasteurization, solvent-detergent treatment, immunoaffinity purification, and nanofiltration are the main contrivances used to attenuate this contamination and prevent transmission-related infection [4].

The availability of these factor replacement products has drastically diminished the morbidity and mortality associated with hemophilia and remains the backbone of hemophilia treatment. However, the development of neutralizing alloantibodies i.e. inhibitors, is the most despairing and problematic treatment-related complication that affects at least one-third of individuals with severe hemophilia [5]. Inhibitor formation has an estimated incidence of 30% in severe HA [6] and 9.3% in severe HB [7] The fundamental method for inhibitor eradication is immune tolerance induction which is a technique to tolerize the individual’s immune system to the clotting factor and reduce antibody production via the administration of repeated doses of the factor [8]. This method is intensive, costly and requires frequent and long-term administration of factor concentrates and is associated with significant complications including anaphylactic reactions or complications related to nephrotic syndrome, the latter evident in HB [9]. ITI protocols to eliminate inhibitors are not effective in all patients, hence new experimental therapies are being developed. One such investigational therapy is an oral tolerance protocol based on transgenic lettuce plants that suppressed inhibitor formation in hemophilic mice and dogs [10]. Furthermore, studies are ongoing to determine factors affecting the inhibitor development in hemophiliacs, one such study is a prospective multicenter longitudinal cohort study the “Hemophilia Inhibitor Previously Untreated Patients (PUP) Study” that revealed distinct antibody signatures prior to FVIII inhibitor development [11].

Presently, more effective and less cumbersome treatments have been intended to overcome these unmet needs of current therapeutic strategies, such as non-replacement factor therapies that are effective regardless of the presence of inhibitors. These innovative therapies are bypassing agents that seek to rebalance the hemostatic defect by targeting the natural anticoagulant pathways that regulate hemostasis such as activated prothrombin complex concentrates (aPCC), recombinant activated factor VII [12] and plasma-derived FVIIa/FX complex [13]. Emicizumab-kxwh, that has been licensed for routine use in patients with HA, is a bispecific monoclonal antibody that bridges activated FIX to factor X, mimicking the function of activated FVIII, thereby increasing thrombin formation [14]. Another way besides enhancing coagulation is to inhibit anticoagulant pathways by the use of fitusiran, an antisense oligonucleotide that ultimately decreases transcription and translation of native antithrombin RNA [15], and marstacimab/concizumab that are monoclonal antibodies against tissue factor pathway inhibitor (TFPI) [16,17]. Although studies have reported thrombotic complications with emicizumab, it has been widely used as prophylaxis. Fitusiran remains in development, its clinical trial progress interrupted by unexpected thrombotic complications in a few study subjects [16,18]. Thus, even though the evidence for efficacy of the “non-factor therapies is reassuring, their safety profiles have raised concern, hence caution is necessary when prescribing or encouraging participation in clinical trials.

Another shortcoming of these factor replacement agents is that standard half-life (SHL) coagulation products for prophylaxis typically need 2–4 injections per week. Newer techniques with Fc-fusion technology and PEGylation has led to the development of extended half-life (EHLs) FVIII [19] and FIX that allow longer intervals between dosing schedules [20]. Subcutaneous (SQ) and oral administration that is currently underway would also streamline prophylaxis, improve compliance by eliminating the need of intravenous (IV) access, reducing dosage frequency, and extending protection from bleeding. For over three decades, researchers have ardently pursued efforts to potentially cure hemophilia through the development of gene therapy. Gene therapy includes introduction of either a wild-type factor gene or a modified gene with enhanced properties such as B-domain deletion to facilitate vector loading (FVIII), or using a gain-of-function gene variant to enhance gene product activity (FIX Padua). Hepatocytes are an appropriate target cell for transduction since liver is the site of synthesis of most clotting factors. Diverse technologies have been used to introduce the F8 or F9 gene, either using ex vivo genetic modification followed by implantation of the modified cells or by means of a vector carrying a construct that introduces the normal gene or vectors that produce other coagulation factors such as factor VIIa that can be used in hemophiliacs with immune tolerance [21,22] Autologous bone marrow cells derived mesenchymal stromal cells transduced with a lentiviral vector also showed promising results with elevated FVIII levels [23].

In this article, we will critically analyze the current therapies and highlight the noteworthy advancement in the existing therapeutic resources for the management of patients with HA and HB.

2. Current therapies

Factor VIII or IX replacement, nevertheless, is broadly used with years of undisputable data supported by clinical and real-world experience to treat and prevent bleeds in patients with hemophilia and to prevent long-term complications such as arthropathy. The hallmark longitudinal study by Nilsson set the footing to establish primary prophylaxis to prevent orthopedic complications of repeated bleeds [24]. Primary prophylaxis starts at young age [≤2 years] and is long term, before joint disease develops, whereas secondary prophylaxis begins after the onset of joint disease [25,26].

In 1992, the first commercially available recombinant factor VIII product became available for HA and then subsequently in 1997 for HB [27]. Since then, a plethora of plasma-derived and recombinant products have been developed. The existing standard products have relatively short half-lives (8–12 h for FVIII and 18–24 h for FIX), often necessitating treatments 2–3 times per week [28].

Modern advances, such as EHL products and pharmacokinetic-guided dosing, provide new opportunities to tailor regimes for each individual patient. There are two key techniques of extending the half-life of replacement products. The first is the coagulation factor fusion to proteins like the Fc portion of IgG1 or albumin which extends biological activity by recycling via the neonatal Fc receptor [29]. The second method is the binding with chemicals such as polyethylene glycol (PEG) that acts by slowing their degradation and renal elimination [30].

Despite EHL therapy, hemophilia patients with FVIII inhibitors remain poor candidates for prophylaxis [31] and often require bypassing agents like recombinant human factor VII and aPCC for acute bleeding and preoperatively.

[31] For prophylaxis, non-replacement agents have been studied that act by either mimicking the coagulant activity of FVIII or “rebalancing agents” by increasing defective thrombin formation through the inhibition of the naturally occurring anticoagulants (antithrombin, TFPI, and activated protein C) [32].

To date, only emicizumab that mimics the coagulant activity FVIII activity has been licensed and available commercially [33]. Emicizumab is largely being used now for prophylaxis in patients with HA. Based on phase 2 results, the US Food and Drug Administration (FDA) granted concizumab (previously called mAb2021), a monoclonal antibody against TFPI, “Breakthrough Therapy” designation for HB with inhibitor patients [34].

2.1 Plasma derived Factor VIII and IX products

Once carefully screened donor plasma is designated, the factors are then prepared by commercial fractionation which include either chromatography or monoclonal antibody affinity [35]. Pasteurization, solvent/detergent treatment, chemical disruption with sodium thiocyanate, or ultrafiltration are methods of viral inactivation that augment protection against HIV and hepatitis viruses. These products are thus graded based on purity. Higher purity reflects a higher ratio of FVIII to non-factor VIII proteins [35]. These are divided into Intermediate purity, high purity, and Ultrahigh purity. The main adverse events (AEs) noted with FVIII are increased FVIII inhibitors and inflammation at injection site [36]. AEs with FIX products are rare and involve inhibitor development, skin reactions, and hypersensitivity [36]. The various available plasma-derived products have been described in table 1.

Table 1. Depicting Plasma derived products and their characteristics [36]

Plasma derived	FDA approval	Prophylaxis Dose	Treatment dose (Major trauma or surgery)	Half-life (hours)	Viral Attenuation Method	Other characteristics
Factor VIII
Hemofil M (Baxter)	1966	20–40 IU/dL plasma	80–100 IU/dL plasma	15	Solvent and detergent and Nanofiltration	Ultrahigh Purity
Koate (previously called Koate DVI) (Kedrion Biopharma)	1974	15 units per kg	80–100 units per kg	16	Solvent and detergent and Polyethylene glycol (PEG) precipitation/depth filtration	High Purity
Factor IX
AlphaNine SD (Grifols Biologicals)	1996	25–40 IU/kg two times weekly or 15–30 IU/kg two times weekly	30–50 IU/kg - Repeat dose every 12 hours as needed for 3–5 days	18	Solvent and detergent	High Purity
Mononine (CSL Behring)	1992	up to 20–30 IU/kg repeat in 24 hours if necessary	up to 75 IU/kg	23	Immunoaffinity chromatography	High Purity

Table 1: Table 1 depicts Plasma-derived products and their characteristics [36]

2.2 Recombinant Factor VIII and IX products

Recombinant human FVIII are made using modified versions of the human FVIII gene. They are categorized into four generations with the first three based on the decreasing exposure to animal proteins [37]. Additional modifications of the FVIII gene including B domain deletion and single chain products are manufactured to enhance the pharmacokinetic profile of the product. Examples of “B-domain deleted” products include Xyntha, turcotococog alfa (Novoeight), simoctocog alfa (Nuwiq), Eloctate [38–40]. Multiple clinical trials have demonstrated excellent efficacy and safety profiles [41–44]. Recombinant human FIX is genetically engineered by insertion of the human FIX gene into a Chinese hamster ovary cell line. These products have been demonstrated to be safe and effective in the treatment of previously treated patients (PTPs) and PUPs with HB [45–48].

The recombinant products (second generation and above), however have a safety advantage over plasma-derived concentrates as they have no added albumin [49]. Thus, it is advantageous as it reduces the risk of transmitting animal or human infectious agents. The second-generation octocog alfa (Kogenate FS, Refacto) does not contain albumin and have replaced it with a carbohydrate stabilizer, sucrose [50].

The RODIN study concluded that the risk of developing inhibitors among PUPs was similar in those receiving plasma-derived and recombinant products (95% confidence interval [CI], 0.62 to 1.49). The study also concluded that second-generation recombinant products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37).

[51]. However, the 2016 Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) trial remains the only prospective randomized trial to assess the incidence of FVIII inhibitors among patients treated with plasma-derived FVIII containing von Willebrand factor (vWF) or recombinant FVIII. This study, in contrast showed that the cumulative incidence of all inhibitors was higher with recombinant factor VIII therapy in contrast to plasma derived fVIII (44.5% vs. 26.8%) 44.5%. The cumulative incidence of high-titer inhibitors was 18.6% [95% CI, 11.2 to 26.0] and 28.4% [95% CI, 19.6 to 37.2], respectively [52].The main adverse events noted with rFVIII products are increased factor VIII inhibitors, skin reactions, headache, arthralgia, pyrexia, upper respiratory tract infection and nasopharyngitis [36]. AEs reported with rFIX include antibody development and headache [36]. The various available recombinant FVIII and FIX products have been described in table 2.

Table 2. Depicting Recombinant products and their characteristics [36]

Recombinant	FDA approval	Prophylaxis Dose	Treatment dose (Major trauma or surgery)	Half-life (hours)	Viral Attenuation Method	Other characteristics
Factor VIII
Octocog alpha, Recombinate (Baxter Healthcare Corporation and Wyeth BioPharma)	1992	None	60–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	15	Immunoaffinity chromatography	First Generation
Kogenate FS (Bayer)	1993	25 units per kg of body weight three times per week.	25 units per kg of body weight three times per week.	11–15	Solvent/detergent virus inactivation step in addition to the use of the purification methods of ion exchange chromatography and monoclonal antibody immunoaffinity chromatography	Second Generation
Octocog alpha,Advate (Takeda)	2003	20 to 40 International Units of Factor every other day (3 to 4 times weekly)	30–60 International Units/kg (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	9–12	Immunoaffinity chromatography includes a dedicated, viral inactivation solvent-detergent treatment step	Third Generation.
Xyntha (Pfizer)	2008	30 IU/kg administered 3 times weekly.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	8–11	Affinity chromatography includes a solvent-detergent viral inactivation step and a virus-retaining nanofiltration step.	Third Generation.
Turoctocog alpha, Novoeight (Novo Nordisk)	2013	20–50 IU/kg three times per week.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	8–12	Nanometer filtration with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Third Generation.
Simoctocog alfa, Nuwiq (Octapharma)	2015	20 to 40 IU per kg of body weight every other day	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	12–17	Nanometer filtration with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Fourth Generation
Octocog alpha, Kovaltry (Bayer)	2016	20 to 40 IU per kg of body weight two or three times per week.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	12–14	Nanometer filtration with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Third Generation.
Factor IX
BeneFIX (Pfizer)	1997	100 IU/kg once weekly	20–100 IU/dL	16–19	Four-step chromatography purification	Genetically engineered Chinese Hamster Ovary (CHO)
Rixubis (Baxter)	2013	60 to 80 IU/kg twice weekly for patients <12 years of age 40 to 60 IU/kg twice weekly for patients ≥12 years of age.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	23–26	Chromatography purification with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Genetically engineered Chinese Hamster Ovary (CHO)
Ixinity (Aptevo)	2021	40 to 70 IU/kg twice weekly	50–80 IU/dL	24	Four-step chromatography purification	Genetically engineered Chinese Hamster Ovary (CHO)

Table 2: Table 2 depicts Recombinant products and their characteristics [36]

2.3 EHL rFVIII products

In 2014, the first EHL was licensed for the management and prevention of bleeding and for perioperative management of individuals with HA. It was the recombinant FVIII Fc-fusion protein Efmoroctocog alfa (Eloctate, Sanofi Genzyme), engineered with recombinant, B-domain deleted, human FVIII fused with a monomeric human immunoglobulin (IgG) Fc domain [53]. This recombinant FVIII Fc-fusion protein demonstrated a 1.5–1.7-fold longer plasma half-life compared with a SHL rFVIII [54]. In various phase III studies, it was found to be well tolerated and efficacious for the management of perioperative hemostasias in patients with severe hemophilia. In the A-LONG trial, for individualized prophylaxis, weekly prophylaxis and episodic treatment arms, the median annualized bleeding rate (ABR) was 1.6, 3.6, and 33.6, with no bleeding episodes occurring in 45.3% and 17.4% of patients in either of the prophylactic arms [55]. Although at-risk patients with a history or evidence of FVIII inhibitors, as well as PUPs, were excluded from the pivotal clinical trial, the use of rFVIII-Fc in these PTPs did not cause any detectable FVIII inhibitors [55–58]. Moreover, it has also been used for ITI in patients with severe HA and high-titer inhibitors and revealed variable levels of success [59].

Another product, Rurioctocog alpha pegol (Adynovate, BAX 855, Takeda Pharmaceutical) that was licensed in 2017 with indications for the treatment and prevention of bleeding and perioperative management of HA [60,61]. The mean half-life of Adynovate was 1.3–1.5-fold longer than that of SHL rFVIII (Advate) with no inhibitors developing in the PTP subjects [62]. The PROLONG-ATE trial demonstrated the efficacy, pharmacokinetics, and safety of BAX 855 for prophylaxis of bleeding and perioperative management of patients with severe HA [63] The median ABR in the group assigned to twice-weekly prophylaxis was 1.9 vs 41.5 in the group assigned to on-demand treatment, with no bleeds reported in 39.6% of patients receiving prophylaxis [63]. No inhibitors or AEs were reported. Another product with similar technology was licensed in 2018 was the Damoctocog alfa pegol (Jivi, BAY 94–9027, Bayer HealthCare) [64,65]. This product established a longer FVIII half-life and higher area under the curve than a SHL rFVIII (rFVIIIFS, KogenateFS) in a phase I trial in patients with severe HA [64,66] . No developed FVIII inhibitors in the PTP subjects. The PROTECT VIII trial demonstrated the safety and efficacy of BAY 94–9027 in the treatment of patients undergoing major surgeries [67]. The trial demonstrated median ABRs of 4.1, 1.9 and 3.9 in the twice-weekly, every 5 days and every 7 days interval groups, respectively [68]. AEs were typical of events occurring in the hemophilia population. Recent preclinical studies demonstrating complete excretion of PEG-60-Mal-Cys in BAY 94–9027 and no indication of irreversible binding to tissues [69]. . Turoctocog alfa pegol (Esperoct; N8-GP, Novo Nordisk) is yet another PEG rVIII product is also a EHL FVIII product [70]. This product also demonstrated a 1.6-fold longer half-life than patients’ previous FVIII products in PTPs with severe HA [71]. N8-GP was also efficacious and well tolerated in the treatment of patients undergoing major surgeries in the pathfinder 5 trial. No inhibitors or AEs were detected. Patients in the prophylaxis arm had a median ABR of 1.95 and 42.6% of them experienced zero bleeds during the study [72]. The various available EHL FVIII products have been described in table 3.

Table 3. Depicting EHL factor products and their characteristics [36]

EHL	FDA approval	Prophylaxis Dose	Treatment dose (Major trauma or surgery)	Half-life (hours)	Viral Attenuation Method	Other characteristics
Factor VIII
Eloctate (Sanofi Genzyme)	2014	50 IU/kg administered every 4 days.	25–50 IU per kg (Every 8 to 24 hours for major surgery)	19 1.5-fold longer than rFVIII (Advate)	Nanofiltration along with viral clearance- detergent treatment step for inactivation and a nanofiltration step for removal of viruses.	Recombinant protein consisting of a B-domain deleted analogue of human Coagulation Factor VIII covalently linked to the human immunoglobulin G1 (IgG1) Fc domain
Adynovate (rurioctocog alpha pegol, BAX 855, Takeda)	2015	55 IU per kg body weight two times per week for < 12 years of age with a maximum of 70 IU/kg 40–50 IU/ kg twice weekly in adults and adolescents for 12 years and older.	30–60 IU per kg (Every 8 to 24 hours for major surgery)	18 1.3–1.5 fold longer than rFVIII (Advate)	Chromatography column along with viral inactivation solvent-detergent treatment step	Recombinant full-length human coagulation factor VIII covalently conjugated with one or more molecules of polyethylene glycol
Jivi (BAY 94–9027, Bayer)	2018	45–60 IU/kg every 5 days	15–50 IU per kg (Every 8 to 24 hours for major surgery)	18 1.4–1.5-fold longer than rFVIII (Kogenate-FS)	Chromatography and ultrafiltration	Conjugation of recombinant B-domain deleted human coagulation Factor VIII to 60-kDa branched PEG molecule
Esperoct (turoctocog alfa pegol; N8-GP, Novo Nordisk)	2019	50 IU/kg every 4 days.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	22 1.6 fold longer than rFVIII (Novoeight)	Two step: detergent (Triton X-100) treatment for inactivation of enveloped viruses, and nano- filtration for removal of enveloped and non-enveloped viruses.	40-kDa PEG molecule is conjugated to the O-glycan moiety of the B domain using an enzymatic reaction to produce a glycopegylated FVIII.
Factor IX
Alprolix (Efrenonacog alfa, Bioverativ)	2014	60 IU/kg once weekly for < 12 years of age 50 IU/kg once weekly, or 100 IU/kg once every 10 days for > 12 years of age	20–100 IU/dL	54–90 3 to 5 fold longer than SHL-rFIX	Two step: detergent treatment for inactivation of viruses, and nano- filtration for removal of viruses.	Human coagulation Factor IX sequence covalently linked to the Fc domain of human immunoglobulin G1 (IgG1).
Idelvion (albutrepenonacog alfa, CSL Behring)	2016	25–40 IU per kg every 7 days. Once well controlled, 14-day interval at 50–75 IU per kg for < 12 years of age 40–55 IU per kg every 7 days for > 12 years of age.	30–100 IU/dL (Repeat infusions every 8 to 24 hours for major trauma/ surgery)	102 5.6 fold longer than SHL-rFIX	Virus inactivation by solvent/detergent treatment and virus removal by filtration.	Genetic fusion of recombinant albumin to recombinant coagulation Factor IX.
Rebinyn (nonacog beta pegol [N9-GP], Novo Nordisk	2017	Not indicated	40–80 IU/dL	93 5 fold longer than SHL-rFIX	Two step: detergent treatment for inactivation of viruses, and nano- filtration for removal of viruses	40 kDa PEG group is selectively attached to specific -N-linked glycans in the rFIX activation peptide, with mono-PEGylated rFIX

2.4 EHL rFIX products

Efrenonacog alfa (Alprolix, Bioverativ Therapeutics Inc.) is a recombinant product composed of FIX fused with a monomeric human immunoglobulin Fc domain was approved by the FDA in 2014 for the prophylaxis and treatment of bleeding in adults with HB, in both the routine and perioperative settings and further approved for pediatric use in 2017. The half-life is three- to fivefold compared with unmodified FIX (i.e half-life of 54 to 90 hours) [73,74]. In a study involving 123 PTPs with HB (age ≥12 years) who received once weekly prophylaxis or as needed prophylaxis ABR were significantly lower than those for patients receiving on-demand therapy (3, 1.4, and 17.7, respectively) [75]. In another study involving previous treated boys younger than 12 years who received once-weekly prophylaxis the median ABR was two for all bleeds and zero for joint bleeds [76]. No PTP patient developed an inhibitor, and no safety concerns were identified [76]. It demonstrates a linear response dose vs efficacy up to 150 IU/kg as it saturates the extravascular compartment and no increased risk for thrombosis at 250 IU/kg, thus doses ∼3 times higher than the currently recommended 40 to 50 IU/kg because of large extravascular compartment, efficiently prolong hemostasis without thrombotic risk [77].

Albutrepenonacog alfa (Idelvion, CSL Behring) is a coagulation FIX [Recombinant], recombinant albumin Fusion Protein (rIX-FP), a recombinant DNA-derived coagulation FIX concentrate first approved by the FDA in 2016 to control and prevent bleeding episodes, management of peri-operative bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes use in children and adults with HB [78]. This is the first coagulation factor–albumin fusion protein product and the second FIX fusion protein product to be licensed in the United States. The product’s approval is based on results from two multi-center clinical trials that demonstrated the safety and efficacy of albutrepenonacog alfa in 90 adult and pediatric patients with HB (age range = 1–61 years) [20,79]. The half-life of this product is approximately 102 hours (approximately 5.6-fold prolongation). Based on the analysis of the 40 subjects treated with this product for weekly prophylaxis, the estimated mean ABR was 0.83, 0.56, and 0.65 in the 14-, 10-, and 7-day prophylaxis regimens, respectively. No patient developed an inhibitor, and no safety concerns were identified [20].

Another product, Nonacog beta pegol (Rebinyn, N9-GP, Novo Nordisk) is a recombinant FIX product produced in Chinese Hamster Ovary cells composed of the activation sequence of the FIX attached to PEG that was licensed in 2017 [80]. This rFIX demonstrated approximately fivefold prolongation with a half-life of approximately 93 hours [81]. The approval was based on a study involving 74 PTPs (aged 13 to 65 years) with HB, ABR for individuals who received once weekly prophylaxis were significantly lower than that for patients receiving on-demand therapy (1.0, 2.9, and 15.6, respectively) [82]. The therapy was well tolerated, and there were no inhibitors during one year of therapy [82]. The various available EHL FIX products have been described in table 3.

Table 3: Table 3 depicts EHL factor products and their characteristics [36]

2.5 Non-replacement therapies

Emicizumab (Hemlibra, previously designated ACE910) is a bispecific recombinant monoclonal antibody, engineered to bind activated FIX (FIXa) and factor X simultaneously, and thereby promotes thrombin formation by mimicking FVIIIa activity regardless of FVIII deficiency and/or the presence of FVIII inhibitors [83]. It was approved by the FDA for individuals with HA with inhibitors in 2017 and for those without inhibitors in 2018. The recommended dose for HA prophylaxis is 3 mg/kg once weekly for 4 weeks initially followed by 1.5 mg/kg once weekly or 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks as maintenance [84]. Advantages of emicizumab include SQ administration and a long plasma half-life allowing administration every week or even every two weeks [85].

The first two key trials were carried out in patients with FVIII inhibitors were the HAVEN 1 and HAVEN 2. HAVEN 1 included 109 individuals ages 12 years or older and HAVEN 2 trial included 85 children aged 2 to 11 [86,87]. The ABR ranged between 0.2 and 2.9 and the rate of zero bleeding events ranged between 63% and 90% in both the trials. Following the promising results obtained in HAVEN 1 and 2, emicizumab has also been evaluated in patients without inhibitors. In the HAVEN 3 trial, 152 individuals ages 12 years or older with severe HA without inhibitor were enrolled. Study participants had much lower ABR than those not on prophylaxis [1.5 and 1.3 vs. 38.2] and much higher rates of zero bleeds (50% and 40% vs. 0%). In the subgroup of 48 patients previously treated with routine FVIII prophylaxis, transition to emicizumab reduced the ABR by 68% [88] .

Additionally, ABR and the zero bleeding rates appeared to be better than those obtained with the EHL FVIII products, however, there are no head on comparison studies between replacement and non-replacement products. A published matching adjusted indirect comparison for efficacy of rFVIIIFc (in A-LONG trial) versus emicizumab (in HAVEN trial) for mean ABR showed that there were no significant differences between either (with emicizumab administered q1, q2 or q4 weeks). rFVIIIFc has significantly higher proportion of patients with zero bleeds as compared to emicizumab administered 4 weekly but similar to those administered weekly and biweekly [89] . Thus, the difference between either is based on safety profile that is yet to be compared.

One of the complications that was noted in the HAVEN 1 was that a few patients developed thromboses and thrombotic microangiopathies when patients with inhibitor patients had a bleeding episode and were concomitantly treated with large and frequent doses of aPCC [86]. 13 deaths (including in 11 patients with inhibitors) have now been reported since the original clinical trial was published [90]. A post hoc analysis has shown concomitant use of emicizumab and rFVIIa as safe with no reported thrombotic events [91].

Other potential disadvantages may emerge in cases in which FVIII replacement is required to prevent or treat breakthrough bleeds, because the delayed FVIII inhibitors may develop in high-risk circumstances, such as at the time of major trauma or surgery. Another unknown fact is that whether, it provides the same functional benefits of the conventional coagulation factor, such as the long-term preservation of joint health and wound healing [92]. Also, the differences between emicizumab and FVIII also compromises the capacity to interpret FVIII bioequivalence.

3. Future directions and products in development

The current therapies have numerous shortcomings. In hemophilia patients without inhibitors, the reduction in the frequency of IV infusions by means of EHL therapy was still based on the need for a venous access [32]. Hence, newer agents with SQ and oral delivery are underway with recognizable benefits including ease of administration thus improved compliance and lesser cost. The transition to a SQ or oral route of administration would have a considerable effect on treatment feasibility and adherence, thus greatly reducing the chance of breakthrough bleeds related to missed infusions.

Also, the half-life of the current FVIII EHL products ranges from 19 to 22 hours, thus necessitating two weekly IV injections. Thus, despite the advantages of EHL-FVIII, the improvements of pharmacokinetics were only modest at the best. The reason of this is described by the fact that the EHL-FVIII molecules bind with endogenous VWF to form FVIII-VWF complex, that is cleared and has a relatively short half-life (~15 hours) [93]. To counteract this problem, in development is a novel FVIII with VWF fusion, Efanesoctocog Alfa (BIVV001), has an extended half-life (higher dose) of up to 42.5 hours. After seven days of injection, the mean factor activity at one week after infusion was 17% [94].

Now 5 years after FDA approval in the US, emicizumab is considered a “standard of care” product for prophylaxis in patients with HA [14]. A similar agent in development is Mim 8, another bispecific antibody like emicizumab, but in comparison with emicizumab, Mim8 normalized thrombin generation and clot formation, with potencies 13 and 18 times higher than a sequence-identical analog of emicizumab [95].

Additional prospective agents that pursue to target natural anticoagulants thus “rebalancing” a hemorrhagic tendency by introducing a thrombotic tendency are in various stages of development.

Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant that prevents unrestricted amplification of the clotting cascade. It acts not only by inhibiting factor Xa but also inhibits factor VIIa, thereby preventing the generation of factor Xa by the extrinsic pathway [16]. Multiple monoclonal antibodies targeting TFPI are in various stages of development [16,17].

Antithrombin is a natural anticoagulant, a serine protease inhibitor (SERPIN) that inhibits factor IIa, factor Xa, and other serine proteases such as factor IXa, FVIIa, and FXI. Reduced AT activity can lead to a prothrombotic state. Fitusiran is an investigational agent targeting AT [16,18].

Factor V Leiden mutation is a point mutation in the FV gene, which encodes the factor V protein and confers resistance to APC mediated FVa degradation. Over two decades ago, it was observed that the presence of this mutation in hemophiliacs is beneficial to control bleeding, thus hypothesizing the presence of Factor V Leiden mutation as a target in the management of hemophilia [96].

The next incremental improvement in factor replacement therapy may be in the form of factor VIII and IX gene delivery. Gene therapy for hemophilia offers the potential to restore normal or near normal hemostatic function while relieving the problem of frequent infusions with FVIII or FIX concentrates [97]. In hemophilia, gene therapy includes introduction of either a wild-type factor gene or a modified gene with enriched properties such as greater activity or longer half-life. Hepatocytes are an appropriate target cell for transduction since liver is the site of synthesis of most clotting factors. Diverse technologies have been used to introduce the F8 or F9 gene, either using ex vivo genetic modification followed by implantation of the modified cells or by means of a vector carrying a construct that introduces the normal gene or vectors that produce other coagulation factors such as factor VIIa that can be used in hemophiliacs with immune tolerance [21,22]. Adeno-associated viruses (AAV) as vectors are the most frequently used since they do not cause infectious disease in humans, generally do not integrate into the native nuclear genome and are replication-deficient thus decreasing the risk of insertional mutagenesis, Promising findings have been reported from multiple clinical trials [98–100]. The non-integrating nature of AAV vectors leads to low risk of genotoxicity and long-term carcinogenesis but implies some loss of efficacy with replication of the transduced hepatocytes [101]. Despite improved outcomes, several challenges remain, including the presence of pre-existing neutralizing antibodies to the AAV capsids and the unpredictability of transgene expression [102].

So far, data on toxicity leaves unanswered questions, as studies have demonstrated hepatotoxicity with increased transaminases that may affect transgene expression. There is a theoretical risk of late genotoxicity as some vectors (like retroviruses), due to insertional mutagenesis. that may affect naturally occurring tumor suppressor genes. Even though adeno-associated virus vectors have a lower risk of genomic insertion, the ultra high number of vectors required may escalate that risk. To date, one case each of tonsillar carcinoma, acinic cell carcinoma, and hepatocellular carcinoma have been reported in patients with hemophilia post-gene therapy. In all cases, there was little to no evidence of AAV genome integration [103,104] Cellular therapy, another contemporary technique to manage hemophilia is under development that comprises introducing intact cells rather than manipulation of coagulation factor genes. Autologous cells may be treated with a gene construct ex-vivo and then re-introduced [23] .

3.1 Half-life extension

Efanesoctocog alfa (BIVV001, rFVIIIFc-VWF-XTEN, Sanofi, and Sobi) is a novel recombinant FVIII molecule that uses innovative techniques of Fc fusion to the D’D3-domain of vWF and the two XTEN polypeptides to extend its time in circulation. This overrides the dilemma of native VWF mediated clearance, and provides and additional approach to half-life extension [105,106]. In June 2022, the U.S. FDA granted Fast Track Designation for BIVV001in patients with HA [107]. The mean half-life was three to four times as long as that of recombinant FVIII. The dose is 50–65 IU/kg once weekly, and the half-life varies from 37 to 41 hours. In the initial phase 1–2a open-label trial, 16 patients (18 to 65 years of age) with severe HA were assigned to receive BIVV001. No inhibitors to FVIII were detected and no hypersensitivity or anaphylaxis events were reported [108]. A single IV injection of BIVV001 resulted in high sustained FVIII activity levels. Efanesoctocog alfa is currently being evaluated in the ongoing Phase 3 XTEND-1, an open-label, non-randomized interventional study in PTPs ≥12 years of age [n = 150] with severe HA [107].

3.2 Subcutaneous and oral replacement agents

Even though in late 1990s, the administration of SQ FVIII was reported, many animal studies suggested only limited bioavailability of 5 to 10% [109]. It was later revealed that the cause of poor bioavailability was its inactivation in the SQ tissue after binding to phospholipids leading to its degradation [110]. In later studies, it was determined that VWF protects FVIII from proteolytic degradation by C3 domain binding to the C1 domain of FVIII and the best bioavailability was obtained with vWF-12 [111,112]. Various studies have confirmed superior bioavailability up to 41% when rFVIII was co-administered with vWF-12 as opposed to 2% with rFVIII alone [113].

Based on the encouraging preclinical trials, a phase 1, double-blinded, multicenter trial of Turoctocog alfa pegol (SQ N8-GP, Novo Nordisk) in 26 PTPs with severe HA was conducted. However, it was associated with a high incidence of neutralizing antibodies in pretreated patients with severe HA. Hence, further clinical development of SQ N8-GP was suspended [114]. Another agent is SubQ-8 that uses a novel approach for SQ delivery of the recombinant FVIII (simoctocog alfa, Nuwiq) co-administered with a recombinant human VWF fragment dimer that contains the D’D3 domain of VWF that augments bioavailability. The safety and efficacy of SubQ-8 in patients with severe HA is under investigation in a phase 1 and 2 study (NCT04046848) [115].

rFIXFc-XTEN (BIVV002, Sanofi) is a rFIXFc fusion protein that was studied in HB mice that uses recombinant XTEN conjugates to enhance efficacy via SQ injection compared with IV dosing [116]. Another FIX variant is Dalcinonacog alfa (formerly CB 2679d; also designated as ISU 304, Catalyst) which is an rFIX with better properties, including resistance to antithrombin inhibition and increased affinity for FVIIIa. It has a 22-fold potency and 8-fold prolongation of plasma activity than native human FIX as seen in animal and in vitro studies [117]. This was evaluated in a phase 1/2 trial in which there are multiple cohorts, wherein the highest tier of the multidose SQ dosing cohort, the patients received a single loading dose of IV 75 IU/kg, followed by nine daily SQ doses of 150 IU/kg. There were two patients in this cohort. The two patients achieved through FIX levels of 34% and 31%. Unfortunately, 1 subject showed the presence of a non-neutralizing antibody and a neutralizing antibody was identified in a second subject [118]. A phase 2 study demonstrated that SQ dalcinonacog alfa is effective in raising FIX levels comparable to IV EHL rFIX [119].

An overarching and common theme that seems to plague the successful development of SQ factor VIII or IX products is the development of neutralizing antibodies. This suggests that the processing or alteration of the agent in the pathway from the SQ to intravascular space is creating immunogenic epitopes on the product that would not occur if delivered intravenously, directly.

Another agent that was being developed was activated marzeptacog alfa (MarzAA, Catalyst) administered SQ which is a variant of rFVIIa used for the management of hemophilia with inhibitors. It is a recombinant activated human factor VII with four site-specific amino acid changes, two within the catalytic domain to enhance procoagulant activity and two to increase the terminal half-life [120]..

Production of SQ FVIII and FIX, MarzAA, Dalcinonacog alfa (Catalyst) and BIVV002 (Sanofi) and has been halted, however other pharmaceutical companies have SQ agents, such as simoctocog alfa in phase 1/2 trials [121].

Finally, the oral administration of replacement agents is in development. But, achieving functional preservation and bioavailability remains a challenge. The first preliminary, preclinical safety and efficacy data of orally administered rFVIII compared it to a similar dose of FVIII 150 IU/kg administered IV or intraperitoneally. This early study suggested that the orally delivered FVIII restored hemostasis in HA dogs [122]. Because of the technical challenges, it was redirected and found to be effective for oral tolerization. The cholera toxin B subunit fused with FIX is stable in commercially prepared lyophilized lettuce cells [123]. When these lettuce cells were fed to mice with HB, they stimulated latency-associated peptide 1 regulatory T cells that suppressed inhibitor/IgE formation and anaphylaxis against FIX. This was further confirmed in another study including dogs with HB wherein the CTB FIX–expressing lettuce cells led to the suppression of IgG/inhibitor and IgE formation against the IV-administered FIX in 3 of 4 dogs, which led to the marked shortening of coagulation times by IV FIX in the orally tolerized dogs [124].

3.3 Bispecific antibody

Mim8 is a fully human bispecific antibody under development that substitutes the role of FVIII by bridging FIXa and FX on the phospholipid surface of activated platelets, enhancing the proteolytic activity of FIXa, and thus facilitating effective FX activation. It can also be administered SQ in individuals with HA, both with and without inhibitors [95]. In a nonclinical safety and pharmacodynamics study in cynomolgus monkeys, Mim8 was well tolerated in doses ranging from 0.3 to 60 mg/kg/week IV or SQ and thrombosis-related findings were observed in doses above 6 mg/kg/week. Based on the encouraging in vitro and animal studies [125]. Phase 1 and Phase 2 clinical trials are underway (NCT04204408).

3.4 Rebalancing agents: anti-TFPI

Befovacimab (BAY 1093884, Bayer) is a monoclonal antibody against TFPI, an IgG2 fully human monoclonal antibody that binds to both the Kunitz 1 (K1) and Kunitz 2 (K2) domains of the TFPI was not further pursued after three individuals developed central nervous system thromboses [16]. Concizumab (mAb2021, NovoNordisk) is a humanized IgG4 monoclonal antibody against TFPI that targets the K2 domain of the TFPI, that can be administered either via SQ or IV route. It is administered SQ once daily at a starting dose of 0.15 mg/kg and increased as needed or a single IV dose of 0.5–9,000 µg/kg [16]. The safety and efficacy were established in a randomized trial involving 53 patients that included 36 with HA, 9 with HA and inhibitors, and 8 with HB with inhibitors. The patients treated with concizumab prophylaxis versus on-demand rFVIIa demonstrated an 80–90% greater reduction in bleeding than seen with on-demand rFVIIa (ABR with concizumab, 4.5, versus 20.4 with rFVIIa) [17]. Another ongoing phase 3 program evaluating concizumab was put on hold due to thrombotic events, and then the study was restored after a risk mitigation strategy was established [16].. Across both the concizumab phase 2 trials, 7/25 in explorer 4 and 13/36 in explorer 5 receiving daily concizumab prophylaxis underwent 1 or more surgeries during the 18 and 22 months, respectively, and excluded patients requiring major surgery. The number of surgery-related bleeds was low and classified as mild or moderate, with one exception [126].

Marstacimab [PF-06741086, Pfizer] is another human monoclonal antibody IgG1 that binds to the K2 domain of TFPI that can also be administered SQ or IV [16]. In an ongoing trial 26 individuals with HA or HB were treated with marstacimab for six months. The mean ABRs were reduced by 84.5% to 92.6% [127] No complications were reported. MG1113 (Greencross) is humanized IgG4 monoclonal antibody that binds to the Kunitz-2 domain [K2] of TFPI that in preclinical studies has been shown to restore thrombin generation in FVIII or FIX deficiency with and without inhibitors [128]. Both IV and SQ injection resulted in a decreased blood loss from cuticle injury. A pharmacological profile study showed a non-linear pharmacokinetic profile at the dosing range from 2.5 to 10 mg/kg [129].

3.5 Rebalancing agents: reducing AT

Fitusiran (ALN‐AT3, Sanofi) is a small-molecule RNA interference agent that acts by binding to and degrading the mRNA (SERPINC1 gene) encoding AT. It can be administered SQ. In a phase 1 dose escalation study of 25 individuals with moderate to severe HA or HB treated with fitusiran, the number of bleeding events decreased [mean ABR, 0 versus 3] and the effect appeared to be dose-dependent [15]. The drug has short half-life in the plasma [three to five hours]; however, the AT level reduction persists for several weeks [15]. Conversely, in an extension trial, a patient developed a fatal cerebral sinus thrombosis and the study was temporarily halted. It was then restarted with decreased dose intensity following implementation of a risk mitigation strategy [130,131]. A follow-up study did not report thrombotic complications [132]. Nonetheless, it is important to note that if there is a prothrombotic stimulus such as severe injury or infection (such as coronavirus disease 2019 (COVID-19)), that could further potentiate prothrombotic risk.

The initial results from ATLAS A/B study in patients with severe HA and HB with or without inhibitor receiving fitusiran 80 mg once a month compared to daily factor prophylaxis, showed a 90% reduction in ABR in patients receiving fitusiran and no thrombotic events were reported [133]. Dose escalation studies to target AT levels to less than 35% by starting with a dose of 50 mg once in 2 months, if needed escalation to once a month and further to 80 mg once a month [134].

3.6 Modified inhibitors of APC

Apha-1-antitrypsin, plasminogen activator inhibitor 1 and protein C inhibitor are naturally occurring APC inhibitors that are members of the serpin (serine protease inhibitor) family [135,136]. SerpinPC (ApcinteXLtd) which a modification of these serpins was revealed to promote thrombin generation in vitro and improved hemostasis in a murine model of HA [137]. Presently, a phase 1/2 trial (NCT04073498) of Serpin PC is in progress in hemophiliacs and healthy volunteers. Additionally, a monoclonal antibody to APC (HAPC1573) that exhibited encouraging results in a primate study [138].

Besides the reassuring results, it is important to note that AT and APC also has roles in inflammatory signaling and consequently there are concerns that interference of APC function could have effects beyond the coagulation cascade. To evade the other undesirable effects of APC inhibition, modified versions of natural serpins are under investigation that specifically block APC activity in the coagulation cascade without disrupting other pathways.

Protein S acts as a cofactor for APC. A monoclonal antibodies that inhibits protein S and and siRNA knockdown demonstrating increased thrombin generation and resistance to APC and TFPI in murine models are in early stages of development [139].

3.7 Gene Therapy

Valoctocogene roxaparvovec (valrox) for HA showed clinically meaningful improvements in bleeding rates with sustained increase in FVIII activity [99]. No development of inhibitors or thrombosis noted [99]. Patients with anti-AAV5 capsid antibodies and substantial liver dysfunction were excluded from this trial [99]. Valrox (Roctavian in Europe) is a codon-optimized adeno-associated virus serotype 5 (AAV5) vector containing a gene for B-domain deleted human FVIII (AAV5-hFVIII-SQ) which in turn is a non-integrating hepatotropic vector that remains mostly episomal [140]. The 6-year follow-up data of the phase 1/2 trial 5 showed a sustained reduction in the ABR. Twelve out of 13 patients did not require FVIII prophylaxis [141]. The phase 3 trial GENEr8-1 demonstrated an 85% decline in ABR and 98% decline in the annual FVIII utilization [99]. The proportion of zero bleeds (52.7% versus 28.5%; p < 0.05) or zero treated bleeds (79.5% vs 32.9%; p < 0.001) was significantly high with the gene therapy in a post hoc analysis. No liver damage was seen in the five patients of a phase I/II trial that consisted of performing a liver biopsy upto 4 years after treatment [142]. There was no clonal expansion seen and even though one to six integration events per 1000 cells were observed, there was no enrichment in integration sites near the proto-oncogene. Another adenovirus-based gene therapy that is currently being investigated in a phase I/II study in patients with HA is TAK754 which is AAV8 based [143]. On August 2022, the European commission granted Valoctocogene roxaparvovec (BioMarin Pharmaceutical Inc.), conditional marketing authorization for the treatment of severe HA in adult patients without a history of FVIII inhibitors and without detectable antibodies to AAV5 thus launching the commercial availability of gene therapy [144].

For HB F9 Padua variant containing therapy that uses a AAV5 vector is Etranacogene dezaparvovec (Hemgenix). On November 22^nd, 2022, the U.S. FDA approved Hemgenix, for the treatment of adults with HB who currently use FIX prophylaxis therapy [145].

This therapy has been studied in HOPE-B, a phase III trial in adults with severe or moderately severe HB and has demonstrated a significant improvement in quality of life and reduction in treatment burden (nominal p value <0.0001) [146]. The safety and efficacy data in 54 participants over a period of 24 months with or without pre-existing AAV5 neutralizing antibodies showed the mean ABR was significantly reduced by 64% (mean ABR 1.51; p = 0.0002), there was 96% reduction in annualized FIX consumption and the treatment was well tolerated with no serious AEs [147].

Another gene therapy for HB, the F9 Padua variant (F9 p.R338L) contains a naturally occurring missense mutation in the F9 gene that increases its activity approximately 4 to 40-fold and has been most widely used for FIX gene therapy trials [148,149]. A recent phase 1–2 data B-LIEVE established the safety and efficacy of Verbrinacogene setparvovec (FLT180a) in patients with severe or moderately severe HB which is a liver-directed AAV gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize FIX levels. This trial reported that the first three patients achieved normal FIX levels and discontinued prophylaxis by days 33, 56 and 77 and no serious adverse effects were observed [150].

Considering the potential theoretical risk of genotoxicity of viral vector mediated gene transfer, other non-viral means of gene therapy are being explored. One such technique was ultrasound mediated gene delivery, and animal study showed promising results. In this study, the portal vein of mice was injected with plasmid DNA and pulsed therapeutic ultrasound transducer was applied to the liver [151]. Another successful animal study, in mice with HA, demonstrated delivery of lentiviral vectors into bone marrow to drive FVIII expression in platelets [152]. Lipid nanoparticle technology to correct frameshift deletion mutation in exon 1 of FVIII gene by delivering a targeted single guide RNA with CRISPR/Cas9-based gene editing was recently shown to achieve therapeutic levels of FVIII expression [153]. In patients with HB with inhibitors who fail immune tolerance induction, CRISPR/Cas9 expressing plasmid may be a useful method to insert a transgene encoding murine FVIIa into the host genome [154]. Inhibition of antithrombin pathway via nanobodies packaged in an AAV8 vector to control bleeding in patients with HA has also been studied in mice [155].

3.8 Cellular Therapy

Multiple preclinical studies have supported the transduction of hematopoietic stem cells ex vivo with lentiviruses to generate genetically modified platelets to control bleeding in patients with severe HA with inhibitors [156,157].

Hepatocyte transplantation has been studied in mouse model of HA. The study implied that the transplantation of liver sinusoidal endothelial cells from non-hemophilic donor animals resulted in increased factor levels and correction of the bleeding phenotype (23). SIG-001 is a polymer-encapsulated human cell system to express FVIII that was not pursued due to the development of a FVIII inhibitor in one out of three patients [158].

4. Conclusion

In this expert review, we explore the past, present, and future directions in the treatment of people living with Hemophilia A and B. The new innovative therapies could be revolutionary based on the cost and availability of these products. Though optimistic, one cannot apprehend what the future holds in the next decade or two. Whether it was thousands of people contracting HIV before concentrates were rendered safe or thrombotic risk with the newer agents and more so recently a rather uncharted territory of gene modification, caution must be implemented. Despite all this, the benefits that were not expected with prior therapies are a reality for many. However, more than three-fourths of the world’s hemophilia population still do not get the standard therapy. With the sustained efforts by the World Federation of Hemophilia to provide harmonization of health services worldwide, we still see light at the end of the tunnel and hope to achieve consistency in hemophilia management. With continued innovation in the treatment approaches, the clinician and patient need to make an informed decision individualizing priority and prerequisites. With current ongoing clinical trials, we expect that clinicians with their patients can tailor management assessing phenotype, patient goals both for education and vocation and thus provide optimal therapy so that we can make the life of hemophiliac patients more integrated into the framework of society.

5. Expert opinion

Current therapies in the management of hemophilia have demonstrated safety and efficacy over decades of data but the future holds better promise. Numerous techniques have been developed to optimize safety and effectiveness of the existing plasma products. The availability of safer plasma-derived products and recombinant factor concentrates helped improve joint outcomes and quality of life. Nevertheless, the real-world downsides of clotting factor infusions include reliance on venous access, poor adherence, and scarce affordability on a global scale. The advent of EHL product therapies has further enhanced prophylaxis effectiveness and compliance and is being used worldwide through the implementation of humanitarian programs by the World Federation of Hemophilia aiming at providing such therapies to socio-economically disadvantaged countries albeit the task remains challenging. Despite the major advances of these EHL products, breakthrough bleeding, IV administration, inhibitor development and the need for treatment individualization still pose major challenges to the clinician and the patients. Also, though the half-lives of rIX products have been extended by 3–6 folds but the half-life prolongation of rVIII products is only roughly 1.5–1.6 folds. In light of these challenges, the substitution therapy/non-factor therapies (emicizumab) and hemostatic rebalancing therapies bring several few advantages. Since they do not expose the patient to FVIII or FIX to elicit inhibitors, the non-replacement therapies function despite existing inhibitors. The SQ route of administration and the availability of fixed-dose regimens are additional benefits. These therapies also offer the potential to avoid exposure to the immunogenic proteins or to explore more tolerogenic approaches to introduction of the factor replacement therapies in cases of breakthrough bleeding. Thus, non-factor agents may also be useful for prophylaxis from an early age and even from birth.

To circumvent existing concerns in the management of hemophilia, novel therapies are underway. Recombinant FVIII products with extended half-life might prove beneficial without substantially affecting the therapeutic intervals. The use of innovative non-replacement products could be an alternative strategy in patients both with and without inhibitors though long-term data and safety remains a concern. SQ FVIII and FIX agents with the desirability of ease of administration are currently being explored under various stages of clinical trial. Also, animal studies for oral administration of factors have been encouraging. Gene therapy has so far demonstrated a robust and resilient expression of efficacious levels of FVIII and FIX with about half a decade worth of data. Recognized and unfamiliar risks associated to immunologic responses, cellular stress induction, and genome integration remain. Few studies have demonstrated cancer risk; however, a proven association and further long-term data remain to be unraveled. Also, inconsistency of gene expression has generated some ambiguity. Ongoing careful monitoring, investigation long-term data and its application in pediatric population remains to be explored.

Article highlights

• Factor replacement products once the mainstay of hemophilia treatment, however newer products are now available with easier modes of administration, decreased immunogenicity and increased efficacy.

• Recombinant bioengineering with the development of extended half-life replacement therapies are available to diminish the frequency of administration and improved compliance.

• Emicizumab is considered by many to be another standard of care agent for bleed prophylaxis in patients with hemophilia A.

• Subcutaneous administration of some these new therapies makes it further attractive for prophylaxis in patients with poor venous access and studies are underway to develop subcutaneous and even oral replacement therapies.

• The most striking of newer development is gene therapy that involves the introduction of either a wild-type or a modified factor gene with greater activity or longer half-life and establishing continuous endogenous expression of factor VIII or factor IX.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Abbreviations

HA Hemophilia A HB Hemophilia B FVIII Factor VIII and FIX Factor IX TFPI Tissue Factor Pathway Inhibitor SHL Standard half-life EHL Extended half life; IV intravenous; SQ subcutaneous PEG polyethylene glycol FDA Food and Drug Administration ABR annualized bleeding rates vWF Von Willebrand factor AAV adeno-associated virus dL deciliter IU international units aPCC activated prothrombin concentrate PUPs previously untreated patients PTPs previously treated patients

Additional information

Funding

The paper was not funded.