The Dilemma of Providing Advanced Hemophilia Treatments in Developing Countries

Abstract

Hemophilia, a congenital deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B), leads to recurrent bleeding episodes that may cause progressive joint damage and long-term disability. Traditional management relies on intravenous factor replacement therapy; however, limited half-life, immunogenicity, venous access challenges, and the burden of frequent infusions have prompted the development of extended half-life (EHL) factor products. Although EHL therapies represent an important advancement, they only partially reduce treatment burden and do not fully meet expectations for improved convenience and sustained bleed protection. Recent innovations are reshaping the therapeutic landscape. Nonfactor subcutaneous therapies such as anti-TFPI molecules, antithrombin reducing agents, and anti-protein C agents offer simplified administration with the potential for improved adherence. Gene therapy provides the prospect of a long-term therapeutic effect in selected patients. In Türkiye, hemophilia care remains largely factor-based; however, clinical trial participation and recent regulatory approvals for selected novel therapies have begun to expand real-world experience with these emerging treatment options. As global practice shifts toward individualized, less invasive treatment approaches, expanding availability of novel therapies and optimizing patient-specific treatment strategies will be essential. This review examines current and evolving treatment options, key challenges, and future opportunities shaping the trajectory of hemophilia management.

Keywords

hemophilia advanced hemophilia treatments non-factor therapy developing countries gene therapy

1. Introduction

Hemophilia, a hereditary bleeding disorder, is characterized by a deficiency in clotting factor VIII (FVIII) for hemophilia A (HA) or factor IX (FIX) for hemophilia B (HB). This deficiency leads to spontaneous hemorrhagic manifestations, predominantly affecting muscles and joints. In severe cases, intra-articular bleeding episodes can result in painful and debilitating joint destruction.¹ Historically, the cornerstone of hemophilia management has been intravenous replacement therapy with FVIII or FIX. However, the standard half-life of these clotting factors, the necessity for regular recurrent intravenous administration, and their potential immunogenicity present significant challenges.^1,2

To address these challenges, extended half-life factor (EHL) replacement therapies were developed. These strategies, such as pegylation or fusion to proteins like albumin and immunoglobulins, aimed to reduce the frequency of infusions.¹ However, EHL factor products still require intravenous infusion, which only partially addresses the issue for patients with difficult venous access and does not fully meet the expectations regarding ease of administration. Furthermore, while EHL products have been hailed for their potential to reduce treatment frequency, this benefit has not been universally experienced. Some patients continue to require relatively frequent infusions or experience suboptimal factor levels, leading to some disappointment as the expected improvement in quality of life and treatment convenience remains only partially realized.^3,4

Recent advancements have brought forth therapies that mimic FVIIIa and rebalancing agents that interfere with anticoagulant pathways. These include anti-tissue factor pathway inhibitor (anti-TFPI) molecules, antithrombin reducing agents, and anti-protein C Agents.¹ Such novel agents offer the potential to revolutionize hemophilia treatment by providing more effective and convenient treatment options. Among the emerging treatments, gene therapies still hold a unique position. These therapies, with the potential to provide a long-term solution for hemophilia patients, represent a significant leap forward in the treatment paradigm.^3,4 However, the integration of gene therapies into standard care is not without its challenges, from ensuring safe and effective delivery to addressing ethical and cost considerations.⁵

In light of these advancements, the main aim of this article is to explore the future landscape of hemophilia treatment. As a plethora of treatment options become available, the challenge will be to tailor therapy based on individual patient characteristics and needs. Through a comprehensive review of current and emerging therapies, we seek to provide insights into the optimal treatment selection for hemophilia patients, paving the way for personalized medicine in this field. We also aim to explore current and future challenges of access to these treatments in some countries and Türkiye and provide specific recommendations where relevant.

2. Methodology

This narrative review is based on a structured literature search conducted in PubMed, Embase, and Google Scholar databases. The search included articles published between January 2010 and March 2025. Keywords used in various combinations included “hemophilia A″, “hemophilia B″, “non-factor therapy”, “gene therapy”, “extended half-life factors”, “developing countries”, and “healthcare systems”. The inclusion criteria comprised peer-reviewed original research articles, clinical trials, review articles, meta-analyses, and relevant international guidelines published in English. Case reports, conference abstracts without full text, and non-English publications were excluded. Additional relevant publications were identified through manual screening of reference lists of selected articles. Priority was given to recent and clinically relevant publications, with particular emphasis on clinical trial data, emerging therapies, and real-world applicability.

3. Challenging the Status Quo: Do Non-factor Therapies Truly Outshine Traditional Hemophilia Treatments?

In 2014, the first EHL product was licensed for the management and prevention of bleeding, as well as for the perioperative management of individuals with HA.¹ EHL products employ two primary techniques to extend their plasma half-life.⁶ The first involves the fusion of coagulation factors to proteins, such as the Fc region of IgG1 or albumin, which prolongs biological activity through recycling via the neonatal Fc receptor. The second technique involves chemical binding with substances like polyethylene glycol, which slows their degradation and renal elimination.^1,6 Studies have shown that EHL products possess 1.5-1.7 times longer plasma half-life compared to standard recombinant factors.⁴ Phase III studies have demonstrated that various EHL products are well tolerated and effective in managing hemostasis in patients with severe hemophilia.^1,2,6,7 The mechanisms, indications for use, and approvals of EHL factor products, both globally and in Türkiye are summarized in Table 1.^1,2,4,6,7

Table 1.

FVIII and FIX Products With Extended Half-Life^1,2,4,6,7

Generic name	Mechanism of action	Type	Dosing frequency	Application	Child use	ABT/P	Approved
Generic name	Mechanism of action	A/B	Dosing frequency	Application	Child use	ABT/P	FDA/EMA	Turkiye
Efral-octogog alfa*	Fusion protein (FVIII/Ig)	A	twice weekly/every third-day	IV	✓	ABT/P	✓	✓
Damactocog*	PEGylated FVIII	A	twice weekly/weekly	IV	✓	ABT/P	✓	✓
Octacog pegol	PEGylated FVIII	A	2 to 3 times a week.	IV	✓	ABT/P	✓	✓
Turoctocog pegol*	PEGylated FVIII	A	every 3-4 days	IV	✓	ABT/P	✓	✓
rFIX-Fc	Fusion protein (FIX/Ig)	B	Weekly/Every 10 days	IV	✓	ABT/P	✓	✓
rF-IX- FP	Fusion propein (FIX/albumin)	B	Every 10 days	IV	✓	ABT/P	✓	✓
Nonacog pegol	PEGylated protein F-IX	B	Weekly/Every 10 days	IV	✓	ABT/P	✓	✓
Efanes-octocog	X-TEN technology for EHL-FVIII	A	Weekly	IV	✓	ABT/P	✓	X

*Included in the reimbursement list in Turkiye.

ABT: Acute bleeding treatment, P: prophylaxis, FDA: U.S. Food and Drug Administration, EMA: European Medicines Agency.

Currently, the most challenging complication in the treatment of hemophilia is the development of anti-FVIII or -FIX alloantibodies, affecting approximately one-third of patients with severe HA and about 3-5% of those with severe HB.⁸ These inhibitors neutralize the functional activity of administered FVIII and FIX clotting factors, compromising patients’ access to safe and effective care and increasing their risk of morbidity and mortality. Patients with HA or HB and inhibitors are not suitable candidates for EHL prophylaxis and generally require bypass agents such as recombinant human factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC) during acute bleeding episodes and in the preoperative period.^8,9

Non-factor treatments, initially developed for patients with inhibitors, include bispecific antibody technology that mimics the FVIII coagulation function and the inhibition of anticoagulant proteins using antibodies, aptamers, or RNA interference technology. Scheme for the coagulation and the mechanism of action of non-factor therapies in Figure 1.^10,11 These non-factor therapies have emerged as a promising approach, offering potential advantages over traditional factor replacement therapies, including subcutaneous (SC) administration, which can significantly ease the treatment burden and enhance the QoL for hemophilia patients.² By targeting various components of the coagulation cascade or its natural inhibitors, these therapies aim to restore the balance between pro- and anti-coagulant forces in the blood. Non-factor therapies have shown the potential to provide more consistent and prolonged bleed protection, with pivotal clinical trials reporting reductions in breakthrough bleeding episodes and suggesting possible improvements in joint outcomes over time. Emerging evidence also points to a potentially lower risk of inhibitor development compared with traditional factor replacement.¹²

Figure 1.

Coagulation cascade and the mechanism of action of non-factor therapies^10,11

Non-factor treatments are categorized into two groups: therapies that mimic FVIIIa and therapies that interfere with anticoagulant pathways. The mechanisms, indications for use, and approvals of non-factor treatments, both globally and in Türkiye, are summarized in Table 2.^13-23

Table 2.

Non-factor Products^13-23

Generic name	Mechanism of action	Type	Dosing	Application	Phase III trial	Safety	Child use(<12y)	Approved
Generic name	Mechanism of action	A/B	Dosing	Application	Phase III trial	Safety	Child use(<12y)	FDA/EMA	Türkiye
Emicizumab	FVIIIa-mimetic	A	Weekly to monthly	SC	HAVEN 1-4	ISR: %15-31⁺	✓	✓	✓
						ADA:<%1
						TMA: %0.3⁺
						TE: %1⁺⁺
Mim-8	FVIIIa-mimetic	A	Weekly to monthly	SC	Phase 3 ongoing	ISR: % 2.1	Phase 3 ongoing	X	X
						ADA: %0
						TMA: No severe TEAEs
						TE: No severe TEAEs
Concizumab	TFPI inhibition	A+B	Daily	SC	Explorer 7	ISR: %20.5	Phase 3 ongoing	✓	X
					Explorer 7	ADA: %25
					Explorer 8	TE: %0-3
Marstacimab	TFPI inhibition	A+B	Weekly	SC	Phase 3 ongoing	ISR: 8-10%	Phase 3 ongoing	✓	✓
						ADA*: %20
						TE: %0
Fitusiran	Antithrombin inhibition	A+B	Monthly Bimonthly	SC	ATLAS-INH, ATLAS-PPX, ATLAS-A/B	ALT increase: %23-33*	Phase 3 ongoing	✓	X
						Cholelithiasis + cholecystitis: %6-15*
						ISR:0
						ADA:0
					ATLAS-NEO (ongoing)	TE: %3-5^^
SerpinPC	Protein C inhibition	A+B	-	SC	PRESent-2 phase IIb discontinued	PRESent-2 phase IIb discontinued	There is no study <12y	X	X

ISR: injection-site reaction, ADA: antidrug antibodies, TMA: thrombotic microangiopathy, TE: thromboembolic events.

⁺associated with concomitant aPCC use in Haven1 study.

⁺⁺%0.5 associated with concomitant aPCC use in Haven 1 study.

*ATLAS-INH and ATLAS-A/B phase 3 study.

**ATLAS PPX and ATLAS-INH phase 3 study, #: FDA only.

A-Therapies That Mimic FVIIIa

The hallmark of these therapeutic agents is their ability to mimic the function of FVIIIa in the coagulation cascade, ensuring the continuity of coagulation. It is crucial to note that they are applicable only in cases of HA.

Emicizumab

FVIIIa is composed of two subunits and one light chain. It facilitates coagulation by binding to FIXa with one subunit and its light chain, while the other subunit binds to FX, acting as a cofactor in the coagulation cascade. In HA, the absence of FVIII disrupts this cascade. To overcome this, the development of a bispecific IgG4 antibody was proposed, with one arm recognizing FIXa and the other arm recognizing FX. This antibody would spatially position FIXa and FX in a manner akin to FVIIIa, thereby promoting the activation of FX catalyzed by FIXa. This led to the creation of Emicizumab, a recombinant monoclonal antibody that is chimeric, bispecific, and humanized, directed against FIXa and FX. It mimics the co-factor function of FVIII by binding to FIXa and FX, positioning them to facilitate FIXa-catalyzed FX activation and tenase formation.^3,24

Emicizumab has emerged as a cornerstone therapy for patients with or without inhibitors, marking the first approved SC agent for HA¹⁰. The initial trial, HAVEN-1, focused on adult patients with inhibitors. Although this treatment significantly reduced bleeding episodes among participants with HA, there were reports that three patients developed thrombotic microangiopathy and two participants experienced thromboembolism.^10,13,25 These thrombotic events were interpreted as a result of combining aPCC with emicizumab; hence, this combination was avoided in subsequent trials. The HAVEN 2-4 studies were successfully completed, demonstrating that emicizumab prophylaxis significantly reduced annualized bleeding rates (ABRs) for treated bleeds, regardless of FVIII inhibitor status. Emicizumab was well tolerated across the HAVEN trials, exhibiting a favorable safety profile.^10,14-16,25 The most common related adverse events were injection-site reactions, with no need for treatment modification. The development of antidrug antibodies (ADAs) with neutralizing potential was rare (<1%); 3 participants developed ADAs with neutralizing potential (HAVEN 1, n = 1; HAVEN 2, n = 2), leading to a decline in pharmacokinetics. Among these, one participant discontinued treatment due to loss of efficacy. No fatalities, thrombotic microangiopathy, or thromboembolic events were reported in the primary analysis of HAVEN 2, HAVEN 3, or HAVEN 4.^14-16,25 The HAVEN-2 study, focusing on children with HA with inhibitors, included multicenter participation from Türkiye and demonstrated that emicizumab was safe and effective in this population.¹⁵ HAVEN-7 is an ongoing study investigating infants ≤12 months with severe HA without FVIII inhibitors, including both minimally treated and previously untreated patients (PUPs). The trial involves multicenter participation from Türkiye and follows patients over a planned duration of 3 years.²⁶

It was first approved by the U.S. Food and Drug administration (FDA) and then by the European Medicine Agency (EMA) for patients with HA with inhibitors, and later for patients without inhibitors. The approved loading dose regimen starts at 3 mg/kg per week for four weeks, followed by a maintenance dose of 1.5 mg/kg weekly or 3 mg/kg biweekly or 6 mg/kg monthly.^27,28 The Turkish government approved this molecule for all indications in HA in September 2019. Since March 2025, emicizumab has also been included in the Turkish Social Security Institution’s (SGK) reimbursable medication list for children under 18 with HA and for all inhibitors patients regardless of age. This policy change represents an important step toward improving access to prophylactic treatment options for eligible patients in Türkiye.²⁹

Mim-8

Mim8 represents a promising advancement in HA treatment as a human bispecific IG4 antibody designed to mimic the function of FVIIIa by bridging FIXa and FX in similar to emicizumab. It is currently under development for SC prophylactic treatment in patients with and without inhibitors. As a next-generation molecule, Mim8 is characterized by its high potency, efficient activation of FX by FIX in the presence of a procoagulant membrane (such as a phospholipid membrane), minimal target binding, and a low risk of immunogenicity.^1,3,4,17

FRONTIER-1 (NCT04204408) was a two-part Phase I/II study that assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending doses of mim8 in healthy participants and multiple ascending doses in patients with hemophilia A, with or without FVIII inhibitors.¹⁷ Clinical sites in Türkiye also participated. Building on these findings, the subsequent FRONTIER-2 Phase III study (NCT05053139) assessed mim8 in patients with hemophilia A aged ≥12 years. Once-weekly or once-monthly subcutaneous dosing of mim8 resulted in substantial reductions in treated bleeding episodes and mim8 was generally well tolerated, with no safety concerns were reported.³⁰ Further confirmatory and extension studies are ongoing, including FRONTIER-3 (NCT05306418, pediatric population), FRONTIER-4 (NCT05685238, long-term extension), and FRONTIER-5 (NCT05878938, transition from emicizumab to mim8).^31-33

Mim8 can be administered in small volumes compatible with an autoinjector, potentially reducing drug wastage by enabling the use of an entire vial for a range of body weights. This feature may offer a logistical and economic advantage compared with emicizumab.³⁴ Mim8 is currently an investigational therapy for individuals with hemophilia A and has not received regulatory approval in Türkiye or elsewhere globally.

B-Therapies That Interfere With Anticoagulant Pathways (Rebalancing Agents)

A key feature of these therapeutic agents is their targeted inhibition of tissue factor pathway inhibitor (TFPI), antithrombin (AT), and protein C. By inhibiting these natural anticoagulants, these therapies can restore a more balanced hemostatic environment, potentially reducing the frequency and severity of bleeding episodes. As these rebalancing agents modulate the coagulation cascade independently of the deficient clotting factor, they represent versatile treatment options for patients with either hemophilia A or B, regardless of inhibitor status.⁴

Anti-TFPI Molecules

Concizumab

Concizumab introduces a novel hemostatic treatment mechanism aimed at restoring coagulation balance in hemophilia by targeting TFPI, a principal negative regulator of the coagulation system. As a humanized monoclonal IgG4 antibody, concizumab specifically binds to the K2 domain of TFPI, where it exhibits high affinity. This interaction not only prevents TFPI from inhibiting the tissue factor (TF)-FVIIa complex but also facilitates increased formation of tenase and thrombin.³ Phase I trials of concizumab demonstrated improved thrombin generation, with antibody plasma levels directly correlating with thrombin generation and inversely with TFPI levels. These trials also reported a favorable safety profile, with no serious adverse events or ADAs detected.³⁵ Concizumab is administered as a once-daily SC injection with weight-based dosing regimen. While the requirement for daily administration may be considered a limitation, SC delivery via pen device offers ease of use and generally well tolerated. However, an assessment of plasma drug concentration at week 4 is required to guide the adjustment of the individual maintenance dose.³⁶

In the phase II Explorer4 and Explorer5 studies—enrolling 15 HA patients with inhibitors, 10 HB patients with inhibitors, and 36 severe HA patients without inhibitors, respectively—daily SC concizumab prophylaxis suggested effective bleeding prevention across all observed hemophilia groups. The estimated ABRs were 7.0, 3.0, and 5.9, respectively, with no thromboembolic events reported. Although 25% of patients ADAs, these were not associated with clinical changes.^37,38 Results from the extension phases (52-102 weeks) of these trials were analyzed to assess the long-term safety and efficacy of concizumab. The estimated ABRs at the final dose level in the main extension phases were 4.8 for Explorer4 and 6.4 for Explorer5, compared to spontaneous ABRs of 1.8 and 2.1, respectively. Most adverse events were mild, with no deaths, withdrawals, or thromboembolic events reported. The findings from the extension phases were consistent with those from the main trial phases.³⁹

However, the phase III Explorer7 and Explorer8 studies, which aimed to further evaluate Concizumab in a larger population of patients with HA or HB, with and without inhibitors, temporarily halted recruitment and dosing due to nonfatal thrombotic events. Before the pause in the Explorer7 trial, one serious thromboembolism (renal infarction) occurred, and two thromboembolic events were reported in the Explorer8 trial involving patients without inhibitors. Following these events, risk mitigation measures were implemented, including a reduction in the initial dosing regimen of concizumab from 0.25 mg/kg to 0.20 mg/kg and the introduction of a dose adjustment step. No further thromboembolic events were reported after the resumption of concizumab therapy, and plasma concentrations of the drug remained stable over time.^18,40

Concizumab has received regulatory approval in multiple regions for patients with HA or HB. It is approved in Japan, Australia, and Switzerland for use in patients with inhibitors, while in Japan and Australia approval also extends to patients without inhibitors. The FDA has granted approval for patients aged ≥12 years with HA or HB, with or without inhibitors. Similarly, the EMA approved concizumab for patients with HA or HB with inhibitors in December 2024, followed by an additional approval in 2025 extending its use to those without inhibitors. Concizumab has not yet received regulatory approval in Türkiye. Importantly, expert centers from Türkiye participated in the phase studies, contributing to the global effort to evaluate concizumab’s efficacy and safety.^4,41,42

Marstacimab

Marstacimab, a human monoclonal IgG1 antibody targeting the K2 domain of TFPI, is designed to mitigate the inhibition of Factor Xa (FXa) by TFPI, thereby enhancing hemostasis via the extrinsic pathway. In a Phase I study involving 32 healthy male volunteers, marstacimab was administered as a single dose, either intravenously or subcutaneously. The study reported no serious adverse events or infusion/injection site reactions. ADAs were detected in 47% of participants; however, neutralizing antibodies were identified in only three individuals, with no significant impact on pharmacokinetics and pharmacodynamics suggested by the available data.⁷

The subsequent Phase Ib/II study, involving multiple doses, demonstrated a reduction in ABRs by more than 85% across all dose cohorts compared to prior on-demand replacement regimens. Marstacimab was generally well tolerated, with injection site reactions reported at a rate of less than 1%. Three participants developed non-neutralizing ADAs, and four discontinued the treatment due to adverse events (appendicitis, physical assault, cholelithiasis, and tooth socket hemorrhage), none of which were related to the treatment. Importantly, no thrombotic events were reported.^2,43

Further evaluation in a short-term Phase II parent study and a long-term Phase II extension study reaffirmed marstacimab’s tolerability. No treatment-related serious adverse events or thrombotic events were reported. Marstacimab was associated with clinically meaningful reductions in ABR across all dose cohorts, alongside treatment-related changes in all pharmacodynamic biomarkers, indicating effective targeting of TFPI. No treatment-induced ADAs were detected.^7,19

The Phase III BASIS trial (NCT03938792) evaluated once-weekly subcutaneous marstacimab in patients aged 12–74 years with severe hemophilia A and moderately severe to severe hemophilia B, with or without inhibitors. Treatment outcomes with marstacimab during a 12-month period were compared against a six-month lead-in period of usual care, consisting of prophylaxis or on-demand intravenous FVIII, FIX, or bypassing agents. In the non-inhibitor cohort, marstacimab demonstrated a 92% reduction in ABR compared with on-demand factor replacement (mean ABR 39.86 vs 3.20; P < 0.0001) and showed superiority over routine prophylaxis (mean ABR 7.90 vs 5.09; P = 0.0349), corresponding to a 35.5% reduction.⁴⁴ In the inhibitor cohort, efficacy was further confirmed, with patients achieving a 93% reduction in ABR compared with the lead-in period of on-demand bypassing agents (1.39 vs 19.78), as reported in a recent press release.⁴⁵ Superiority was also observed across key secondary endpoints, including spontaneous bleeds, joint bleeds, target joint bleeds, and total bleeds. Marstacimab prophylaxis was generally well tolerated across both populations. Although no thromboembolic events were reported during the active treatment phase, a thrombotic event was documented in the open-label extension. Importantly, no deaths or new safety signals identified, supporting marstacimab’s role as a potential long-acting prophylactic option in hemophilia management. Recent long-term extension data reported a median OLE exposure of 18.9 months (range 1.2–29.4) and a combined median exposure of 30.0 months (range 0.9–41.5) across BASIS and the OLE, supporting the durability of bleed control and a favorable benefit–risk profile of marstacimab.⁴⁶ Türkiye was among the participating countries, contributing to the global evaluation of marstacimab’s efficacy and safety.^4,7,44 Another Phase 3 ongoing clinical study, BASIS KIDS (NCT05611801), is investigating the safety and efficacy of marstacimab in pediatric patients with severe HA and moderate to severe HB with or without inhibitors. This study will enroll pediatric participants from ages 1 to 17, from ages 1 to 17, with the first cohort consisting of 12-17 years olds enrolling first, followed by participants 6-11 years of age, and lastly those 1-5.⁴⁷ The once-weekly SC administration of marstacimab provides ease of use, and its fixed-dose regimen, which does not require dose adjustment based on body weight, can be considered an advantage.⁴⁸ The FDA has approved marstacimab for the use of patients aged 12 years or older with HA or HB without inhibitors.⁴⁹ In November 2024, the EMA approved marstacimab for patients with severe HA or HB without inhibitors.⁵⁰ More recently, in Türkiye, the Turkish Medicines and Medical Devices Agency (TİTCK) approved marstacimab for use in patients aged 12 years or older with HA or HB without inhibitors.⁵¹

Antithrombin Reducing Agents

Fitusiran

Fitusiran, an RNA interference therapy, targets antithrombin messenger RNA to inhibit the synthesis of AT in the liver, thereby promoting increased thrombin generation.¹¹ This approach aims to rebalance hemostasis and prevent new bleeding episodes in patients with moderate to severe HA or HB. In a Phase I study, a dose-dependent reduction of AT by 70-89% was observed, alongside increased thrombin generation with a monthly dosing strategy in 25 patients. Notably, no thromboembolic episodes were recorded during the study.^7,8,11

Interim results from the open-label extension of the Phase II OLE study in HA and HB patients, with or without inhibitors, receiving 80mg of SC fitusiran once monthly, reported sustained reductions in AT levels and improved thrombin generation. A median ABR of 1.5 was observed, with no ADAs detected. However, the occurrence of a fatal cerebral sinus venous thrombosis in one patient led to the discontinuation of Phase II and III studies. The studies were restarted in December 2017 with revised protocols and a risk mitigation strategy, including reduced doses and frequency of infusions of hemostatic agents and avoidance of concomitant use of antifibrinolytics.^7,11,52

On October 30, 2020, ongoing fitusiran clinical studies were paused again due to non-fatal thrombotic events. In December 2020, following regulatory approval, the dosing regimen of fitusiran was revised, with the aim of targeting an AT range of 15–35%. Clinical studies resumed under modified protocols, initially starting patients on a 50 mg dose every two months. The dose and/or frequency could be adjusted as needed to maintain patients within the target AT range, thereby aiming to mitigate the risk of thrombosis.¹¹

The ATLAS-INH Phase III study, focusing on participants with HA or HB with inhibitors, showed that once-a-month, 80 mg SC prophylactic fitusiran resulted in a median ABR of zero, with two-thirds of participants experiencing no bleeds and reporting improvements in quality of life (QoL). The most frequent treatment-emergent adverse event (TEAEs) in the fitusiran prophylaxis group was increased alanine aminotransferase (ALT) (33%). Thromboembolic events were reported in two (5%) participants, and six (15%) of 41 participants experienced treatment-emergent cholecystitis or cholelithiasis, with specific cases of concurrent cholecystitis and cholelithiasis, acalculous cholecystitis, and cholelithiasis alone.²⁰

In the ATLAS-A/B study, fitusiran prophylaxis led to significant reductions in ABR, with approximately half of the participants without inhibitors experiencing no bleeding events. Increased ALT concentration (23%) was the most common TEAE. TEAEs were reported in five (6%) participants, with no treatment-related thrombosis or deaths reported.²¹

The ATLAS PPX study highlighted that fitusiran prophylaxis significantly reduced bleeding compared to clotting factor concentrate or bypassing agent prophylaxis, achieving a median ABR of zero in HA/HB with and without inhibitors, and resulting in a meaningful improvement in health-related QoL. The most frequent TEAE was increased ALT or aspartate transaminase elevations (AST) exceeding three times the upper limit of normal (25.4%). Thromboembolic events were reported in two (3%) participants, and cholelithiasis and cholecystitis each occurred in 7.5% of patients.²²

The ongoing ATLAS-OLE (NCT03754790) study, a single-arm, phase III, open-label study evaluating the safety and efficacy of fitusiran with a revised AT-DR, which was designed to maintain an AT target range of 15%-35%. This study includes lower doses and less-frequent dosing than earlier studies.⁵³ Of the 286 participants analyzed in the ATLAS-PPX (NCT03549871), ATLAS-OLE (NCT03754790) and a Phase I/II open-label extension study (NCT02554773), 2.8% and 2.1% experienced ALT or AST elevations exceeding three times the upper limit of normal with the AT-base dose regimen treatment. One participant discontinued fitusiran treatment due to asymptomatic transaminase elevation, but there was no severe liver issue reported. Additionally, 3.8% experienced cholecystitis or cholelithiasis, with one cholecystectomy performed, yet none led to fitusiran discontinuation. The underlying mechanisms for these events are still being investigated.⁵⁴

ATLAS-NEO (NCT05662319) is an additional phase 3 study currently recruiting participants to assess the frequency of treated bleeding episodes with fitusiran under the AT-based dose regimen in male adult and adolescent (≥12 years old) participants with HA or HB, with or without inhibitory antibodies to factor VIII or IX, who have switched from their prior standard-of-care treatment.⁵⁵ Patients from Türkiye were included in the ATLAS studies, contributing to the global evaluation of Fitusiran’s efficacy and safety. In March 2024, the FDA approved fitusiran for the routine prophylactic treatment of adults and adolescents with hemophilia A or B, with or without factor inhibitors. This approval represents an advancement in care, offering a novel subcutaneous treatment option that targets AT to rebalance hemostasis in affected individuals.⁵⁶

Anti-Protein C Agents

SerpinPC

SerpinPC represents an innovative approach in the quest to rebalance hemostasis in hemophilia patients. As a serine protease inhibitor, SerpinPC targets activated protein C (APC), a natural anticoagulant pivotal in the regulation of blood clotting. APC functions by cleaving activated factors V and VIII, crucial components in the coagulation cascade, and also inhibits a range of coagulation-specific proteases including thrombin, factor Xa, factor XIa, and the factor VIIa-tissue factor complex.²³

SerpinPC has shown promise in both in vitro and in vivo settings, demonstrating an ability to promote thrombin generation and normalize bleeding times in mouse models. These preliminary results have paved the way for further investigation into its therapeutic potential for humans. A phase I/IIa trial designed to investigate the safety, tolerability, pharmacokinetics, and efficacy of SerpinPC in patients with severe HA or HB, is the first-in-human, open-label, multicenter trial. Previously presented data from completed segments of the study have demonstrated that SerpinPC was well tolerated in study participants.⁵⁷ However, the PRESENT-2 Phase IIb trial (NCT05789524), which aimed to evaluate the efficacy and safety of SerpinPC in a broader patient population, was recently discontinued.⁵⁸ Although the interim analysis of SerpinPC demonstrated a favorable safety and tolerability profile, the company determined that discontinuation was a strategic decision driven by a shift in investment priorities toward its OX2R agonist program. Furthermore, the continued development of SerpinPC would require substantial time and investment to achieve a more competitive position, particularly in light of the evolving hemophilia B treatment landscape.⁵⁹

4. Gene Therapies in Hemophilia: Navigating Their Role in the Age of Non-factor Treatments

The limitations of intravenous administration, the scarcity of factor concentrates in developing countries, the risk of developing inhibitors that diminish the efficacy of EHL clotting factors, the potential thrombogenicity of newly introduced subcutaneously administered molecules, and the requirement for lifelong treatment without achieving normal hemostasis underscore the necessity for a phenotypic solution.⁶⁰ Gene therapy has emerged as a promising approach in addressing these challenges in hemophilia treatment. However, due to its inapplicability in patients with inhibitors, approximately 30% of hemophilia patients still do not have access to gene therapy.

Identified in the early 1990s as an ideal candidate for gene therapy, hemophilia has since seen significant advancements in this area. The primary strategy involves liver-directed delivery of the F8 or F9 genes using recombinant adeno-associated viral (AAV) vectors. These vectors are capable of transferring therapeutic genes into postmitotic tissues, such as the liver, leveraging the cellular tropism determined by their protein capsids. Clinical trials have thus far been limited to adult men with endogenous factor levels ≤2% and without advanced liver disease.^60-62

Clinical trials for AAV gene therapy in both HA and HB have shown promising results, as detailed in Table 3.^5,60-62 Despite a high rate of treatment-related adverse events in the Phase I/II dose-escalation study of valoctocogene roxaparvovec, only one event was classified as a serious adverse event related to treatment. Common adverse events included elevations in ALT, occurring in approximately 85% of participants across dosing cohorts within the first year. Infusion-related reactions were also noted, affecting 43% to 67% of recipients.⁶²

Table 3.

AAV Gene Therapy Trials^5,60-62

	Phase	NCT	Product	Participation from Turkiye FDA/EMA Aproved
Hemophilia B	Pfizer/BENEGENE-2 Phase3 study	1/2,3	NCT02484092	AAV-SPARK100-FIXco-Padua (SPK-9001)	✓	✓
	Pfizer/BENEGENE-2 Phase3 study	1/2,3	NCT03307980	AAV-SPARK100-FIXco-Padua (PF-06838435, formerly SPK-9001)	✓	✓
	CSL/UniQure	1,2,3	NCT02396342	AAV5-hFIXco (AMT-060)		✓
			NCT03489291	AAV5-FIXco-Padua (AMT-061)
			NCT03569891	AAV5-FIXco-Padua (AMT-061)
Hemophilia A	BioMarin	1,2,3	NCT02576795	AAV5-FVIII-BDD (Valoctocogene roxaparvovec, BMN 270-201)	✓^*	✓
			NCT03392974	AAV5-FVIII-BDD (Valoctocogene roxaparvovec, BMN 270-302)
			NCT03370913	AAV5-FVIII-BDD (Valoctocogene roxaparvovec, BMN 270-301)
			NCT04684940^*	AAV5-FVIII-BDD (Valoctocogene roxaparvovec, BMN 270-205)^*
	Pfizer/AFFINE Phase3 study	1,2	NCT03061201	AAV2/6-FVIII-BDD (SB-525, PF-07055480)	✓

AAV: Adeno-Associated Virus, FDA: U.S. Food and Drug Administration, EMA: European Medicines Agency.

^*Participation from Turkiye only in NCT04684940 BMN 270-205.

The Phase III study of valoctocogene roxaparvovec included 134 men with severe HA. All participants reported at least one adverse event, with 16.4% experiencing serious adverse events. ALT elevations were again common, observed in 85.8% of participants, all of whom were treated with immunosuppression. The post-prophylaxis period saw ABRs of 1.2, 0.5, and 0.6 events in the first three years, respectively, with median values consistently at zero. These outcomes suggest that gene therapy can provide sufficient long-term factor levels to significantly reduce bleeding with a single application.⁶³ In 2022, the EMA granted conditional marketing authorization to valoctocogene roxaparvovec (AAV5-hFVIII-SQ) for treating HA.⁶⁴ Valoctocogene roxaparvovec is the first gene therapy approved for this indication in the European Union. In 2023, the FDA approved valoctocogene roxaparvovec for adults with severe HA.⁶⁵ Real-world adoption indicate that the therapy has been used in only a limited number of patients to date. Recently, it has begun to gain traction with reimbursement approvals in the USA, Germany, and Italy.

The Phase I-II study of AMT-060, a precursor to etranacogene dezaparvovec-drlb, deemed the product safe, though FIX expression levels were below the desired therapeutic range. This led to the development of AMT-061, incorporating the high-activity FIX Padua (R338L) variant, which achieved desired FIX plasma levels in a Phase IIb trial.⁶² An open-label Phase III study is underway. ALT elevations associated with treatment were noted, with a smaller proportion of participants requiring corticosteroid intervention compared to those treated with valoctocogene roxaparvovec. Hepatocellular carcinoma was detected in one participant, deemed unrelated to the vector. Post-treatment, the ABR decreased significantly, and the need for FIX concentrate dropped markedly. The FDA approved etranacogene dezaparvovec-drlb (AAV5-FIX Padua) for HB treatment after demonstrating its efficacy in providing long-term bleeding alleviation with a single administration.⁶⁶ The EMA followed with conditional marketing authorization in early 2023.⁶⁷

Fidanacogene elaparvovec is an innovative gene therapy, comprising a bio-engineered AAV capsid and a high-activity variant of the human coagulation FIX gene. The BENEGENE-2 study, a phase III, open-label, single-arm investigation, aims to assess the efficacy and safety of fidanacogene elaparvovec in adult males aged 18 to 65 with moderately severe to severe HB. The study successfully met its primary endpoint, demonstrating both non-inferiority and superiority in ABR for total bleeds post-fidanacogene elaparvovec infusion compared to FIX prophylaxis regimen. Moreover, fidanacogene elaparvovec exhibited a generally well-tolerated safety profile, consistent with Phase I/II results.⁶⁸ Five centers in Türkiye contributed to the study by enrolling a total of 15 patients. Fidanacogene elaparvovec received approval by the FDA and licensed in Canada for adults with HB.⁶⁹

The Phase III AFFINE (NCT04370054) study is an open-label, multicenter, single arm study to evaluate the efficacy and safety of a single infusion of giroctocogene fitelparvovec in more than 60 adult (ages 18-64 years) male participants with moderately severe to severe HA. Eligible study participants will have completed at least six months of routine FVIII prophylaxis therapy during the lead-in Phase 3 study (NCT03587116) in order to collect pretreatment data for efficacy and selected safety parameters. Primary analysis results from the phase 3 AFFINE study demonstrated that giroctocogene fitelparvovec was generally well tolerated and showed significantly reduced bleeding events.⁷⁰ A total of 20 patients with severe HA from four different centers in Türkiye participated in the study.

Once gene therapies for both HA and HB receive approval from the FDA and EMA, they are expected to become an important potential treatment option in the Western world; however, challenges related to long-term follow-up, treatment accessibility, adaptation to clinical practice, and cost considerations will need to be addressed. Furthermore, the successful application of gene therapy in 46 patients with HA and HB, along with effective follow-up, is enhancing the experience of Turkish physicians in this field. As a result, this therapy is expected to be integrated into the treatment options available in Türkiye after its adoption in the Western world.

5. Challenges and Comparing True Costs: Access to Advanced Hemophilia Therapies vs. Traditional Factor Replacement in Developing Countries

Many individuals with hemophilia born before the 1980s contracted iatrogenic HIV, HBV, and/or HCV infections due to contaminated plasma-derived factor concentrates.⁶² Today, this risk has been virtually eliminated thanks to the adoption of highly effective techniques in the production of these concentrates. Despite these significant advancements in treatment, which have notably improved survival and QoL for people with hemophilia, health equity compared to unaffected peers has not yet been realized. Regrettably, these advancements have not translated into improved care for approximately 80% of hemophilia patients living in developing or underdeveloped countries, primarily due to high costs. Additionally, these patients often have very limited or no access to factor concentrates, leaving them at a high risk of complications and with a markedly reduced life expectancy.⁶⁰ To better contextualize these disparities, selected developing regions are compared in terms of economic background, healthcare structure, and access to hemophilia therapies (Table 4).

Table 4.

Economic and Health-System Context for Hemophilia Care in Selected Developing Regions^71-78

Country/Setting^*	Population (2024)	GDP per capita, current US$ (2024)	Hemophilia care/Reimbursement context	Access to advanced therapies and practical interpretation	Key limitations
Türkiye	∼86 million	∼15,000	Predominantly public healthcare system through the Social Security Institution (SGK), covering standard prophylaxis for hemophilia A and B; selected advanced therapies (e.g., emicizumab) are reimbursed for defined hemophilia A subgroups, while access to newer agents and gene therapies remains limited or conditional	Relatively strong access compared to many developing countries	High budget impact; long-term sustainability of advanced therapies
Iran	∼92 million	∼5,000	Organized hemophilia care through referral centers, with established access to standard factor replacement and prophylaxis for hemophilia A and B in specialized settings	Moderate access to standard therapies; limited and evolving access to newer non-factor agents	Economic constraints; variability in access to advanced therapies
India	∼1.5 billion	∼2,500	Heterogeneous healthcare system with limited public reimbursement; hemophilia A and B management largely dependent on out-of-pocket payments, with substantial underdiagnosis and variable access to care; presence of major referral centers	Access to advanced therapies is limited and largely restricted to selected tertiary centers; availability remains uneven	Cost barriers, infrastructure gaps, underdiagnosis, and regional disparities in care
Gulf Countries (e.g., Saudi Arabia, UAE, Qatar)	∼3-35 million	∼35,000 – 70,000	High-income health systems with government-supported coverage for citizens; hemophilia A and B care generally available in specialized centers, with procurement often based on national tender systems; coverage may vary for expatriate populations	Better access to advanced therapies compared to other developing regions, particularly in urban and specialized settings	Variability in access across population groups; concentration of expertise in major centers

^*Data are derived from World Bank indicators and published literature. Available cost data in developing settings are limited and largely derived from hemophilia A populations; comparable data for hemophilia B and standardized cross-country comparisons remain scarce. Therefore, this table reflects general economic context and access patterns rather than direct cost comparisons.

The comparison across selected developing regions highlights the marked heterogeneity of hemophilia care delivery. Türkiye and Iran represent relatively structured models, with broader access to standard prophylaxis for both hemophilia A and B, supported by public or semi-public healthcare systems. Published data from Türkiye and Iran indicate a substantial economic burden of hemophilia care, particularly for hemophilia A and in patients with inhibitors, although such data remain limited and not directly comparable across settings.^72-74 In contrast, India illustrates a dual reality, where major referral centers and access to selected advanced therapies coexist with substantial underdiagnosis, limited reimbursement, and restricted access at the population level.^75,76 Similar challenges have also been reported across other South and Southeast Asian countries, where financial toxicity, limited reimbursement structures, and restricted access to advanced therapies continue to represent major barriers to optimal hemophilia care.⁷⁹ In Gulf countries, despite stronger economic capacity, access to hemophilia care is generally better than in South Asia; however, it remains variable across countries and population groups, often depending on citizenship status and being concentrated in specialized urban centers. Importantly, direct cross-country cost comparisons remain challenging due to heterogeneity in healthcare systems, reimbursement mechanisms, and the limited availability of standardized economic data. Most available cost analyses in developing settings are derived from hemophilia A populations, while comparable data for hemophilia B remain scarce. Therefore, economic context and health system characteristics may provide a more appropriate and reliable framework for understanding disparities in access to advanced hemophilia care.^77,78

Both EHL factor products and non-factor treatments effectively reduce bleeding rates in hemophilia; however, they do not correct the underlying coagulation defect and requiring lifelong administration. EHL factor products, administered via intravenous infusion, do not uniformly reduce treatment frequency across all patients and exhibit diminished effectiveness in those with inhibitors. In contrast, non-factor therapies represent a heterogeneous group of agents, each with unique pharmacological characteristics. While they share the advantage of subcutaneous administration, their safety and tolerability profiles differ, with varying rates of events observed across agents and clinical trials. This highlights the need to consider each therapy within its own risk–benefit framework, rather than as a uniform class.

These treatments, designed primarily for prophylactic use, necessitate that episodic bleeding still be managed with factor replacement. The management of hemophilia patients during the perioperative period or in instances of breakthrough bleeding, the accurate monitoring of dosing protocols, and the use of concomitant therapy with bypassing agents remain complex. The risk of inhibitor development, a significant concern requiring factor replacement products for breakthrough bleeding or surgical procedures, adds another layer of complexity. Questions about neutralizing ADAs, factor and antibody activity, immunogenicity, and inhibitor eradication persist due to incomplete long-term data. The impact of these treatments on joint health over time is also yet to be fully understood.

Given the importance of understanding genetic thrombophilia risk factors in Türkiye to mitigate thrombotic risks, this is a significant consideration. Unfortunately, therapies mimicking FVIIIa are ineffective in HB, whereas rebalancing therapies show promise in both HA and HB patients. To date, only the phase III studies of emicizumab and fitusiran have been completed, with research on other agents ongoing. Among non-factor treatments that mimic FVIIIa, only emicizumab has sufficient data in pediatric patients. Emicizumab is the sole non-factor treatment for adult and pediatric patients approved by the FDA/EMA.^27,28

Both marstacimab and concizumab are administered via prefilled pen-shaped devices, offering portability and ease of use. Concizumab is administered as a daily subcutaneous injection with weight-based dosing, whereas marstacimab is given once weekly subcutaneously without the need for weight-based adjustments. These differences in administration frequency and dosing may influence patient adherence and overall treatment experience. Although these therapies constitute an important step forward for patients with hemophilia B with inhibitors and their favorable ease of use, tailored clinical management may be required in certain scenarios, such as surgical interventions or acute traumatic events.

Fitusiran may exhibit a relatively higher side-effect profile compared to other non-factor agents, with important concerns reported for thrombosis, abdominal pain, and gallbladder-related complications such as cholangitis-cholelithiasis. While dose reductions appear to attenuate risks of thromboembolism and abdominal symptoms, frequent monitoring of AT activity to guide dosing adjustments could pose practical challenges. According to the U.S. Prescribing Information (USPI), once a maintenance dose is established, annual re-evaluation of AT levels is recommended to inform long-term monitoring strategies.⁸⁰ The prevalence of thrombophilia risk factors in the Turkish population raises questions about the suitability of Fitusiran for these patients. Comparative preclinical studies suggest that emicizumab achieves an estimated factor VIII equivalence of approximately 9–20%, whereas fitusiran may elicit a coagulation effect corresponding to approximately 20% FVIII activity.⁸¹ These equivalence estimates originate from animal models and should be interpreted with caution. Moreover, the effectiveness of fitusiran may vary depending on AT levels, a factor that warrants careful consideration in clinical use.

In light of these advancements, gene therapies for HA and HB are heralded as the future of treatment, offering a potentially ideal prophylactic regimen. A single administration of the gene delivery product could provide sustained, long-term factor levels sufficient to significantly reduce bleeding episodes. While gene therapy presents a potentially long-term treatment option for hemophilia, it has not yet become an established or standardized treatment. Despite recent progress in gene therapy for hemophilia, several challenges and uncertainties remain that need to be addressed to improve efficacy and minimize toxicity.

One significant barrier to gene therapy eligibility is pre-existing immunity to AAV vectors, which can prevent the gene therapy from being effective. Additionally, early transient liver toxicity has been observed in approximately 60% of patients between 4 and 12 weeks following vector delivery, posing a concern for patient safety.⁵ The duration and level of transgene expression also present uncertainties regarding the long-term outcomes of gene therapy products. Moreover, while achieving high coagulation factor levels is a goal of treatment, there is a risk that supraphysiological levels of factor activity induced by gene therapy could trigger thrombosis. The potential for AAV gene transfer to increase the risk of oncogenicity remains an unresolved question. Furthermore, as the enrollment of subjects of reproductive age in gene therapy clinical trials increases, the risk of germ line transmission of vector sequences emerges as a significant safety concern. It is also unclear whether the recent successes in gene therapy can be replicated in pediatric populations, presenting a gap in treatment options for younger patients. Additionally, the current lack of solutions for patients with inhibitors highlights a known shortcoming in today’s gene therapy approaches. In Türkiye, seropositivity to adeno-associated viruses poses a significant challenge to the widespread application of gene therapies. With seropositivity rates not falling below 50% nationally, and reported between 70-80% in major cities like Istanbul, Adana, and Izmir, only about 2 out of 10 hemophilia patients might be eligible for gene therapy. Until new technologies emerge, the current gene therapy modalities, even if financially accessible in Türkiye, could be applicable to a maximum of 30-40% of patients over the age of 18. In light of these developments, results from the Phase 1 trial of ex vivo gene therapy using a lentiviral vector instead of AAV were recently published. The study investigated the safety and efficacy of using lentiviral vector-transduced autologous hematopoetic stem cells to deliver gene therapy in patients with severe HA. The results demonstrated stable factor VIII expression, with activity levels correlating to vector copy numbers in peripheral blood. Over a median follow-up of 14 months, none of the participants experienced bleeding episodes, and the treatment was generally well-tolerated.⁸²

The advent of new treatment options for hemophilia raises critical questions about the optimal choice of therapy for individual patients. Despite the progress yet to be made, we have synthesized existing data into a decision-making guide (Table 5) in our article.^{5,13-25,35-37,40,43,51,56}

Table 5.

Which Treatment for Which Patient?^{5,13-25,35-37,40,43,51,56}

		EHL	Emi-	Mim8	Conci-	Marsta-	Fitu-	SerPC*	GeneT
Pediatric patient	HA	+	+	-	+^*	+^*	+^*	-	-
Pediatric patient	HB	+	-	-	+^*	+^*	+^*	-	-
Patient with inhibitor	HA	-	+	+	+	+	+	+	-
Patient with inhibitor	HB	-	-	-	+	+	+	+	-
Patients with liver disease	HA	+	+	+	+	+	-	+	-
Patients with liver disease	HB	+	-	-	+	+	-	+	-
Bleeding episodes that cannot be controlled by factor therapy	HA	-	+	+	+	+	+	+	+
	HB	-	-	-	+	+	+	+	+
Breakthrough bleeding or surgery	HA	+	-	-	-	-	-	-	-
Breakthrough bleeding or surgery	HB	+	-	-	-	-	-	-	-
Adenovirus seropositivity	HA	+	+	+	+	+	+	+	-
Adenovirus seropositivity	HB	+	-	-	+	+	+	+	-
Patients with a personal or family history of cancer	HA	+	NE	NE	NE	NE	NE	NE	-
Patients with a personal or family history of cancer	HB	+	NE	NE	NE	NE	NE	NE	-

NE: no evidence, HA: hemophilia A, HB: hemophilia B, EHL: extended half-life factor, Emi-: Emicizumab, Conci-: Concizumab, Marsta-: Marstacimab, Fitu-: Fitusuran, SerPC: Serpin-PC, GeneT: gene therapy; * >12 y.

This guide helps tailor treatment choices to specific patient profiles based on their unique clinical characteristics and risks. Although these recommendations have not yet been proven by studies, we believe that they may be useful in clinical practice. Patients characterized by high antibody levels, absence of thromboembolic risk, no comorbid conditions, younger age, challenges with vascular access, demanding work schedules, frequent bleeding episodes, and joint complications might prefer non-factor treatments. These options could offer a more manageable and less invasive treatment regimen, aligning better with their lifestyle and clinical needs. Conversely, for patients at an elevated risk of thromboembolic events—attributed to factors such as advanced age, immobility, thrombophilia, coronary artery disease, arrhythmia, heart failure, chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary disease, among other comorbidities— EHL products, non-factor products and gene therapy could introduce additional risks. Fitusiran may carry risks for individuals with a history of gallstones, cholecystitis, or liver disease, especially those with risk factors such as cirrhosis, excessive alcohol consumption, hepatitis carrier status, or a history of autoimmune hepatitis. For children under 12 years old, EHL products and emicizumab emerge as long-acting treatment options, potentially offering extended protection and reduced treatment burden. In addition, several non-factor agents, including marstacimab, concizumab, fitusiran, and Mim8, are currently being investigated in pediatric clinical trials.^43,83-85 Gene therapy could be a viable option for younger patients without liver disease, who are not at high risk for thromboembolic events, have no history of cancer, lead active work lives, have issues with vascular access, experience frequent bleeding episodes, and suffer from related joint damage. However, the landscape of hemophilia treatment is complex and evolving. More research is necessary to refine and solidify these recommendations further, and ongoing clinical observation is crucial to fully understand the side effects and long-term outcomes of these novel therapies.

6. Conclusion

In Türkiye, the landscape of hemophilia treatment is at a pivotal juncture. While nonfactor treatments and gene therapy represent the forefront of innovation in hemophilia care, their availability is currently limited to the context of clinical trials, with emicizumab standing as the sole licensed nonfactor treatment yet to receive reimbursement. This situation mirrors the broader challenge, where the cost barrier significantly restricts access to these advanced therapies. Consequently, hemophilia management in Türkiye predominantly relies on traditional and long-acting factor treatments.

The participation in clinical trials of nonfactor treatments and gene therapies offers a valuable opportunity for countries like Türkiye to access cutting-edge hemophilia interventions. The next decade is poised to see SC drugs emerge as a leading option in preventive treatment, heralding a new era in the management of this condition. In Türkiye, approximately 250 patients with HA and HB are receiving treatment with six different SC agents. Turkish hematologists have developed significant expertise in the administration and monitoring of SC drug therapy. In the coming years, the routine use of SC products was expected to become widespread, while gene therapy approaches were anticipated to gain significant momentum, eventually assuming a leading role, particularly in wealthy countries. However, considering the developments in 2024, despite the availability of three different approved gene therapy options for HA and HB, it is noteworthy that real-world data on HA gene therapy have been progressing at a notably slow pace, particularly in terms of obtaining reimbursement. Current trends suggest that newly approved SC therapies for both HA and HB will gain priority within the first decade, becoming the cornerstone of routine treatment in Western countries. In contrast, gene therapy is likely to remain in the background for a longer period due to its exceptionally high cost, as well as concerns regarding variability and durability, particularly in HA.

The potential establishment of alternative reimbursement approaches that encompasses both factor and SC drugs, and possibly extends to cover gene therapy through innovative treatment models, could significantly alter the treatment landscape. Different economic models should be explored to understand if the costs of these innovative treatments are justifiable from multiple perspectives.

In the interim, prophylaxis with nonfactor treatments presents a promising alternative, eliminating the challenges of vascular access for patients with HA and HB, including those with inhibitors. The option for weekly and monthly administrations enhances life comfort, offering a glimpse into the potential for a more manageable hemophilia care regimen.⁸⁶ The prospect of a single gene therapy administration providing a continuous source of clotting factor is particularly compelling, suggesting that a long-term treatment for hemophilia may be within reach. However, realizing this potential necessitates comprehensive data on both the short- and long-term efficacy and safety of these therapies in patients.

As we stand on the brink of these transformative developments, the collective focus must be on ensuring equitable access to these treatments, fostering innovation, and rigorously evaluating the outcomes to pave the way for a future where hemophilia can be effectively managed.

Footnotes

Acknowledgments

Medical writing and editorial support (including manuscript editing and formatting) were provided by Dr Ferda Kiziltas (Remedium Consulting Group) and funded by Pfizer. The authors authorized the submission of this manuscript via a third party and confirm that they reviewed and approved the final manuscript and all statements, including funding and conflict of interest declarations.

ORCID iDs

Kaan Kavaklı

Bulent Zulfikar

Ethical considerations

N/A since this is a narrative review article with expert opinions, this study did not require ethical approval.

Author contributions

All authors equally contributed to: Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing. All authors read and approved the final manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Pfizer.

Declaration of conflictiong interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.K. has acted in advisory board of Pfizer, Takeda, Roche, Novo Nordisk, CSL-Behring and has received speaker honorarium from Pfizer, Takeda, Roche, Novo Nordisk, CSL-Behring, Biomarin. B.A. has acted in advisory board of Novo Nordisk, Pfizer, Proceutica, Sobi, Roche, CSL Behring and Genveon. C.B. has acted in advisory board Takeda, Pfizer, Proceutica, Sobi, Novo Nordisk, Roche and has received speaker honorarium from these companies. A.K. has acted in advisory board of Novo Nordisk, Pfizer, Roche, Sobi and has received speaker honorarium from Novo Nordisk, Pfizer, Roche, Sobi. V.O. has received honorarium from Takeda, Novo Nordisk, Alexion, Roche, Astra Zeneca, Pfizer and Proceutica. F.S. has acted in advisory board of Pfizer, Novo Nordisk, Alexion. M.S. has received honorarium from Pfizer, Novo Nordisk and Roche. E.U. has acted in advisory board of Novo Nordisk, Takeda, Pfizer; and has received speaker honorarium from Novo Nordisk, Pfizer, Takeda, Genveon, Inpharmus, Sentinuspharma. B.Z. has acted in advisory board of CSL Behring. Novo Nordisk, Sanofi, Genveon and has received honorarium from Pfizer, Takeda. C.A., S.A., Z.K. declare that there are no conflicts of interest to disclose.

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The Dilemma of Providing Advanced Hemophilia Treatments in Developing Countries – For Whom,by Whom and Where?

Abstract

Keywords

1. Introduction

2. Methodology

3. Challenging the Status Quo: Do Non-factor Therapies Truly Outshine Traditional Hemophilia Treatments?

A-Therapies That Mimic FVIIIa

Emicizumab

Mim-8

B-Therapies That Interfere With Anticoagulant Pathways (Rebalancing Agents)

Anti-TFPI Molecules

Concizumab

Marstacimab

Antithrombin Reducing Agents

Fitusiran

Anti-Protein C Agents

SerpinPC

4. Gene Therapies in Hemophilia: Navigating Their Role in the Age of Non-factor Treatments

5. Challenges and Comparing True Costs: Access to Advanced Hemophilia Therapies vs. Traditional Factor Replacement in Developing Countries

6. Conclusion

Footnotes

Acknowledgments

ORCID iDs

Ethical considerations

Author contributions

Funding

Declaration of conflictiong interests

References