Nonfactor Therapies for Hemophilia: Current Evidence, Clinical Relevance and Cost Considerations

Introduction

Hemophilia is a congenital, X-linked bleeding disorder caused by deficiencies in coagulation factor VIII (FVIII) (hemophilia A) or factor IX (FIX) (hemophilia B) that result from mutations in the F8 or F9 genes on the X chromosome.¹ These deficiencies impair thrombin generation, producing a lifelong predisposition to bleeding.¹ Hemophilia A is more common, with recent epidemiologic estimates suggesting a prevalence of approximately 1 in 4,000 male live births compared with 1 in 20,000 male live births for hemophilia B.¹ However, female carriers are about 1.6 times more prevalent than affected males, with some carriers experiencing reduced factor levels and clinically significant bleeding.¹ Importantly, up to one-third of affected males in high-income countries have no family history, reflecting the high rate of de novo mutations.¹

The clinical phenotype is categorized as mild, moderate or severe.¹ Severe hemophilia often presents in the neonatal period or early infancy, with intracranial hemorrhage, prolonged bleeding after circumcision or spontaneous joint and muscle hemorrhages as children begin weight-bearing activities.¹ In untreated patients, bleeding frequency can reach between 20 and 40 episodes annually; these most commonly involve the ankles, knees, elbows and shoulders and lead to chronic arthropathy and disability.¹

Before the introduction of effective therapies, the median life expectancy was approximately 11 years, and fatal hemorrhage was possible with any bleeding event.¹ The development of plasma-derived and recombinant factor replacement therapies has dramatically improved survival and quality of life (QOL) for people with hemophilia.^1,2 Nevertheless, substantial challenges remain. Intravenous (IV) administration of factor products requires reliable venous access, prophylactic regimens are burdensome and often difficult to sustain and interindividual variability in pharmacokinetics complicates dosing strategies.² Moreover, approximately 30% of patients with severe hemophilia A and up to 5% with severe hemophilia B develop neutralizing alloantibodies (inhibitors) that render factor replacement ineffective and further complicate management.² Beyond these clinical barriers, the high cost of lifelong replacement therapy presents significant economic challenges for patients, payers and health systems.³

These unmet needs have driven the development of nonfactor therapies, a new class of agents designed to provide sustained hemostatic protection independent of FVIII or FIX replacement.² By addressing inhibitor development, reducing treatment burden and offering alternative routes of administration, nonfactor therapies are a paradigm shift in hemophilia care.¹

This review will summarize the current treatment landscape for hemophilia; compare the mechanisms of action, efficacy and safety of nonfactor therapies; and evaluate the economic and health system implications of these treatments in managed care.

Current hemophilia landscape

Historically, hemophilia treatment has relied on exogenous factor replacement.¹ Plasma-derived and recombinant FVIII and FIX concentrates enabled both on-demand treatment and prophylaxis, dramatically reducing morbidity and mortality.^1,4 Regular prophylactic infusions became the standard of care for severe disease, decreasing spontaneous joint and muscle bleeds and delaying the progression of hemophilic arthropathy.² For patients with inhibitors, however, hemostasis required the use of bypassing agents, such as activated prothrombin complex concentrates (aPCC) and recombinant activated factor VII.¹ Although these products improve outcomes, their effectiveness varies, and dosing strategies often require trial-and-error adjustments.²

Despite these advances, substantial challenges persist. The development of inhibitors remains one of the most significant complications, limiting the efficacy of factor replacement and necessitating immune tolerance induction, a burdensome process with variable success rates.² Even in the absence of inhibitors, the need for lifelong IV administration poses considerable barriers, including difficulties with venous access (particularly in young children) and the logistical burden of frequent infusions.^1,2 Adherence to prophylaxis is often suboptimal, especially in young adults, which undermines treatment effectiveness.¹

These limitations underscore the need for therapeutic innovation. The advent of nonfactor therapies represents an important shift in hemophilia care.^1,2 By offering an alternative to a reliance on FVIII or FIX replacement, these agents offer novel mechanisms of action, alternative routes of administration, potential reduction of treatment burden and improvement in efficacy and safety.^1,2

Mechanisms of action of nonfactor therapies

Nonfactor therapies restore hemostatic balance through novel mechanisms, circumventing the limitations of factor-based approaches and offering efficacy regardless of inhibitor status.^1,2

BISPECIFIC ANTIBODIES

Emicizumab, sold under the brand name Hemlibra, is the first licensed nonfactor therapy and the prototype of bispecific antibody design in hemophilia.⁵ It simultaneously binds activated FIX and factor X, thereby mimicking the cofactor function of activated FVIII (FVIIIa) within the tenase complex.⁵ Unlike exogenous FVIII, emicizumab is not structurally homologous to FVIII. As a result, it is not neutralized by FVIII inhibitors.⁶ Its subcutaneous (SC) route of administration and extended half-life permit dosing intervals of every week to every four weeks, reducing treatment burden while maintaining consistent hemostatic protection.^5,7

RNA INTERFERENCE THERAPIES

Fitusiran, sold under the brand name Qfitlia, employs small interfering RNA (siRNA) technology to suppress hepatic synthesis of antithrombin (AT).⁸ By reducing AT levels, fitusiran increases thrombin generation capacity, thereby rebalancing the coagulation system independently of FVIII or FIX activity.8 In clinical studies, fitusiran use resulted in lowered annualized bleeding rates in both hemophilia A and B with and without inhibitors.^8,9 However, thrombotic complications remain a potential concern, underscoring the importance of careful dose titration and monitoring.⁸

TISSUE FACTOR PATHWAY INHIBITOR (TFPI) ANTIBODIES

Concizumab, sold under the brand name Alhemo, and marstacimab, sold under the brand name Hympavzi, rebalance hemostasis by neutralizing TFPI.^1,10 TFPI inhibits the initiation pathway of coagulation by targeting the tissue factor-activated factor VII complex and factor Xa.^1,10 Both concizumab and marstacimab are administered SC, with phase 3 trials demonstrating significant reductions in bleeding rates among hemophilia patients.^10-13

Clinical evidence: Efficacy and safety

The clinical development programs for nonfactor therapies have produced robust evidence of substantial bleed-rate reductions across hemophilia populations, including patients with and without FVIII/FIX inhibitors^.7,9,12-15 However, the efficacy gains achieved with these agents are accompanied by safety signals that are mechanism-dependent and, at times, agent-specific. Pivotal trial evidence and safety findings for the major nonfactor classes are summarized below.

EMICIZUMAB (BISPECIFIC ANTIBODY)⁷

Emicizumab, the first nonfactor therapy to reach clinical practice, has the most extensive clinical experience.⁵ The HAVEN program (HAVEN 1-4 and subsequent extension studies) demonstrated large and clinically meaningful reductions in annualized bleeding rates (ABRs) relative to on-demand therapy and historical prophylaxis in people with hemophilia A regardless of the presence of inhibitors; a substantial proportion of treated patients experienced zero treated bleeds on active dosing regimens.⁵ The SC delivery of emicizumab and its infrequent dosing schedules (weekly, every 2 weeks or every 4 weeks) contributed to its rapid uptake in the hemophilia treatment landscape.⁵ Long-term follow-up and real-world series support durable efficacy and safety across age groups.⁵

Safety with emicizumab has generally been favorable, but early pivotal trials and postmarketing experience identified important therapy-related warnings.⁵ The most significant safety concerns are thromboembolic complications and thrombotic microangiopathy linked to concomitant high-dose aPCC (> 100 U/kg/day for > 1 day); subsequent postmarketing data have identified additional thromboembolic events, with most occurring in patients with pre-existing thrombotic risk factors.⁵ These events prompted guidance on limiting use and cumulative aPCC dosing while on emicizumab and reinforced the need for careful hemostatic planning for breakthrough bleeds and surgery.^5,16 Given the drug’s long elimination half-life of approximately 30 days and to mitigate the heightened risk of thrombotic complications, emicizumab should be discontinued several months before elective major surgery if prolonged perioperative or postoperative use of aPCC is anticipated.⁵

FITUSIRAN (RNA INTERFERENCE TARGETING ANTITHROMBIN) ⁹

In March 2025, the FDA approved fitusiran for routine prophylaxis in adults and adolescents (≥ 12 years) with hemophilia A or B, irrespective of inhibitor status.¹⁷ Fitusiran is administered SC as infrequently as once every two months, marking a notable advance in reducing treatment burden compared with traditional factor replacement or use of bypassing agents.¹⁸

The pivotal evidence supporting approval came from two randomized, multicenter trials (ATLAS A/B and ATLAS-INH) enrolling 177 patients with hemophilia A or B, who were stratified by inhibitor status^.17 Participants were randomly assigned to receive either fixed-dose fitusiran prophylaxis or on-demand therapy with bypassing agents (for inhibitor-positive patients) or factor concentrates (for inhibitor-negative patients).¹⁷ In participants with hemophilia A or B with inhibitors in the ATLAS-INH trial, fitusiran prophylaxis produced reductions in mean ABRs (1.7; 95% CI, 1.0-2.7) compared with the bypassing agent on-demand group (18.1; 95% CI, 10.6-30.8), indicating a 90.8% reduction in bleeding rate.9 In the ATLAS-A/B trial, fitusiran prophylaxis again demonstrated reductions in mean ABRs, this time in participants with hemophilia A or B without inhibitors.¹⁹ In the fitusiran group, a significantly lower mean ABR (3.1; 95% CI, 2.3-4.3) was noted when compared with the on-demand clotting factor concentrates group (31.0; 95% CI, 21.1-45.5); this represented a 90% reduction among the fitusiran group.¹⁹

Safety considerations remain important. Fitusiran carries a boxed warning for thrombotic events and gallbladder disease. It requires liver enzyme monitoring at baseline and for at least 6 months following initiation or dose escalation.¹⁸ Thrombotic and thromboembolic events in a minority of participants were noted in trial programs, and transient alanine aminotransferase elevations were among the more frequent laboratory abnormalities reported. These findings have led to careful dose-finding, risk-mitigation measures (including AT level monitoring and periprocedural guidance) and continued regulatory and postmarketing vigilance focused on thrombotic risk.¹⁷

CONCIZUMAB AND MARSTACIMAB (TFPI-TARGETING ANTIBODIES)

In October 2024, the FDA approved marstacimab for routine prophylaxis in patients at least 12 years of age with hemophilia A and B without inhibitors.²⁰ Approval was based on data from an open-label, multicenter clinical trial in 116 patients with either severe hemophilia A or severe hemophilia B, both without inhibitors.²⁰ ABRs were reduced from 38 in the control group to 3.2 in the treatment group, demonstrating a substantial bleed reduction compared to routine prophylaxis.²⁰

In December 2024, the FDA approved concizumab for routine prophylaxis in adults and adolescents (≥ 12 years) with hemophilia A or B complicated by FVIII or FIX inhibitors.²¹ Concizumab is administered by once-daily SC injection, offering a nonfactor prophylactic option specifically for patients with inhibitors, for whom factor replacement is often ineffective.^21,22

Approval of concizumab was based on data from the multinational, multicenter, open-label phase 3 explorer7 trial, which enrolled 133 patients with hemophilia A or B with inhibitors who required bypassing therapy.¹² Efficacy was evaluated by comparing the number of treated bleeding episodes in patients receiving concizumab prophylaxis versus those without prophylaxis.¹² The estimated mean annualized rate ratio for bleeding episodes between the treatment and control groups was 0.14 (95% CI, 0.07-0.29), demonstrating substantial protection from bleeding episodes.¹²

The safety profiles of TFPI-targeting antibodies are characterized by mild to moderate injection-site reactions and headache.^16,23 Importantly, concizumab carries a boxed warning for increased risk of thrombotic events, necessitating careful monitoring, particularly when used alongside aPCC.¹⁶

Place in therapy and clinical relevance

The integration of nonfactor therapies into clinical practice is a major shift in the management paradigm for hemophilia, with implications that extend beyond bleed prevention to QOL, adherence and use of healthcare resources.

Patient selection is guided by disease phenotype, comorbidities and individual treatment priorities. Emicizumab has become the agent of choice for many pediatric patients with severe hemophilia A (particularly in those with inhibitors) due to its demonstrated efficacy in inhibitor-positive populations, SC administration and simplified dosing.² In older children and adults, emicizumab offers an alternative for individuals struggling with adherence to IV prophylaxis or facing challenges with venous access.² Fitusiran, which may be used to manage both hemophilia A and B regardless of inhibitor status, may be attractive for patients requiring unified treatment across subtypes.² Its prolonged duration of action and less-frequent administration is appealing, although thrombotic risk and the need for monitoring AT levels remain key considerations.² The TFPI inhibitors concizumab and marstacimab provide additional options across hemophilia populations, expanding the range of nonfactor therapies for individualized care plans.

The nonfactor therapies have reduced treatment burden. The ability to administer these agents SC instead of via IV infusion addresses one of the most persistent barriers to prophylaxis adherence, particularly in children and adolescents.² Extended dosing intervals that range from weekly to every other month further alleviate treatment fatigue and enable more consistent prophylaxis and improved QOL.

Despite the advantages that nonfactor agents provide in terms of administration and dosing frequency, factor prophylaxis remains an established standard, particularly in regions where nonfactor therapies are unavailable or cost prohibitive. Further, it continues to play a role in acute bleeding management and surgical coverage.²

The development of gene therapy introduces an additional layer of complexity. Although gene therapy offers the potential for long-term endogenous factor expression after a single infusion, it continues to be studied in terms of durability, safety profile and applicability.²

Major guidelines reflect the rapid integration of nonfactor therapies into hemophilia care. The World Federation of Hemophilia 2020 guidelines recognize emicizumab as an established prophylactic option for hemophilia A, particularly in patients with inhibitors; they highlight the promise of RNA interference and TFPI-targeted therapies.² The guidelines emphasize the need for individualized selection of therapy, careful monitoring of novel agents, continued reliance on factor replacement for breakthrough bleeding and surgery and availability in regions where novel therapies remain inaccessible.²

Economic and practical considerations

The introduction of nonfactor therapies has transformed the clinical and economic landscapes of hemophilia management. These agents promise substantial clinical and QOL benefits; however, their high acquisition costs, evolving payer coverage frameworks and implications for healthcare budgets require careful consideration.

Drug acquisition remains the dominant driver of treatment costs in hemophilia, especially in patients with inhibitors and those with severe disease.²⁴ Estimates for annual per-patient expenditures for prophylactic regimens — including FVIII replacement concentrates, bypassing agents and emicizumab — range from $350,000 to over $1 million, with the highest costs attributed to patients with hemophilia A with inhibitors who are treated with bypassing agents.²⁴

Nonfactor therapies may reduce costs associated with bleeding-related hospitalizations and use of bypassing agents. One study in pediatric patients with inhibitors reported a decrease in the total annual cost of prophylaxis with emicizumab (before emicizumab use, $1,269,500; after emicizumab use, $337,910).²⁴

Given the potential cost savings with nonfactor therapies, payers are re-evaluating formulary strategies in response to the expanding therapeutic landscape. Although emicizumab is now broadly covered as standard prophylaxis for patients with inhibitors and is increasingly being covered for those without inhibitors, newer agents (e.g., fitusiran and concizumab) may face varying degrees of formulary restriction pending long-term safety and cost-effectiveness data.²⁵ Payers increasingly adopt prior authorization or step therapy for novel hemophilia agents, requiring a trial of factor replacement before the approval of nonfactor agents.²⁵ Coverage decisions often depend on real-world evidence on the safety and efficacy of new treatments, reflecting cautious adoption of innovative therapies despite their clinical advantages.²⁵

Given the financial sustainability of lifelong prophylaxis, and particularly with the introduction of multiple high-cost therapies, the cumulative cost burden of hemophilia care continues to challenge both public and private payers. Nonfactor therapies may reduce indirect costs through fewer infusions, reduced bleeding episodes and lower caregiver burden, yet the near-term budget impact remains to be seen. Health systems will increasingly need to explore outcomes-based agreements and value-based contracting to mitigate financial risk while maintaining patient access.

Emerging cost-effectiveness analyses suggest that nonfactor therapies offer favorable incremental cost-effectiveness ratios compared with bypassing agents or episodic therapy, especially in inhibitor-positive populations.²⁴ Nonfactor therapies offer a predictable, sustained cost model with well-established safety and efficacy data.

Gene therapies may offer long-term cost offsets by reducing lifetime treatment costs, but their up-front pricing and uncertain durability complicate payer adoption. The Institute for Clinical and Economic Review (ICER) assessed the long-term value of gene therapies for hemophilia A and B in 2022.²⁶ In the ICER report, a traditional analysis assigning the entire amount of any therapeutic cost offset to therapeutic value showed that the gene therapies etranacogene dezaparvovec and valoctocogene roxaparvovec had values of $3,500,000 and $2,500,000, respectively; these agents were described as dominant therapies that offered cost savings compared with prophylactic factor therapy or eculizumab (for only hemophilia A).²⁶ The panel advised that payers work collaboratively with manufacturers to develop outcomes-based agreements aimed at alleviating uncertainty about the long-term durability of benefit and to address the substantial costs associated with gene therapies.²⁵

Access to hemophilia treatment remains uneven worldwide. In resource-constrained countries, the cost and distribution requirements of factor replacement therapies limit availability.² The high price of nonfactor therapies further compounds these disparities and carries implications for equity and global access, underscoring the need for coordinated international efforts to promote equitable distribution and affordability. As the therapeutic landscape continues to expand with gene therapy and additional rebalancing agents, value-based care models will play an increasingly central role in balancing innovation, access and sustainability.

Future directions and unanswered questions

The rapid emergence of nonfactor therapies has transformed the therapeutic landscape of hemophilia, but several unanswered questions and evolving research areas continue to shape their role in long-term care.

Regulatory and payer frameworks are adapting to the rapid uptake of nonfactor agents. The FDA and the European Medicines Agency continue to refine approval pathways for rebalancing therapies, often requiring postmarketing surveillance to address long-term safety concerns. On the reimbursement side, frameworks for high-cost therapies for rare diseases are being reconsidered; these profiles include value-based contracts and outcomes-based reimbursement models intended to balance innovation with sustainability for health systems.

Despite robust short- and medium-term efficacy data, long-term safety remains incompletely understood. Reported risks of thromboembolic events underscore the importance of vigilance as these therapies are adopted more broadly. The durability of bleed protection over decades of use remains unknown, particularly in pediatric populations that are expected to remain on therapy for extended periods. Optimal strategies for switching between factor and nonfactor therapies, especially around surgery or breakthrough bleeds, also require further consensus. Furthermore, questions persist regarding the management of immunogenicity and potential drug-drug interactions in patients requiring concomitant therapies.

The relationship between nonfactor therapies and gene therapy is an evolving frontier. Ultimately, the coexistence of these modalities may allow for individualized care pathways in which nonfactor therapies remain central to pediatric and inhibitor-positive populations, as gene therapy may be offered to carefully selected adult patients.

Key priorities include addressing unresolved safety concerns, expanding equitable access and developing evidence-based strategies for treatment sequencing and switching. Confrontation of these issues will define the future trajectory of hemophilia care and determine whether the promise of sustained bleed prevention can be realized equitably across diverse patient populations.

Conclusion

As a significant advance in hemophilia care, the introduction of nonfactor therapies offers substantial reductions in bleeding episodes, improved safety and convenience and meaningful improvements in patient QOL. Clinical evidence from pivotal trials and real-world studies confirms their efficacy across inhibitor and non-inhibitor populations, whereas economic analyses suggest that, despite high acquisition costs, these agents may reduce overall healthcare use through fewer hospitalizations and the circumvention of alternative agents.

Given the complexity of hemophilia presentation and patient needs, therapy selection must remain individualized. Inhibitor status, venous access, adherence challenges, patient age and comorbidities and other issues should guide treatment decisions along with careful consideration of both clinical efficacy and patient-reported outcomes.

Looking ahead, nonfactor therapies are expected to remain central to hemophilia management, complementing both factor prophylaxis and emerging gene therapies. Their ease of administration, sustained efficacy and applicability across diverse patient groups make them a transformative addition to current practice with a range of benefits for patients. Continued long-term surveillance, equitable access strategies and integration with novel treatment modalities will be critical in promoting durable and global improvements in hemophilia outcomes. •

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