Redefining Hemophilia Management: Treatment Goals, Nonfactor Replacement Therapies, and the Role of Fitusiran

This supplement was sponsored by Sanofi.

ABSTRACT

Hemophilia is a rare, but debilitating congenital bleeding disorder. Current therapeutic guidelines, last updated in 2020, recommend recombinant clotting factor concentrates as the standard replacement therapy, with emicizumab offered as an alternative nonfactor standard of care. Since the publication of those guidelines, approvals of new gene-based and nonfactor therapies have reshaped the therapeutic landscape. This supplement describes the safety and efficacy of those therapies approved after the 2020 guidelines were published. It also presents managed care considerations describing how opportunities for resource optimization, therapeutic efficiency, and alternative administration approaches may advance progress toward aspirational treatment goals. A main focus is on fitusiran, the most recently approved nonfactor therapy, which introduced a novel mechanism of action and dosing strategy to the hemophilia therapeutic landscape in addition to its broad patient applicability. As this and other therapeutic advancements redefine the standard of care for patients with hemophilia, managed care and policy frameworks must adapt to ensure timely access and affordability. Likewise, updates to clinical guidelines and care pathways are essential to capture the rapidly evolving therapeutic landscape.

Am J Manag Care. 2026;32(suppl 2):S15-S24. https://doi.org/10.37765/ajmc.2026.89879

For author information and disclosures, see end of text.

Introduction

Hemophilia A and B are inherited bleeding disorders caused by deficiencies in clotting factors VIII (FVIII) and IX (FIX), respectively.¹ Congenitally linked to sex-linked genes on the X chromosome,² hemophilia A occurs in approximately 1 in every 6000 males and hemophilia B in approximately 1 in every 26,000 males, according to US prevalence estimates.³ An estimated 33,000 males with either subtype currently reside in the US.³ Inhibitors are antibodies against exogenous clotting factor replacement therapy that render the treatment less effective.⁴ They are the most concerning treatment complication among people with hemophilia (PwH) due to increased rates of morbidity and mortality.⁵ In their lifetime, an estimated 25% to 40% of patients with severehemophilia A and an estimated 1% to 5% of those with severe hemophilia B will develop inhibitors.⁴ Immune tolerance induction is the only therapeutic method to potentially eliminate persistent inhibitors, but the treatment burden is substantial, characterized by regular infusions either daily or several times weekly for an extended period.⁴ Bypassing agents (BPAs) are an alternative that may be used to treat breakthrough bleeds or as prophylaxis in PwH with inhibitors, but their clinical effectiveness is less reliable than factor replacement used in patients without inhibitors, and treatment burden remains a concern with these agents.⁴

In 2020, the World Federation of Hemophilia (WFH) Guidelines for the Management of Hemophilia stated that intravenous (IV) prophylaxis using plasma-derived or recombinant clotting factor concentrates constituted standard replacement therapy for PwH.⁶ However, prophylactic factor replacement requires frequent, lifelong IV infusions, and a proportion of PwH may remain inadequately protected from bleeding and joint damage despite prophylaxis.^7,8 Nonfactor replacement therapies have emerged as an alternative standard of care,^9,10 and WFH suggests these may be less burdensome to patients, improving uptake and adherence to prophylactic intervention.⁶ Toward exploring these and other unmet needs for PwH, this supplement briefly reviews WFH’s treatment guidelines and the evolving therapeutic goals, explores subsequent treatment advances especially in nonfactor replacement therapies, and highlights fitusiran (Qfitlia®; Sanofi), an antithrombin (AT)-directed nonfactor therapy that was approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients aged 12 and older with hemophilia A or B, with or without FVIII or FIX inhibitors, on March 28, 2025.¹¹

Guidelines and Emerging Therapeutic Goals

Until the 1970s, controlling bleeds to decrease morbidity and mortality was the major clinical goal of hemophilia intervention because most PwH could not expect to live past age 30 years.¹² With the development of recombinant factor replacement therapies (rFVIII and rFIX) and standard-of-care guidelines to initiate prophylaxis early in life, PwH are now able to have a life expectancy comparable to that of the general population in the US.^6,13,14 Although current clinical priorities continue to focus on bleed prevention, they additionally emphasize patient education and counseling and improving quality of life.⁶

The potential benefits of prophylactic intervention initiated early in the lives of PwH may allow them to achieve a quality of life similar to that of individuals without hemophilia, including health, social participation, and physical activity.^6,14 Toward this degree of health equity, Skinner et al proposed a 7-step treatment model that defines a progressive path toward a functional cure, achieving normal hemostasis as the ultimate clinical goal.¹⁵ The first 3 steps—sustained life, minimized joint impairment, and freedom from spontaneous bleeds—were considered achievable in most PwH as long as they had access to current prophylactic regimens and adequate health care resources.¹⁵ Clinical outcomes—such as achieving “normal” mobility and being able to sustain trauma or undergo surgery without additional intervention—are now attainable through earlier intervention, coordinated care within hemophilia treatment centers, and the use of both clotting factor replacement and nonfactor therapies to optimize prophylaxis, along with emerging gene therapies.¹⁵ This functional cure would promote health equity by enabling individuals to live free from the fear of bleeding episodes and simultaneously facilitating access to both routine elective and emergency medical care.^15,16

Alongside aiming for the aspirational zero-bleed goal, providers may also focus on shared decision-making strategies, enabling patients to make treatment decisions that align with their lifestyle while simultaneously lowering treatment burden for patients and caregivers.^6,14 Achieving these treatment goals would alleviate the continuous psychological burden thatPwH face by constantly having to focus on their condition,^16,17 but PwH are largely responsible for their own day-to-day self-management and require sufficient education and training from a multidisciplinary care team to engage in health care discussions regarding short- and long-term treatment plans.⁶ Among the core members of this team, nurse coordinators may provide initial care and educate patients/caregivers in self-delivery of home therapy; physical therapists and musculoskeletal specialists may counsel on bleed prevention strategies and facilitate postbleed recovery, addressing specific conditions as necessary per their expertise; and psychologists or social workers may attend to patients’ mental health needs, providing referrals to community resources as needed.⁶ Ideally, this care would be coordinated through a hemophilia comprehensive care or treatment center, although primary care providers and family physicians are capable of managing minor complications, particularly for patients who live far from their nearest center.⁶

Treatment Landscape

Historical Treatment Landscape

The therapeutic landscape for hemophilia has evolved dramatically over the past several decades. The Figure details a simplified version of the human coagulation cascade to indicate how deficiencies in clotting factors (FVIII and FIX) contribute to hemophilia A and B pathogenesis and where current treatment options function in this cascade.^18-25 The first available treatments were whole blood, fresh frozen plasma, and cryoprecipitate. Subsequently, the development ofplasma-derived FVIII and FIX concentrates offered a means to replace the specific missing clotting protein with smaller infusion volumes.^6,13,26 However, the tragedy of blood-borne viral transmission in the 1980s—including HIV and hepatitis—underscored the need for safer alternatives.²⁶

The introduction of recombinant standard half-life (SHL) factor replacement therapies in the 1990s represented a major advance, providing standardized options for both prophylaxis and on-demand treatment.²⁶ Routine IV infusions significantly reduced bleeding episodes and extended life expectancy.²⁶ Despite these gains, treatment adherence remained a challenge due to the high infusion burden and difficulties with venous access, particularly in children.⁶ Additionally, some patients develop inhibitors that reduce the efficacy of factor replacement.⁴ Potentially compounding infusion burden, patients without the training or capability to self-administer IV factor replacement infusions at home would require frequent trips to a clinical setting.²⁷ Even though central venous access devices are recognized as an aid that eases frequent IV infusions and circumvents venous access difficulty, these are associated with appreciable discomfort, infection risk, and other complications that preclude their long-term use.⁶ Additional burdens of factor replacement include complex dose calculations that may vary by product and patient-specific factors such as age, body weight, planned surgical procedures, and frequency of severe bleeds.⁶

Extended half-life (EHL) products addressed some of these barriers by prolonging the circulation of FVIII and FIX through different technologies, such as PEGylation and Fc fusion. These modifications allowed less frequent dosing, typically twice per week for hemophilia A and once every 7 to 14 days for hemophilia B, though still requiring IV access. However, plasma trough levels may not be as high as expected for some, leading to breakthrough bleeds. Moreover, inadequate bleed protection and concerns over long-term joint health maintenance remain for some patients.⁶

Efanesoctocog alfa is the most recent rFVIII EHL product, approved in 2023 for use in adults and children with hemophilia A as routine prophylaxis to reduce the frequency of bleeding episodes, as on-demand treatment and to control bleeding episodes, or for perioperative management of bleeding.²⁸ Touted for its ultralong half-life,²⁹ routine prophylaxis with efanesoctocog alfa may allow administration of a standard 50 IU/kg dose once per week, with lower doses available on a more frequent basis should the need arise for on-demand treatment of a bleeding episode.²⁸ However, as with other factor replacement products, efanesoctocog alfa still requires IV access, and some patients may develop inhibitors that detrimentally affect the efficacy of this therapy.²⁸

For patients who developed inhibitors, BPAs such as activated prothrombin complex concentrate (aPCC) and recombinant activated FVII (rFVIIa) are critical treatment options. Although lifesaving, these agents offer less predictable bleed control, carry thrombotic risk, and are limited in prophylactic use.⁶

Taken together, factor replacement therapies (SHL and EHL products) and BPAs established the foundation of modern hemophilia care. Still, inadequate bleed protection and treatment burden highlighted the need for better therapeutic interventions, setting the stage for the development of novel nonfactor and gene-based therapies.

Emerging Therapeutic Areas

Monoclonal Antibody Therapies

The first FDA approval of a nonfactor therapy for hemophilia came in 2017 with emicizumab, initially for people with hemophilia A (PwHA) with inhibitors and later in 2018 for PwHA without inhibitors.²⁰ A humanized bispecific monoclonal antibody, emicizumab binds FIXa and FX, creating a bridge between the 2 to mimic the function of missing activated FVIII in PwHA.²⁰ Details of this and other nonfactor replacement therapies’ indication, mechanism of action, mode of administration, and dosing strategies are available in Table 1.^20-22,25

Emicizumab was extensively investigated in the HAVEN clinical trials program, a series of 7 open-label, phase 3 trials evaluating emicizumab prophylaxis in PwHA with or without inhibitors.^30-36 Emicizumab was associated with significant reductions in annualized bleed rates (ABRs) relative to on-demand treatment (HAVEN 1 [NCT02622321]: 1.5 mg/kg weekly, 87%; 95% CI, 72.3%-94.3%; HAVEN 3 [NCT02847637]: 1.5 mg/kg weekly, 96%; 95% CI, 92.5%-98%; 3 mg/kg once every 2 weeks, 97%; 95% CI, 93.4%-98.3%; P < .0001 for all) and relative to prior FVIII prophylaxis (68%; 95% CI, 48.6%-80.5%, P < .0001). Reductions were also evident in PwHA with inhibitors (vs prior prophylaxis: 79%; 95% CI, 51.4%-91.1%; P = .0003) and in patients without inhibitors.²⁰

Across the HAVEN clinical trials program, a substantial proportion of patients both with or without FVIII inhibitors experienced 0 bleeding events while they were treated with emicizumab prophylaxis. By emicizumab dose, this included 62.9% (95% CI, 44.9%-78.5%), 86.4% (95% CI, 75%-94%), and 55.6% (95% CI, 38.1%-72.1%) on 1.5 mg/kg once weekly; 60% (95% CI, 42.1%-76.1%) on 3 mg/kg once every 2 weeks; and 56.1% (95% CI, 39.7%-71.5%) on 6 mg/kg once every 4 weeks. The comparable proportions among those not on emicizumab prophylaxis in these trials were 5.6% (95% CI, 0.1%-27.3%) and 0% (95% CI, 0%-18.5%). Different proportions at the same dose reflect variance across trials.²⁰

The most common adverse reactions associated with emicizumab were injection site reactions (22%, n=85), headache (15%, n=57), and arthralgia (15%, n=59). Serious thrombotic adverse reactions were evident in a small proportion of patients, observed in patients who received aPCC at high doses and for more than 24 hours for breakthrough bleeding concomitant with their emicizumab prophylaxis.²⁰ Emicizumab has become the preferred approach to prophylaxis throughout the developed world, as a standard of care for PwHA with inhibitors and as a preferred approach for PwHA without inhibitors.¹⁰

In 2024, concizumab and marstacimab also received FDA approval, both of which are monoclonal antibodies with a new mechanism of action as antagonists of tissue factor pathway inhibitor (TFPI), the primary inhibitor of the extrinsic coagulation cascade.^21,22 The safety and efficacy of concizumab prophylaxis were explored in phase 3 clinical trials in PwHA or B with inhibitors (explorer7, NCT04083781) or without inhibitors (explorer8, NCT04082429). The primary comparison was between concizumab prophylaxis and on-demand therapy. Both trials enrolled participants at least 12 years of age with hemophilia A or B. Efficacy was determined by comparing the rate of bleeding episodes between the concizumab and comparator arms.^37,38 Overall in patients with inhibitors, concizumab prophylaxis resulted in an estimated mean ABR of 1.7 (95% CI, 1.01-2.87), meeting the threshold for superiority relative to on-demand therapy for which the estimated mean ABR was 11.8 (95% CI, 7.03-19.86), an 86% reduction (P < .001).^22,37 By 24 weeks post randomization, 64% (n=21) in the concizumab arm experienced 0 bleeding episodes compared with 11% (n=2) in the on-demand therapy arm.³⁷

Results were similar in patients without inhibitors, demonstrating superiority of concizumab prophylaxis relative to no prophylaxis regardless of patients’ hemophilia A or B diagnosis.³⁸ In PwHA, the estimated mean ABR for the concizumab arm was 2.7 (95% CI, 1.63-4.59) vs 19.3 (95% CI, 11.25-33.03) in the no prophylaxis arm, an 86% reduction (P < .0001); respectively, 33% (n=6) and 0% (n=0) experienced 0 bleeding episodes.³⁸ Meanwhile in PwHB, the estimated mean ABR for the concizumab arm was 3.1 (95% CI, 1.91-5.04) vs 14.8 (95% CI, 8.14-26.86) in the no prophylaxis arm, a 79% reduction (P < .0001); the respective proportions exhibiting 0 bleeding episodes were 42% (n=10) and 8% (n=1).^22,38

Safety assessments revealed the most common adverse reactions to concizumab were injection site reactions (18%, n=6; and 7%, n=3 in explorer7 and explorer8, respectively) and urticaria (6%, n=2; and 7%, n=3, respectively).²² Several patients (1.9%, n=6) with risk factors experienced thromboembolic events while taking concizumab, warranting the suggestion to monitor patients who may be at increased risk of these events.²² Based on these outcomes, concizumab prophylaxis is approved for patients 12 years and older with hemophilia A or B with or without inhibitors.²² Note that concizumab dose optimization, which occurs 4 weeks after initiating treatment, requires measurement of the drug’s plasma concentration using an FDA-approved laboratory assay.²²

The safety and efficacy of marstacimab were evaluated in the phase 3 BASIS clinical trial (NCT03938792). Participants were males aged 12 to less than 75 years with severe hemophilia A or moderate to severe hemophilia B with or without inhibitors. Efficacy data in the form of ABR are only available for the cohort without inhibitors, with key comparisons made between marstacimab prophylaxis and patients receiving either a routine prophylactic regimen or on-demand treatment of bleeding events. Compared with on-demand therapy, marstacimab prophylaxis was associated with an overall 92% reduction in ABR evidenced by observed mean ABRs of 39.86 (95% CI, 33.05-48.07) and 3.20 (95% CI, 2.10-4.88), respectively, and meeting the threshold for superiority (P < .0001); the respective proportions of patients who exhibited 0 bleeding episodes were 3% (n=1) and 30.3% (n=10). Compared with routine prophylaxis, the observed mean ABR for marstacimab was 5.09 (95% CI, 3.40-6.78) vs 7.90 (95% CI, 5.14-10.66), an estimated ABR difference of –2.81 (95% CI, –5.42 to –0.20; P = .0349), corresponding to a 35.5% ABR reduction (95% CI, 6.2%-55.7%), which met criteria first for noninferiority, then superiority; the respective proportions of patients who exhibited 0 bleeding episodes were 39.8% (n=33) and 34.9% (n=29). This comparison was more favorable among PwHA (estimated ABR difference: –3.96; 95% CI, –7.14 to –0.77) than PwHB, which only met criteria for noninferiority (estimated ABR difference: 1.33; 95% CI, –1.47 to 4.12).³⁹

The most common adverse reactions reported in the BASIS clinical trial were injection site reactions (9%, n=11), headache (7%, n=8), and pruritus (3%, n=4). There may also be increased risk for thromboembolic events among patients prescribed marstacimab.²¹

Gene Therapies

The FDA has approved 2 commercially available gene therapies for the treatment of hemophilia: valoctocogene roxaparvovec-rvox and etranacogene dezaparvovec-dlrb for the A and B subtypes, respectively.^23,24 A third, fidanacogene elaparvovec-dzkt, received FDA approval for hemophilia B, but it is no longer commercially available in the US.⁴⁰ All 3 are adeno-associated virus (AAV) vector-based gene therapies that use the AAV5 serotype to target the liver.^23,24,41 Valoctocogene is indicated for the treatment of adults with severe hemophilia A who do not have preexisting neutralizing antibodies (NAbs) to AAV5.²⁴ Likewise, etranacogene is indicated for the treatment of adults with hemophilia B who currently use FIX prophylaxis; have current or historical life-threatening hemorrhage; or have repeated, serious spontaneous bleeding episodes, but does not exclude patients with preexisting NAbs to AAV5.²³ Both are administered only once by IV infusion after performing baseline testing to confirm patients are candidates. Patients are ineligible if they have presence or history of FVIII or FIX inhibitors.^23,24 Patients’ liver health requires special consideration given that these therapies target hepatocytes and because postinfusion immunologic injury to transduced hepatocytes may reduce the efficacy of AAV-based gene therapies.²³ Likewise, patients must be able to withstand potential post infusion immunosuppressive agents, warranting thoughtful treatment decisions among patients with conditions like HIV.^23,24

Initially approved in 2022, etranacogene delivers a copy of the gene encoding the highly active Padua variant of human FIX resulting in increased circulating FIX activity in PwHB. A clinical trial of this therapy showed that it was noninferior to standard-of-care FIX prophylaxis; during a lead-in period from month 0 to 6 after etranacogene infusion when patients were allowed to continue FIX prophylaxis, the estimated mean ABR was 4.1 (95% CI, 3.2-5.4) vs 1.9 (95% CI, 1.0-3.4) in months 7 to 18 after infusion, meeting noninferiority criteria.²³ In post infusion measurements of endogenous FIX activity,increases were apparent as early as 3 weeks after treatment (26.8% ± 12.7%), with further increases at 6 months (39.0% ± 18.7%) and sustainably increased activity through 12 and 18 months.⁴² All but 2 patients discontinued FIX prophylaxis between day 21 and month 18 post infusion; among those 2 patients, 1 received only a partial dose of etranacogene and the other had the highest AAV5 NAb titer on the day of infusion.⁴² The most common adverse reactions in safety assessments were increased alanine and aspartate aminotransferase levels (42%, n=24 each), increased blood creatinine kinase level (42%, n=24), infusion-related reactions (33%, n=19), headache (18%, n=10), and flu-like symptoms (14%, n=8); no adverse reactions were deemed serious in nature.²³

Valoctocogene was initially approved in 2023. Mechanistically, this therapy replaces missing FVIII in patients with severe hemophilia A by introducing a functional copy of a transgene encoding the B-domain deleted SQ form of human FVIII.²⁴ In a clinical trial, participants received 1 infusion of valoctocogene at a dose of 6 x 10¹³ vector genomes per kg followed by 4 weeks of FVIII prophylaxis, after which investigators weened FVIII infusions to as-needed intervention.⁴³ Results indicated the gene therapy was noninferior to FVIII prophylaxis in terms of mean ABR; between a retrospective baseline period when participants had received FVIII prophylaxis and the valoctocogene efficacy period that began at 5 weeks post infusion or after FVIII washout, the mean ABR was 5.4 and 2.6, respectively, a mean difference of –2.8 (95% CI, –4.3 to –1.2).²⁴ Safety assessments revealed the most common adverse reactions and laboratory abnormalities were increased alanine aminotransferase (ALT) level (81%, n=109; deemed a severe reaction in 1 patient), increased aspartate aminotransferase level (69%, n=92), increased lactate dehydrogenase level (57%, n=77), increased creatinine phosphokinase level (45%, n=60), nausea (31%, n=42), and fatigue (16%, n=21).²⁴

Despite these therapies being a single IV infusion, there are substantial postinfusion monitoring and lifestyle requirements; the likelihood that patients will develop liver transaminase elevations—likely triggered by an immune-mediated injury to the transduced hepatocytes—risks loss of transgene expression and may necessitate a course of immunosuppression, typically with oral corticosteroids.^23,24 These therapies have been observed to have a wide variability in degree and durability of response with some patients having to resume factor prophylaxis at variable times post dosing.^23,24,44

Antithrombin Directed Therapy with Fitusiran

On March 28, 2025, the FDA approved fitusiran for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years and older with hemophilia A or hemophilia B, with or without FVIII or FIX inhibitors.¹¹ Unlike factor replacement therapy, fitusiran does not replace missing clotting factors; instead, it is a small interfering RNA that targets hepatocytes and leads to degradation of AT mRNA, markedly reducing plasma AT levels leading to an increase in thrombin generation—an enzyme essential for blood clotting.^11,25 As prescribed, fitusiran dosing starts at 50 mg injected subcutaneously once every 2 months, usually with a single-dose prefilled pen.²⁵ Prescribers must monitor AT levels using an FDA-approved test 1, 3, 5, and 6 months after initiating patients on fitusiran or after any dose modifications.²⁵ Modifications to dosage or administration frequency should maintain AT activity between 15% and 35% with dose escalations occurring if AT activity exceeds 35% at 6 months and dose reductions 3 months after the prior dose if AT activity falls below 15%.²⁵ The INNOVANCE Antithrombin companion diagnostic test is FDA cleared and designed to accurately measure AT activity and guide treatment to maintain levels within the target range that minimizes both bleeding risk and the risk of excessive clotting.¹¹ For patients who require fitusiran dose adjustments based on AT activity, 20-mg single-dose vials are available.²⁵ Importantly, this AT-based dosing regimen (AT-DR) differs from the original dosing regimen (ODR; 80 mg once monthly) investigated in the initial phase 3 clinical trials and reflects learnings from the clinical development program toward optimizing fitusiran’s safety and efficacy.¹¹ The primary efficacy data of the clinical trials investigating the ODR appear in Table 2.^45-47 The open-label extension trial, ATLAS-OLE (NCT03754790), that investigated fitusiran AT-DR is discussed in more detail below.⁴⁸

Because investigators observed thrombotic events (1 of which was fatal) among 2.6% of participants in phase 3 trials of the fitusiran ODR, ^25,49 ATLAS-OLE proceeded with an amended dosing protocol in which participants began on 50 mg fitusiran once every 2 months adjusted as needed to 20 mg or 50 mgonce monthly, or 20 mg once every 2 months based on monthly AT activity measurements.^48,50 The actual dose adjustments as observed in ATLAS-OLE included 35.8% of patients maintained on 50 mg once every 2 months, dosing frequency increased to 50 mg once monthly in 15.7% of patients, dose decreased to 20 mg once every 2 months in 30.9% of patients, and both dose and frequency adjusted to 20 mg once monthly in 2.9% of patients; 14.7% of patients discontinued fitusiran due to more than 1 monthly AT measurement below the 15% threshold.²⁵ Dose adjustment to 10 mg once monthly or once every 2 months was not performed in ATLAS-OLE, but this dose is also approved.²⁵ The below results include integrated safety analyses that incorporated data from all participants who had received fitusiran prophylaxis in any studies of the ATLAS program and integrated efficacy analyses which incorporated ABR data from participants in the phase 3 parent studies, ATLAS-INH (NCT03417102), ATLAS-A/B (NCT03417245), and ATLAS-PPX (NCT03549871).⁴⁸

Compared with patients with inhibitors treated with on-demand BPAs, fitusiran AT-DR was associated with a significant 73.1% (95% CI, 43.4%-87.3%) reduction in ABR (P = .0006); the estimated mean ABR in these groups was 19.12 (95% CI, 11.80-30.98) and 5.14 (95% CI, 2.78-9.52), respectively. Compared with patients without inhibitors treated with on-demand factor replacement therapies, fitusiran AT-DR was associated with a significant 71.3% (95% CI, 53.0%-82.5%) reduction in ABR (P < .0001); the estimated mean ABR in these groups was 31.42 (95% CI, 20.48-48.21) and 9.01 (95% CI, 5.59-14.54), respectively. Relative to prophylactic interventions, fitusiran AT-DR was associated with a 70% ABR reduction vs prophylactic BPAs, and performed comparably to prophylactic factor replacement therapies. During the primary efficacy period of ATLAS-OLE, a total of 31.5% (n=62) of patients on fitusiran AT-DR had 0 treated bleeding events. When patients experienced a breakthrough bleed on fitusiran AT-DR, those without inhibitors required a lower mean total weight–adjusted dose of factor replacement to treat the event than did patients on factor replacement prophylaxis (FVIII: 12.0 IU/kg [SD, 6.0] vs 45.3 IU/kg [SD, 41.8]; FIX: 22.3 IU/kg [SD, 10.8] vs 73.6 IU/kg [SD, 54.7]). Likewise, patients with inhibitors on fitusiran AT-DR required a lower mean total weight–adjusted dose of aPCC or rFVIIa to treat breakthrough bleed events than patients on BPA prophylaxis (aPCC: 50.1 U/kg [SD, 32.2] vs 207.8 U/kg [SD, 373.5]; rFVIIa: 86.5 μg/kg [SD, 85.8] vs 637.3 μg/kg [SD, 1090.8].⁴⁸ Bleed management guidelines for patients who experience a breakthrough bleed while on fitusiran AT-DR suggest 10 IU/kg FVIII, 20 IU/kg FIX (SHL or EHL), 30 U/kg aPCC, or a dose of rFVIIa not to exceed 45 µg/kg. Neither SHL factor replacement nor aPCC should be repeated within 24 hours; the interval for repeat doses of EHL products is after 5 to 7 days; and that for rFVIIa is after 2 or more hours. Clinicians are advised to use their own situational judgment for breakthrough bleeds that may require higher doses, more frequent administration, or multiple repeat doses of factor replacement or BPAs.²⁵

Regarding the integrated safety analysis, ATLAS-OLE investigators took special interest in the suspected or confirmed occurrence of thrombotic events, gallbladder disease, and hepatotoxicity. In total, 1 embolic stroke (0.3%), 1 incidental cerebral infarction (0.3%), 1 postoperative venous thrombosis (0.3%), and 1 postoperative deep vein thrombosis (0.3%) were noted among participants assigned to fitusiran AT-DR, the 4 events corresponding to an exposure adjusted incidence rate (EAIR) of 0.82 per 100 patient-years and 3 events deemed unrelated to fitusiran treatment by the investigator. The comparable statistics for thrombotic events among participants who received only the ODR was 2.6% (n=7), corresponding to an EAIR of 2.28 per 100 patient-years. Acute and recurrent gallbladder disease including cholelithiasis and cholecystitis was apparent in 3.8% (n=11), corresponding to an EAIR of 2.26 per 100 patient-years, and 0.3% (n=1) underwent cholecystectomy.⁴⁸ Finally, 3.4% (n=10) of patients treated with fitusiran AT-DR had at least 1 ALT value greater than 3 times the upper limit of normal with a median onset of 89 days after initial dosing (range, 15-768 days).^25,48 Otherwise, the most common adverse reactions reported among patients treated with fitusiran AT-DR included viral infection (29%, n=83), nasopharyngitis (26%, n=74), and bacterial infections (11%, n=31).²⁵

Additional outcomes of interest reported at the interim data cutoff for ATLAS-OLE included secondary end points measuring health-related quality of life (HRQOL) and annualized spontaneous bleeding rate (AsBR). As for the primary efficacy outcome, secondary end point data were integrated across the parent phase 3 studies and the -OLE. For HRQOL, participants 17 years or older completed the Haemophilia Quality-of-Life Questionnaire for Adults (Haem-A-QoL) at baseline and again at their final visit to receive fitusiran AT-DR. Compared with on-demand factor replacement therapies, integrated HRQOL results showed significantly improved transformed physical health score within the fitusiran AT-DR group (least squares mean change, −12.00 [95% CI, −18.10 to −5.90] vs −3.84 [95% CI, −8.73 to 1.06] P = .025); relative to participants who received on-demand BPAs, investigators observed improved transformed physical health score in the fitusiran AT-DR group, but this did not reach statistical significance (least squares mean change, −8.72 [95% CI, −17.08 to −0.35] vs −5.03 [95% CI −9.23 to −0.83] P = .453). In addition, fitusiran was associated with a significantly lower estimated mean AsBR than on-demand BPA in patients with inhibitors (3.11 [95% CI, 1.78-5.43] vs 17.09 [95% CI, 9.87-29.60] P < .001) and a lower rate compared to on-demand factor replacement therapy in patients without inhibitors (5.40 [95% CI, 3.65-7.97] vs 20.99 [95% CI, 13.95-31.59] P < .001). Relative to prophylactic factor replacement or BPA therapy, the estimated mean AsBR in the fitusiran AT-DR group was numerically lower, but this did not reach statistical significance (4.16 [95% CI, 2.71-6.39] vs 5.14 [95% CI, 3.58-7.37] P = .4449).⁴⁸

The ability to undergo routine surgery has been described as one of the steps toward a functional cure for PwH.¹⁵ To that end, investigators evaluated all major surgeries that occurred during the fitusiran clinical development program through June 2023. They rated the degree of hemostatic control on the day of the operation through postoperative day 14.⁵¹ These ratings were excellent/good in 89% of cases that followed the bleed management guidelines and 100% of cases without bleed management guidelines. Post-operative thrombotic events occurred in 2 participants for whom bleed management guideline doses were exceeded.⁵¹ Alongside the earlier results supporting good tolerance and clinically meaningful bleed protection among participants on fitusiran AT-DR,^11,48 these results support quality-of-life benefits and clinically meaningful steps toward a functional cure irrespective of patients’ hemophilia subtype and inhibitor status.

Managed Care Considerations

Evolving Guidelines and Treatment Goals

Although the 2020 WFH guidelines remain a cornerstone in hemophilia management, their timing precludes inclusion of therapies approved after 2020. In the absence of updated guidance, hemophilia care in managed care settings should continue to prioritize the overarching treatment goals articulated by WFH. These include advancing health equity, supporting access to treatments that align with the patient’s lifestyle while maintaining safety and efficacy, improving patient-reported outcomes, and reducing caregiver burden.⁶ In turn, the evolving therapeutic landscape highlights the need for payers and providers to consider updates to clinical pathways so that coverage decisions reflect the realities of new treatment paradigms.

Balancing Efficiency and Resource Optimization

Knowing treatment efficiency remains a central factor to payer decision-making, nonfactor replacement therapies are associated with opportunities for resource optimization. For example, emicizumab use has been associated with fewer and less severe bleeds, along with fewer hospitalizations related to breakthrough bleeds, suggesting potential to reduce downstream acute care needs.⁵² By stabilizing bleeding risk, these therapies can also reduce the need for factor replacement products or BPAs in many patients, thereby decreasing reliance on expensive acute interventions.⁶ As previously discussed, patients on fitusiran AT-DR required less BPAs or factor replacement products to control breakthrough bleeds.^48,53 Likewise, patients on fitusiran AT-DR had markedly reduced mean annualized weight–adjusted consumption of BPAs or factor replacement products relative to patients on a BPA or factor replacement prophylaxis regimen (Table 3).⁵³ Additionally, nonfactor therapies may contribute to reduced drug wastage, particularly when these options have doses that directly correspond with pen device or vial-size availability.⁵⁴

Broad Applicability Across Populations

Another critical consideration in managed care evaluation is the breadth of patient populations eligible for treatment. Certain nonfactor therapies are approved for use in both hemophilia A and B, with or without inhibitors.^21,22,25 This broad applicability provides added value from a formulary perspective by reducing the need for highly segmented coverage decisions and supporting consistent access across heterogeneous patient populations.

Administration and Adherence Implications

The mode and frequency of treatment administration are increasingly important factors in payer and provider deliberations. Traditional factor replacement and BPAs require frequent IV infusions, often multiple times per week, which carry a high treatment burden and may negatively affect adherence over time.⁶ Among others, considerations like venous access, therapy storage locations, and patients’ ability to accurately calculate therapeutic doses and keep records affect whether self-managed home therapy with these products may be effectively implemented.⁶ In the absence of adequate patient education, training, or ability to self-manage at home, patients could go without treatment or seek factor replacement or BPA therapy in a clinical setting where treatment of acute breakthrough bleeds may be delayed or undertreated.²⁷ Moreover, therapy preparation and infusion time have been cited as problematic even among patients and caregivers who engage in home self-management.⁵⁵ It follows that these issues and any associated poor treatment adherence may be compounded if patients must frequently travel to a clinical setting due to the considerable time and effort required.

In contrast, nonfactor replacement therapies are administered subcutaneously, most of which have flexible dosing schedules ranging from once weekly to once every 2 months.^20,21,25 Concizumab is administered daily, but still via subcutaneous injection like other nonfactor therapies.²² This route of administration reduces caregiver and patient burden and has the potential to support higher rates of treatment adherence.⁶ Of note, a web-based survey among adult PwH and caregivers of children with hemophilia found treatment frequency, reducing ABR, and change from IV to subcutaneous administration among the most impactful attributes contributing to patients’ treatment preference.⁵⁶ In a separate, survey-based study, results showed that both adult PwH and caregivers of children with hemophilia rated a hypothetical treatment administered subcutaneously every 2 months at home as the least burdensome.⁵⁷ These practical advantages translate into improved quality of life for patients and may reduce costs related to treatment discontinuation or complications from poor adherence.^6,32

Conclusions

Hemophilia care is amid a transformative shift, expanding beyond the long-standing reliance on factor replacement toward innovative therapies that address both improved clinical outcomes and quality of life.^10,11,26,48 Treatment goals have likewise evolved, with greater emphasis on achieving zero bleeds, minimizing treatment burden, and enabling people with hemophilia to fully participate in education, work, and daily life.^6,16 Shared decision-making is becoming increasingly central to these efforts, and individualized treatment strategies support optimization of both safety and efficacy.^11,58 Nonfactor replacement therapies exemplify this paradigm shift by offering effective prophylaxis with subcutaneous administration and/or less frequent dosing,^20-22 which can ease the burden of treatment while supporting adherence.⁶ Among these, fitusiran introduces a novel mechanism of action by targeting AT to enhance thrombin generation, providing a new option for patients with hemophilia A or B, with or without inhibitors.²⁵

As these advances reshape the standard of care, managed care and policy frameworks must adapt to ensure timely access and affordability. At the same time, ongoing updates to clinical guidelines and care pathways are essential to capture the rapidly evolving therapeutic landscape and to promote equitable, evidence-based care for all individuals living with hemophilia A or B, with or without inhibitors.

Authorship Affiliation: Department of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI

Source of Funding: This supplement was supported by Sanofi.

Author Disclosures: Dr Pipe reports consultancies or paid advisory boards at the invitation of Bayer, BioMarin, CSL Behring, Chugai, HEMA Biologics, Inovio, LFB, Metagenomi, Novo Nordisk, Pfizer, Roche/Genentech/Spark Therapeutics, Sanofi, Star Therapeutics, and Takeda. He further reports receipt of lecture fees for speaking at the invitation of Roche, Sanofi, and Chugai; meeting/conference attendance on behalf of Sanofi; and service on Scientific Advisory Boards for GeneVentiv and Equilibra.

Authorship Information: Dr Pipe was responsible for concept and design, acquisition of data, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, and supervision.

Address Correspondence to: Steven W. Pipe, MD, 1500 E Medical Center Drive, MPB D4206, Ann Arbor, MI 48197. Email: ummdswp@med.umich.edu

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