Correlation of antigen expression with epigenetic modifications after rAAV delivery of a human factor IX variant in mice and rhesus macaques.

We investigated long-term human coagulation factor IX (huFIX) expression of a novel variant when delivered into mice and rhesus macaques and compared transduction efficiencies using two different adeno-associated virus (AAV) capsids. In hemophilic mice injected with KP1-packaged recombinant AAV (rAAV) expressing the hyperactive FIX variant specific activity plasma levels were 10-fold or 2-fold enhanced when compared with wild-type or Padua huFIX injected mice, respectively. In rhesus macaques AAV-LK03 capsid outperformed AAV-KP1 in terms of antigen expression and liver transduction. Two animals from each group showed sustained low-level huFIX expression at 3 months after administration, while one animal from each group lost huFIX mRNA and protein expression over time, despite comparable vector copies. We investigated whether epigenetic differences in the vector episomes could explain this loss of transcription. Cut&Tag analysis revealed lower levels of activating histone marks in the two animals that lost expression. When comparing rAAV genome associated histone modifications in rhesus macaques with those in mice injected with the same vector, the activating histone marks were starkly decreased in macaque-derived episomes. Differential epigenetic marking of AAV genomes may explain different expression profiles in mice and rhesus macaques, as well as the wide dose response variation observed in primates in both preclinical and human clinical trials.

Stable transduction of the neonatal mouse liver using a hybrid rAAV/sleeping beauty transposon gene delivery system.

BACKGROUND: Conventional adeno-associated viral (AAV) vectors, while highly effective in quiescent cells such as hepatocytes in the adult liver, confer less durable transgene expression in proliferating cells owing to episome loss. Sustained therapeutic success is therefore less likely in liver disorders requiring early intervention. We have previously developed a hybrid, dual virion approach, recombinant AAV (rAAV)/piggyBac transposon system capable of achieving stable gene transfer in proliferating hepatocytes at levels many fold above conventional AAV vectors. An alternative transposon system, Sleeping Beauty, has been widely used for ex vivo gene delivery; however liver-targeted delivery using a hybrid rAAV/Sleeping Beauty approach remains relatively unexplored. METHODS: We investigated the capacity of a Sleeping Beauty (SB)-based dual rAAV virion approach to achieve stable and efficient gene transfer to the newborn murine liver using transposable therapeutic cassettes encoding coagulation factor IX or ornithine transcarbamylase (OTC). RESULTS: At equivalent doses, rAAV/SB100X transduced hepatocytes with high efficiency, achieving stable expression into adulthood. Compared with conventional AAV, the proportion of hepatocytes transduced, and factor IX and OTC activity levels, were both markedly increased. The proportion of hepatocytes stably transduced increased 4- to 8-fold from <5%, and activity levels increased correspondingly, with markedly increased survival and stable urinary orotate levels in the OTC-deficient Spfash mouse following elimination of residual endogenous murine OTC. CONCLUSIONS: The present study demonstrates the first in vivo utility of a hybrid rAAV/SB100X transposon system to achieve stable long-term therapeutic gene expression following delivery to the highly proliferative newborn mouse liver. These results have relevance to the treatment of genetic metabolic liver diseases with neonatal onset.

Prophylactic Treatment of Children with Hemophilia in Sweden.

Hemophilia A/B are caused by deficiency or lack of coagulation factors VIII (FVIII) or factor IX (FIX), respectively, in plasma. A person with hemophilia develops bleeding in the joints and muscles at an early age, which, if left untreated, leads to early arthropathy. Preventive treatment can be achieved by regular (prophylactic) administration of FVIII/FIX. In 1958, this was implemented on a small scale in Sweden with FVIII in patients with severe hemophilia A, and in those with hemophilia B in 1972 when FIX became available. However, there were problems with human immunodeficiency virus and hepatitis infection from contaminated blood products. In the 1990s, recombinant FVIII and FIX concentrates were introduced. The major remaining problems then were the development of inhibitors, and the need for a venous route for the injections in very young children. High-titer inhibitors were treated by immune tolerance induction according to a modified model of the original Bonn high-dose protocol. A central venous line, i.e., Port-A-Cath, has enabled early prophylaxis in many children with poor venous access and has enabled the early start of home treatment with adequate injection frequency. Scoring systems for X-rays, magnetic resonance imaging, and function of joints were developed early in Sweden and have been widely disseminated worldwide, partly with modifications. Extended half-life products with half-life increased three to five times have been developed, which can provide superior bleed protection when dosed once-weekly and can maintain therapeutic trough levels when administered less frequently. The ultimate prophylaxis therapy in the future may be gene therapy.

Identifying hemophilia B carriers: Utility of aPTT, factor IX levels and ratios of factor IX to other Vitamin K dependent factors.

INTRODUCTION: Diagnosing hemophilia B (HB) carrier status is important to manage bleeding in carriers and to prevent bleeding in potential offspring. Without a family history of hemophilia, diagnosing HB carrier status is challenging. Genetic testing is the gold-standard, however it is reserved for individuals with a high suspicion of carrier status. AIMS: To describe the distribution of activated partial thromboplastin time (aPTT) and factor IX coagulant (FIX:C) levels in HB carriers and assess the ratio of FIX:C to other Vitamin K dependent factors (FII:C, FVII:C, FX:C) as an indicator of HB carrier status. METHODS: In this retrospective, single-centre cohort study, subjects were included if they were obligate or genetically proven HB carriers. Distributions of aPTT and FIX:C were described and the relationship between FIX:C levels in carriers and severity of familial HB was analysed. Ratios of FIX:C to FII:C, FVII:C, FX:C were calculated. RESULTS: Seventy-two female HB carriers (median age: 34 years; IQR 24-43) were included. Median aPTT and FIX:C levels were 33.0 s [IQR 30.0-37.0] and 57 IU/dL [IQR 43-74]. Fifteen carriers (21%) had mild HB (FIX:C levels of 10-40 IU/dL). FIX:C levels trended higher in carriers of mild HB versus carriers of moderate/severe HB. In six carriers, the median ratio of FIX:C to other Vitamin K dependent factors was 0.44, with 92% of ratios being ≤ 0.75. CONCLUSION: aPTT and FIX:C levels were unreliable in diagnosing HB carrier status. A low ratio of FIX:C to other Vitamin K dependent factors may be a useful marker of HB carrier status.

Genetic variant detection in a South African haemophilia B population.

BACKGROUND: Haemophilia B is characterised by a deficiency of factor IX (FIX) protein due to genetic variants in the FIX gene (F9). Genetic testing may have a vital role in effectively managing haemophilia B. However, in many developing countries, comprehensive genetic variant detection is unavailable. This study aimed to address the lack of genetic data in our country by conducting genetic variant detection on people affected by haemophilia B in our region. METHODS: Twenty-one participants were screened with a direct Sanger sequencing method to identify variants in the F9 gene. The identified variants were then compared to previously published variants and/or to a reference database. RESULTS AND DISCUSSION: A total of ten F9 genetic changes were detected, with five of them being novel. These identified variants were distributed across different domains of the FIX protein. Only one participant had a history of inhibitor formation against FIX replacement therapy. Notably, this participant had two distinct genetic changes present adjacent to each other. Thus, we hypothesise that the presence of multiple variants within the same functional region of the gene may increase the risk for inhibitor development. CONCLUSION: The discovery of novel pathogenic variations in the F9 gene highlights the importance of genetic analysis in specific geographical regions. The possible link between a complex variant and inhibitor formation illustrates the potential role that genetic screening has as a pre-treatment tool in predicting treatment reactions and outcomes.

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

INTRODUCTION: The advent of therapeutic recombinant factor VIII (FVIII) and factor IX (FIX) protein infusions revolutionized the care of persons with haemophilia in the 1990s. It kicked off an era with the increasing use of prophylactic factor infusions for patients and transformed conversations around the ideal trough activity levels as well as the ultimate goals in tailored, individualized care. Our knowledge surrounding the immunologic basis of inhibitor development and treatment derives from a time when patients were receiving frequent factor infusions and focused on immune tolerance induction following inhibitor development. DISCUSSION: More recently, care was revolutionized again in haemophilia A with the approval of emicizumab, a bispecific antibody mimicking activated FVIII function, to prevent bleeding. The use of emicizumab prophylaxis has resulted in a significantly slower accumulation of factor exposure days and continued effective prophylaxis in the case of inhibitor development. While emicizumab is effective at reducing the frequency of bleeding events in patients with haemophilia A, management of breakthrough bleeds, trauma, and surgeries still requires additional treatment. Ensuring that FVIII is a therapeutic option, particularly for life-threatening bleeding events and major surgeries is critical to optimizing the care of persons with haemophilia A. Other novel non-factor concentrate therapies, including rebalancing agents, will dramatically change the landscape for persons with haemophilia B with inhibitors. CONCLUSION: This review discusses the changing landscape regarding the timing of inhibitor development and management strategies after inhibitor development, stressing the importance of education across the community to continue to vigilantly monitor for inhibitors and be prepared to treat persons with inhibitors.

Effect of etranacogene dezaparvovec on quality of life for severe and moderately severe haemophilia B participants: Results from the phase III HOPE-B trial 2 years after gene therapy.

INTRODUCTION: For people with haemophilia B (PwHB), bleeding may occur despite prophylaxis, negatively affecting health-related quality of life (HRQoL). The pivotal phase 3 HOPE-B trial investigating the adeno-associated virus gene transfer product, etranacogene dezaparvovec (EDZ), demonstrated sustained factor IX (FIX) activity and bleed protection in PwHB with baseline FIX levels ≤2%. AIM: Assess how EDZ affects HRQoL in HOPE-B trial participants. METHODS: HRQoL was evaluated using generic and disease-specific patient reported outcomes (PROs) including the EQ-5D-5L and the Hem-A-QoL questionnaires. Mean domain and total scores were compared 6 months pre- and the first 2 years post-EDZ administration using repeated measures linear mixed models. The percentage of participants with minimal clinically important improvements in HRQoL was also evaluated. RESULTS: Two years post-EDZ, there were nominally significant increases in the least squares (LS) mean score for the EQ-5D-5L Index Value (.04; p = .0129), reflecting better HRQoL. Nominally significant decreases in the LS mean scores, reflecting better HRQoL, were also found for the Hem-A-QoL total score (-6.0; p < .0001) and the Treatment (-13.94; p < .0001), Feelings (-9.01; p < .0001), Future (-6.45; p = .0004) and Work/School (-5.21; p = .0098) domains. The percentage of participants with ≥15-point improvement ranged from 45.83% (95% CI: 31.37%, 60.83%) for Treatment to 13.89% (95% CI: 4.67%, 29.50%) for Family Planning. Results were similar for Year 1. CONCLUSION: In conclusion, gene therapy with EDZ improved HRQoL in the first and second years in several Hem-A-QoL domains, including Treatment, Feelings, Work/School and Future domains, whereas improvement in other aspects of HRQoL were not demonstrated.

Recombinant factor IX Fc for the treatment of hemophilia B.

Current hemophilia B treatment guidelines recommend routine prophylaxis with factor IX (FIX) replacement products, tailored to maintain plasma activity at levels that will prevent bleeds. However, plasma FIX activity may not be the primary determinant or best indicator of hemostatic efficacy due to its extravascular distribution. FIX replacement therapy has evolved to include extended half-life (EHL) products that provide effective bleed protection when administered at intervals of 7 days or longer. rFIXFc is a recombinant fusion protein with an extended circulation time. rFIXFc has a biodistribution profile consistent with distribution into extravascular space, where it may support hemostasis at sites of vessel injury independent of circulating plasma activity levels. The safety and efficacy of rFIXFc prophylaxis is well established in adults, adolescents and children including previously untreated patients with hemophilia B, with substantial evidence from clinical trials and real-world clinical practice. This review describes the pharmacokinetic characteristics of rFIXFc, summarizes available safety and efficacy data, and evaluates the use of rFIXFc in special populations. Current hemophilia B treatment challenges, including target FIX plasma levels, perioperative use, and management of patients with comorbidities, are discussed together with the potential role of EHL products in the future treatment landscape of hemophilia B.

Pattern of use and clinical outcomes with rIX-FP in pediatric/adolescent patients with haemophilia B in Italy: Results from IDEAL real-world study.

OBJECTIVES: To evaluate pattern of use and clinical outcomes in pediatric/adolescent patients enrolled in the IDEAL study. METHODS: This post-hoc analysis of IDEAL retrospective-prospective observational study focused on patients <18 years, 100% on prophylaxis during the entire observation period. RESULTS: Thirteen subjects (median age 10.0 years; 61.5% ≤ 11 years) were analyzed. The infusion frequency changed from 2/week in 84.6% (N = 11) of patients with previous rFIX, to less than 1/weekly in 76.9% (N = 9) with rIX-FP and the annualized number of infusions reduced of 57% (p = .002), from a mean ± SD of 95.1 ± 22.77 to 40.4 ± 6.79, respectively. Annualized mean consumption decreased of about 56% (p = .001), from 3748.4 ± 1155.40 IU/kg with previous rFIX, to 1656.8 ± 456.63 IU/kg of rIX-FP. Mean FIX trough level changed from 3.0% ± 1.98% to 10.92% ± 3.6%. Low mean Annualized Bleeding Rate was maintained across all prophylaxis regimens (0.8 ± 1.69 vs. 0.3 ± 0.89) and zero bleeding patients moved from 69.2% (N = 9) with previous rFIX to 84.6% (N = 11) with rIX-FP (p = .63). Two adverse events, none related to rIX-FP, occurred in two patients. No inhibitors development was reported. CONCLUSIONS: The results in this pediatric/adolescent subgroup support rIX-FP prophylaxis may reduce infusion frequency, while providing high FIX trough levels, stable annualized bleeding rate and a good safety profile.

Genotype-phenotype analyses of Iranian patients with hemophilia B (Leyden -) and hemophilia B (Leyden +): A single-center study.

BACKGROUND: There is a high prevalence of inherited bleeding disorders in Iran, such as hemophilia A (HA) and hemophilia B (HB). This study aimed to analyze the molecular and clinical profiles of patients with HB. METHODS: A single-center study was conducted among patients with severe HB between March 20, 2000, and June 31, 2023. The polymerase chain reaction (PCR) amplification was used for all of the major regions, such as the promoter, the exons, the adjacent intronic regions, and the untranslated regions of the F9 gene. Finally, Sanger sequencing was performed on the PCR products. RESULTS: A total of 111 HB patients (17 with HB [Leyden +] and 94 with HB [Leyden -]) were enrolled in this study. Among 94 patients with HB (Leyden -), 59 (62.8 %) had missense, 21 (22.3 %) had nonsense, and 8 (8.5 %) had frameshift mutations. Moreover, the most frequent pathogenic variant in HB (Leyden +) was c.-17 A>G in this study. CONCLUSION: The results of this study confirm that HB is caused by a wide range of molecular defects in Iran. Thus, by knowing the genotypes and phenotypes, we would be able to stratify the patients which is important in terms of their management and outcome.

Trends in the Use of Recombinant Activated Factor VII and Prothrombin Complex Concentrate in Heart Transplant Patients in Virginia.

OBJECTIVES: To explore trends in intraoperative procoagulant factor concentrate use in patients undergoing heart transplantation (HTx) in Virginia. Secondarily, to evaluate their association with postoperative thrombosis. DESIGN: Patients who underwent HTx were identified using a statewide database. Trends in off-label recombinant activated factor VII (rFVIIa) use and on-label and off-label prothrombin complex concentrate (PCC) use were tested using the Mantel-Haenszel test. Multivariate logistic regression was used to test for an association between procoagulant factor concentrate administration and thrombosis. SETTING: Virginia hospitals performing HTx. PARTICIPANTS: Adults undergoing HTx between 2012 and 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 899 patients who required HTx, 100 (11.1%) received off-label rFVIIa, 69 (7.7%) received on-label PCC, and 80 (8.9%) received off-label PCC. There was a downward trend in the use of rFVIIa over the 10-year period (p = 0.04). There was no trend in on-label PCC use (p = 0.12); however, there was an increase in off-label PCC use (p < 0.001). Patients who received rFVIIa were transfused more and had longer cardiopulmonary bypass time (p < 0.001). Receipt of rFVIIa was associated with increased thrombotic risk (odds ratio [OR] 1.92; 95% CI 1.12-3.29; p = 0.02), whereas on-label and off-label PCC use had no association with thrombosis (OR 0.98, 95% CI 0.49-1.96, p = 0.96 for on-label use; and OR 0.61, 95% CI 0.29-1.30, p = 0.20 for off-label use). CONCLUSIONS: Use of rFVIIa in HTx decreased over the past decade, whereas off-label PCC use increased. Receipt of rFVIIa was associated with thrombosis; however, patients who received rFVIIa were more severely ill, and risk adjustment may have been incomplete.

Retrospective Comparison of Recombinant Activated Factor VII Versus 4-Factor Prothrombin Complex Concentrate in Cardiac Surgical Patients.

OBJECTIVES: To compare the incidences of postoperative thrombotic complications, transfusion of blood products, and chest tube output in congenital cardiac surgical patients who received either recombinant activated factor VII (rFVIIa) or 4-factor prothrombin complex concentrate (4F-PCC). DESIGN: We performed a retrospective study. SETTING: Patients who underwent surgery at a tertiary academic hospital. PARTICIPANTS: Pediatric patients who underwent cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were obtained from the Society of Thoracic Surgeons and the Pediatric Cardiac Critical Care Consortium databases, as well as from manual chart review. Adjusted p values were obtained from multivariate regression using age (days), surgeon (number), cardiopulmonary bypass time (minutes), and need for deep hypothermic circulatory arrest (yes/no). A total of 55 patients were included in the 4F-PCC group, and 89 in the rFVIIa group. The median dose of rFVIIa was 77 mcg/kg (46-88), and the median dose of 4F-PCC was 31 IU/kg (24-43). The incidences of thrombotic complications were 8% in the 4F-PCC group and 30% in the rFVIIa group (adjusted p = 0.023). No difference was reported between the groups regarding chest tube output on days 1 and 2 or transfusion of blood products. Using a sensitivity analysis with propensity matching, the incidence of thrombosis was 10% in the 4F-PCC group (n = 38), and 31% in the rFVIIa group (n = 39) (p = 0.036). No difference was reported in terms of bleeding or transfusion. CONCLUSIONS: This retrospective study suggested that the administration of rFVIIa was associated with a higher risk of thrombotic complications when compared to 4F-PCC, without benefits in terms of bleeding and transfusions.

[Haemophilia B therapy: impact of the reimbursability of a long-acting recombinant factor on pharmaceutical expenditure in Italy]. / Terapia dell'emofilia B: impatto dell'ammissione alla rimborsabilità di un fattore ricombinante long-acting sulla spesa farmaceutica in Italia.

OBJECTIVES: to assess the variability in expenditure compared to 2022 assuming different rates of shifting of therapy days from current active ingredients used for the treatment of haemophilia B to nonacog beta pegolDesign: descriptive cross-sectional study. SETTING AND PARTICIPANTS: consumption in the year 2022 (data source: Medicines Utilisation Monitoring Centre, Italian Medicines Agency) of all medicinal products available in Italy containing coagulation factor IX. MAIN OUTCOMES MEASURES: for each active ingredient, the total number of therapy days and the variability in expenditure compared to 2022 were estimated on the basis of a switch of therapy days, between 5% and 20%, to nonacog beta pegol. RESULTS: on the basis of considered scenarios, the analysis shows that the total annual expenditure for clotting factors used in the treatment of haemophilia B could remain at most unchanged or reduced. Particularly, the extent of the reduction in spending could vary from 0.11% to 2.26%. This trend would be in contrast to the stable increase seen in recent years, particularly in 2022. CONCLUSIONS: this predictive spending assessment may be useful in evaluating the economic impact from new treatment options, such as etranacogene dezaparvovec gene therapy already approved by the European Medicines Agency and the Food and Drug Administration, and to improve pharmaceutical governance.

Multimodal mechanisms of pathogenic variants in the signal peptide of FIX leading to hemophilia B.

ABSTRACT: Signal peptide (SP) is essential for protein secretion, and pathogenic variants in the SP of factor IX (FIX) have been identified in hemophilia B (HB). However, the underlying mechanism for the genotype-phenotype correlation of these variants has not been well studied. Here, we systematically examined the effects of 13 pathogenic point variants in the SP of FIX using different approaches. Our results showed that these point variants lead to HB by missense variants and/or aberrant premessenger RNA (pre-mRNA) splicing. The missense variants in a hydrophobic core (h-region) mainly affected the cotranslational translocation function of the SP, and those in C-terminal containing cleavage site (c-region) caused FIX deficiency mainly by disturbing the cotranslational translocation and/or cleavage of the SP. Almost absolute aberrant pre-mRNA splicing was only observed in variants of c.82T>G, but a slight change of splicing patterns was found in variants of c.53G>T, c.77C>A, c.82T>C, and c.83G>A, indicating that these variants might have different degrees of impact on pre-mRNA splicing. Although two 6-nt deletion aberrant pre-mRNA splicing products caused FIX deficiency by disturbing the SP cleavage, they could produce some functional mature FIX, and vitamin K could increase the secretion of functional FIX. Taken together, our data indicated that pathogenic variants in the SP of FIX caused HB through diverse molecular mechanisms or even a mixture of several mechanisms, and vitamin K availability could be partially attributed to varying bleeding tendencies in patients carrying the same variant in the SP.

Hemophilia B and gene therapy: a new chapter with etranacogene dezaparvovec.

ABSTRACT: The US Food and Drug Administration (FDA)'s authorization of etranacogene dezaparvovec (Hemgenix) is a significant milestone, constituting not only the first FDA approval of a gene therapy for hemophilia but also the first approval of a liver-targeted adeno-associated virus vector gene therapy. This review summarizes the nonclinical studies and clinical development that supported regulatory clearance. Similar to other gene therapies for single gene disorders, both the short-term safety and the phenotypic improvement were unequivocal, justifying the modest-sized safety and efficacy database, which included 57 participants across the phase 2b (3 participants) and phase 3 (54 participants) studies. The most common adverse reactions included liver enzyme elevation, headache, flu-like symptoms, infusion-related reactions, creatine kinase elevation, malaise, and fatigue; these were mostly transient. One participant had hepatocellular carcinoma on a study-mandated liver ultrasound conducted 1 year after vector infusion; molecular analysis of the resected tumor showed no evidence of vector-related insertional mutagenesis as the etiology. A remarkable 96% of participants in the phase 3 trial were able to stop factor IX (FIX) prophylaxis, with the study demonstrating noninferiority to FIX prophylaxis in terms of the primary end point, annualized bleeding rate. Key secondary end points such as the annualized infusion rate, which declined by 97%, and the plasma FIX activity level at 18 months after infusion, with least squares mean increase of 34.3 percentage points compared with baseline, were both clinically and statistically significant. The FDA's landmark approval of Hemgenix as a pioneering treatment for hemophilia stands on the shoulders of >20 years of gene therapy clinical research and heralds a promising future for genomic medicines.

AAV mediated gene therapy for haemophilia B: From the early attempts to modern trials.

Early gene therapy clinical trials for the treatment of Haemophilia B have been instrumental to our global understanding of gene therapy and have significantly contributed to the rapid expansion of the field. The use of adeno-associated viruses (AAVs) as vectors for gene transfer has successfully led to therapeutic expression of coagulation factor IX (FIX) in severe haemophilia B patients. Expression of FIX has remained stable following a single administration of vector for up to 8 years at levels that are clinically relevant to reduce the incidence of spontaneous bleeds and have permitted a significant change in the disease management with reduction or elimination of the need for coagulation factor concentrates. These trials have also shed light on several concerns around AAV-mediated gene transfer such as the high prevalence of pre-existing immunity against the vector capsid as well as the elevation of liver transaminases that is associated with a loss of FIX transgene expression in some patients. However, this field is advancing very rapidly with the development of increasingly more efficient strategies to overcome some of these obstacles and importantly raise the possibility of a functional cure, which has been long sought after. This review overviews the evolution of gene therapy for haemophilia B over the last two decades.

Analysis of long-term clinical and cost impact of etranacogene dezaparvovec for the treatment of hemophilia B population in the United States.

INTRODUCTION: Etranacogene dezaparvovec (EDZ), Hemgenix, is a gene therapy recently approved for people with hemophilia B (PwHB). OBJECTIVE: To estimate long-term clinical impact and cost of EDZ in the United States (US). METHODS: A decision-analytic model was developed to evaluate the long-term impact of introducing EDZ for PwHB over a 20-year time horizon. Factor IX (FIX) prophylaxis comparator was a weighted average of different FIX prophylaxis regimens based on US market share data. We compared a scenario in which EDZ is introduced in the US versus a scenario without EDZ. Clinical inputs (annualized FIX-treated bleed rate; adverse event rates) were obtained from HOPE-B phase 3 trial. EDZ durability input was sourced from an analysis predicting long-term FIX activity with EDZ. EDZ one-time price was assumed at $3.5 million. Other medical costs, including FIX prophylaxis, disease monitoring, bleed management, and adverse events were from literature. The model estimated annual and cumulative costs, treated bleeds, and joint procedures over 20 years from EDZ introduction. RESULTS: Approximately 596 PwHB were eligible for EDZ. EDZ uptake was estimated to avert 11,282 bleeds and 64 joint procedures over 20 years. Although adopting EDZ resulted in an annual excess cost over years 1-5 (mean: $53 million annually, total $265 million), annual cost savings were achieved beginning in year 6 (mean: $172 million annually; total $2.58 billion in years 6-20). The total cumulative 20-year cost savings was $2.32 billion, with cumulative cost savings beginning in year 8. CONCLUSION: Introducing EDZ to treat PwHB is expected to result in cost savings and patient benefit over 20 years. Initiating PwHB on EDZ sooner can produce greater and earlier savings and additional bleeds avoided. These results may be a conservative estimate of the full value of EDZ, as PwHB would continue to accrue savings beyond 20 years.

This analysis assessed the long-term clinical and financial impact of introducing EDZ in the United States of America for people with severe or moderately severe hemophilia B. A decision-analytic model was developed comparing a scenario with EDZ and one without EDZ over 20 years. Introducing EDZ would avert 11,292 bleeds and 64 joint procedures over 20 years and would achieve cumulative cost savings in year 8, with a total cumulative 20-year cost saving of $2.32 billion.

The impact of capping health system cost savings on the projected cost-effectiveness of etranacogene dezaparvovec compared with factor IX prophylaxis for the treatment of hemophilia B.

This viewpoint discusses cost-effectiveness estimates for EtranaDez, a gene therapy for hemophilia B, using the Institute for Clinical and Economic Review's (ICER) framework for single and short-term therapies (SSTs). EtranaDez offers long-term benefits from a single administration, in contrast to the high costs and frequent dosing required by current factor IX prophylaxis. However, the projected gains in health from EtranaDez are small relative to the cost implications of the therapy, and consequently, how the cost offsets associated with EtranaDez are counted has a substantial impact on assessing its cost-effectiveness. Strategies for assessing cost offsets used in the ICER SST framework include a 50/50 cost-sharing model between the health care system and the manufacturer and a cap of $150,000 annually on health care cost offsets. Results from the standard full cost-offset analysis as reported by ICER depicted EtranaDez as a dominant therapy with substantial cost savings compared with factor IX prophylaxis. However, while considering the ICER SST framework, particularly the $150,000 annual cap scenario, the cost-effectiveness was significantly reduced. The incremental cost-effectiveness ratio varied notably between these scenarios, challenging the conventional perception of value of gene therapy in health care. These cost-sharing scenarios highlight the potential of the ICER SST framework to help curtail inefficient health care spending. In cases in which the cost of existing treatment is exceedingly high, the application of such frameworks would improve efficiency in resource allocation, fostering a balance between incentives for innovation and economic sustainability in managed care systems.

Assessing health plan payer's budget impact of etranacogene dezaparvovec for the treatment of hemophilia B in the United States.

BACKGROUND: Etranacogene dezaparvovec is a recently approved gene therapy for people with hemophilia B (PwHB). Current standard of care is prophylaxis with factor IX (FIX) to prevent bleeding. Etranacogene dezaparvovec increases blood FIX levels such that FIX prophylaxis could be eliminated. OBJECTIVE: To estimate the budgetary impact of etranacogene dezaparvovec adoption and utilization in a commercial health plan of the United States. METHODS: A budget impact model was developed to evaluate the introduction of etranacogene dezaparvovec to treat severe or moderately severe hemophilia B. The model considered a hypothetical 1-million-member plan over a 5-year horizon. FIX therapy prophylaxis use was estimated based on a weighted average of relevant brands using US market share data. A scenario of etranacogene dezaparvovec adoption/utilization was compared with one without etranacogene dezaparvovec utilization. Two etranacogene dezaparvovec uptake (market share growth) analyses were performed: one with gradual uptake and alternatively assuming all eligible PwHB received etranacogene dezaparvovec in year 1. The one-time cost of etranacogene dezaparvovec was assumed to be $3.5 million. Other costs (FIX prophylaxis, disease monitoring, bleed management, and adverse events) were estimated from published literature. All costs were in 2022 US dollars. Bleed and adverse event rates were sourced from the HOPE-B trial comparing etranacogene dezaparvovec to previous FIX therapy prophylaxis. The model estimated annual and per-member per-month costs over 5 years. Secondary analyses were performed considering a 10-year horizon. RESULTS: In the 1-million-member health plan, an estimated 1.8 PwHB were eligible for treatment with etranacogene dezaparvovec. Gradual uptake of etranacogene dezaparvovec resulted in cumulative 5-year budget impact of $848,509 compared with a scenario without etranacogene dezaparvovec. In years 1-5, the incremental annual and per-member per-month costs ranged from $79,824 to $271,435 and from $0.007 to $0.023, respectively. In the alternative uptake analysis, etranacogene dezaparvovec became cost saving annually beginning in year 2 and cumulatively beginning in year 5, for a 5-year savings of $754,844. Secondary analyses over 10 years found both uptake analyses cost saving. Other scenarios considered did not affect results substantially. CONCLUSIONS: Introducing etranacogene dezaparvovec as treatment for PwHB would have a modest budget increase within 5 years after treatment but may become cost saving if all eligible PwHB were treated in year 1. Initiating PwHB on etranacogene dezaparvovec sooner may produce greater overall savings and earlier annual savings. Etranacogene dezaparvovec is a treatment option that may provide overall cost savings for US commercial health plans, which would increase as the plan size increases.