Abstract

Adeno-associated virus (AAV)–based gene therapy is an emerging treatment for hemophilia A (HA) and hemophilia B (HB). In this systematic review and meta-analysis, we searched for studies of adult males with severe or moderately severe HA or HB who received AAV-based gene therapy. Annualized bleeding rate (ABR), annualized infusion rate (AIR), total factor use, factor levels, and adverse events (AEs) were extracted. Eight HA trials representing 7 gene therapies and 211 patients and 12 HB trials representing 9 gene therapies and 184 patients were included. For HA, gene therapy resulted in an annualized decrease of 7.58 bleeding events (95% confidence interval [CI], −11.50 to −3.67) and 117.2 factor infusions (95% CI, −151.86 to −82.53) compared with before gene therapy. Factor VIII level at 12 months ranged from 10.4 to 70.31 IU/mL by 1-stage assay. HB gene therapies were associated with an annualized decrease of 5.64 bleeding events (95% CI, −8.61 to −2.68) and 58.92 factor infusions (95% CI, −68.19 to −49.65). Mean factor IX level at 12 months was 28.72 IU/mL (95% CI, 18.78-38.66). Factor expression was more durable for HB than HA; factor IX levels remained at 95.7% of their peak whereas factor VIII levels fell to 55.8% of their peak at 24 months. The pooled percentage of patients experiencing a serious AE was 19% (10%-31%) and 21% (10%-37%) for HA and HB gene therapies, respectively. No thrombosis or inhibitor formation was reported. AAV-based gene therapies for both HA and HB demonstrated significant reductions in ABR, AIR, and factor use.

Hemophilia A and B (HA and HB, respectively) are inherited X-linked bleeding disorders, characterized by deficiency of factor VIII (FVIII) and FIX, respectively. Hemophilia affect >1.2 million individuals worldwide, with HA being more common than HB.1 Hemophilia primarily affects males, although females can also be affected. Disease severity is characterized by factor level. Severe hemophilia is defined as <1% factor activity, moderate hemophilia as factor activity level ≥1% to ≤5% of normal, and mild hemophilia as factor activity level of >5% to <40% of normal.2 About one-half to two-thirds of patients with HA and approximately one-third to one-half of patients with HB have severe disease.1,3 Patients with severe hemophilia are prone to spontaneous and recurrent bleeding events, most commonly into joints, which can lead to severe degenerative arthropathy over time.

Prophylactic clotting factor replacement has been used for decades to prevent or mitigate bleeding events and hemophilic arthropathy. More recently, subcutaneously administered nonfactor therapies have expanded treatment options for patients.4,5 However, both factor prophylaxis and subcutaneous therapies are costly, require regular administration, and do not fully correct hemostasis, thereby exposing patients to a risk of breakthrough bleeding and the need for intensification of therapy for surgery.

Adeno-associated virus (AAV)–based gene therapy has emerged as a novel treatment strategy aimed at overcoming these limitations. It introduces an AAV vector that inserts a functional copy of the missing clotting factor gene into patients’ hepatocytes so that clotting factor can be expressed.5,6 Valoctocogene roxaparvovec was approved as the first gene therapy for HA in the United States in June 2023.7 Etranacogene dezaparvovec and fidanacogene elaparvovec were approved by the US Food and Drug Administration in November 2022 and April 2024, respectively, for adults with HB. Several other gene therapies are under various stages of development.8,9 Although these therapies appear to have few serious adverse events (AEs), a notable toxicity of hepatotropic AAV-based gene therapy is liver toxicity, which can result in loss of transgene expression of factor.6-8 

Given the rapid advancements and approvals in the field, it is essential to evaluate the overall impact of these therapies. We conducted a systematic review and meta-analysis of AAV-based gene therapies for HA and HB to summarize the efficacy and safety of this emerging therapeutic class.

The protocol for this systematic review was registered in PROSPERO (#CRD42023444873).10 Our study was conducted according to preferred reporting items for systematic reviews and meta-analysis guidelines.11 

Search strategy and study selection

We electronically searched 4 databases (the Cochrane Library, Embase, PubMed, and Scopus) from database inception to 26 May 2024. A search strategy and relevant keywords were determined in consultation with a health sciences librarian. Search terms were focused on HA and HB as well as gene therapy. A full search strategy is available in supplemental Methods. Conference proceedings from 2013 through 2023 (inclusive) from the annual meetings of the American Society of Hematology, International Society on Thrombosis and Hemostasis, and European Hematology Association were hand-searched.

We included human studies on adult males with severe or moderately severe HA or HB (≤2% FVIII or FIX, respectively) who received AAV-based gene therapy targeting hepatocytes. We excluded case reports and series, editorials, and reviews.

Citations were imported into the data management system Covidence (Veritas Health Innovation, Melbourne, Australia). Two investigators (S.R.D. and K.J.) independently completed title and abstract screening. Discrepancies were resolved with consensus discussion between these 2 investigators (S.R.D. and K.J.), and disagreements were arbitrated by a third investigator (A.C.). The same protocol was followed for the full-text review of citations that were included after title and abstract screening. References of included studies were scanned to identify further relevant studies.

Data extraction and risk-of-bias assessment

Because many included studies provided updated results for the same trial, references were grouped into clinical trials. For each included study, 2 investigators (S.R.D. and K.J.) independently extracted data using a standardized form with discrepancies resolved by consensus discussion between 4 investigators (S.R.D., K.J., A.C., and A.P.). Data extraction included trial identifiers, study design, location, inclusion and exclusion criteria, AAV vector, dose, patient demographics and characteristics, and study duration along with efficacy and safety outcomes. Outcomes were permitted to be derived from different references of the same trial. For all outcomes, we prioritized data completeness (eg, inclusion of mean and standard deviation rather than mean alone) over longer term follow-up. Our primary outcome was pooled mean difference (PMD) in total annualized bleeding rate (ABR) from the observational pre–gene therapy period to the post–gene therapy period. Secondary efficacy outcomes included PMD in mean annualized infusion rate (AIR; before therapy, after therapy), PMD in mean annualized use of factor concentrates (before therapy, after therapy), mean factor plasma levels at prespecified intervals (4 weeks, and 6, 12, 18, and 24 months) by 1-stage assay (OSA) and chromogenic substrate assay (CSA), ABR for joint and treated bleeds, and quality of life. For measurements at prespecified time points, we allowed for leeway of 1 week for measurements <1 month, 1 month for measurements between 1 month to 1 year, and 2 months for measurements ≥1 year from time of gene therapy administration. If not directly reported, ABR and AIR were derived with the following calculation: (number of events/number of days) × 365.25. Safety outcomes included AEs including serious AEs, infusion reactions, anaphylaxis, alanine aminotransferase (ALT) elevations, aminotransferase elevations requiring immunosuppression, inhibitor formation, and thrombosis events. When incomplete data were reported, ClinicalTrials.gov was queried for posted results, which were incorporated, provided the results had undergone review by the National Library of Medicine to ensure they met quality control standards. When summary data for an entire study population were not reported, we included data for distinct cohorts within the same trial.

For risk-of-bias assessment, we used the National Institutes of Health/National Heart, Lung, and Blood Institute Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group.12 Two investigators (S.R.D. and K.J.) independently appraised trial-level quality, and discrepancies were resolved by consensus discussion between them. Study quality was rated good (≤4 negative or missing assessment questions and low risk of bias), fair (5-6 negative or missing assessment questions), or poor (>6 negative or missing assessment questions or high risk of bias).

Data synthesis and analysis

Meta-analyses of the predefined efficacy and safety outcomes for HA and HB were performed. For HA, efficacy outcomes included ABR and AIR, whereas safety outcomes included the incidence of any AEs, serious AEs, and ALT elevation. For HB, efficacy outcomes additionally covered factor usage and factor levels at 12 months. Safety outcomes for HB mirrored those of HA. Efficacy outcomes were all continuous, presented as mean values both before and after gene therapy. Safety outcomes are reported as incidence rates after therapy.

Given intrinsic heterogeneity in these outcomes across studies, random-effects meta-analyses were used to derive the pooled point estimates and 95% confidence intervals (CIs). Specifically, for the efficacy outcomes, pooled point estimates were obtained for the pretherapy and posttherapy mean differences. Studies lacking reported standard deviations for efficacy outcomes were included in the meta-analyses, with missing standard deviations imputed from the available data in the sample.13 For safety outcomes, the analyses provided pooled point estimates of the incidence rates after therapy.

Heterogeneity was quantified by Higgins and Thompson heterogeneity measure (I2)14 and tested using Cochran Q statistic,15 which examines the existence of statistically significant differences between subgroups. The values of I2 and Cochran Q test P values were reported. The heterogeneity measure I2 was calculated based on the weighted sum of the difference between the pooled estimate and the effect size (eg, mean difference) for each study. An I2 value of 0% to 25% represents nonsignificant heterogeneity, 26% to 50% represents low heterogeneity, 51% to 75% represents moderate heterogeneity, and >75% represents high heterogeneity. A Cochran Q test with a P value of <.05 indicates statistically significant heterogeneity between studies. For outcomes with significant heterogeneity, a sensitivity analysis was completed by removal of outlier results followed by repeat quantification of the heterogeneity measure I2. Outlier results were determined first by visual inspection of funnel plots and by absolute value of z score.

Potential publication bias was assessed through a funnel plot16 for visual inspection and the Egger test17 to evaluate asymmetry within the funnel plot. The results of the Egger test were reported alongside the funnel plot, with a P value of <.05 leading to rejection of the null hypothesis of symmetry in the funnel plot, indicating that there exists evidence suggesting the significant publication bias. A funnel plot displays the estimated point estimates (eg, mean difference, proportion) on the x-axis against the standard error of the estimated point estimates on the y-axis. The standard error on the y-axis was calculated based on reported standard deviations and sample sizes. All analyses were performed using the R package “meta” in R, version 4.2.1.

Literature search

Of the 8755 citations identified, 8497 were excluded based on duplication or title and abstract screening, leaving 258 for full-text review. Of these, 132 publications met eligibility criteria.7,8,18-123 These references were grouped into 8 distinct trials, representing 7 gene therapies and 211 people with HA (PwHA), and 12 distinct trials representing 9 gene therapies and 184 people with HB (PwHB; supplemental Table 1). Figure 1 shows the PRISMA flow diagram for study selection.

Figure 1.

Trial flow for a systematic review of the literature on AAV-based gene therapy for HA and HB.

Figure 1.

Trial flow for a systematic review of the literature on AAV-based gene therapy for HA and HB.

Close modal

Study characteristics

Studies were primarily early phase trials (phase 1, n = 2; phase 2, n = 1; phase 1/2, n = 14), and 3 trials were phase 3.8,26,63 All phase 3 trials were single-arm, pre/post cohort studies. Twelve trials were multinational. Study characteristics are summarized in Table 1.

Table 1.

Characteristics of included studies

Trial name/NCT (phase)Gene therapy (prior names)SettingDesignN (n for individual dose cohorts)AAV vectorDose(s) (vg/kg)Age (y), mean (range)Non-White, %Duration (mo)Hemophilia severity (severe/moderately severe [%])Time at which ABR measurement started
HA 
Alta/NCT03061201 (1/2) Giroctocogene fitelparvovec (PF-07055480/SB-525) United States Open-label, dose-escalation, cohort study 11 AAV6 9e11, 2e12, 1e13, 3e13 30 (18-47) 18.2 62 100/0 Week 3 
GENEr8-1/NCT02576795 (1/2) Valoctocogene roxaparvovec (BMN-270) United Kingdom Open-label, dose-escalation, cohort study 13 (7, 6) AAV5 6e13
4e13 
30.4 (23-42)
31.3 (22-45) 
14.3
16.7 
72 100/0 Week 4 
GENEr8-1/NCT03370913 (3) Valoctocogene roxaparvovec (BMN-270) 13 countries  Open-label, single-arm, cohort study 134 AAV5 6e13 31.7 (18-70) 28.4 36 100/0 Week 5 
NCT03003533/NCT03432520 (1/2) Dirloctogene samoparvovec (SPK-8011) 5 countries  Open-label, dose-escalation, cohort study 24 AAV3 5e11
1e12
1.5e12
2e12 
32.8 (18-52) NR 60 94.4/5.6 Week 4 
NCT03734588 (1/2) SPK-8016 United States Open-label, single-arm, cohort study AAV-Spark 5e11 (18-63) NR 15 100/0 NR 
NCT03370172 (1/2) TAK-754 8 countries§  Open-label, dose-escalation, cohort study AAV8 2e12
6e12 
(18-75) NR 10 100/0 NR 
NCT03588299 (1/2) BAY 2599023 (AAVhu37.hFVIIIco) 6 countries||  Open-label, dose-escalation, cohort study AAVhu37 5e12, 1e13, 2e13, 4e13 NR NR 23 100/0 NR 
NCT03001830GO-8 (1/2) GO-8 (AAV8-HLP-hFVIII-V3) United States, United Kingdom Open-label, dose-escalation, cohort study 12 (1, 3, 3, 5) AAV8 6e11, 2e12, 4e12, 6e12 NR NR 60 100/0 NR 
HB 
BENEGENE-2/NCT02484092 (1/2) Fidanacogene elaparvovec (SPK-9001) United States, Australia Open-label, single-arm, cohort study 15 AAV-Spark100 5e11 35.6 (18-53) 14.3 12 60/40 Day 0 
BENEGENE-2/NCT03861273 (3) Fidanacogene elaparvovec (SPK-9001) 14 countries  Open-label, single-arm, cohort study 45 AAV-Spark100 5e11 29 (18-62) NR 15 NR Week 12 
B-LIEVE/NCT05164471 (1/2) Verbrinacogene setparvovec (FLT180a) United States, United Kingdom Open-label, single-arm, cohort study AAVS3 7.7e11 NR NR 12 NR NR 
B-AMAZE/NCT03369444 (1/2) Verbrinacogene setparvovec (FLT180a) United States, Ireland, Italy, United Kingdom Open-label, dose-escalation, cohort study 10 (2, 2, 4, 2) AAVS3 3.84e11, 6.4e11, 8.32e11,
1.28e12 
37.2 (25-67) 10 27.2 90/10 Day 15 
NCT02396342 (1/2) AMT-060 Denmark, Germany, The Netherlands Open-label, dose-escalation, cohort study 10 (5, 5) AAV5 5e12
2e13 
69 (35-72)
35 (33-46) 
0
20 
60 80/20
100/0 
NR 
HOPE-B/NCT03569891 (2b) Etranacogene dezaparvovec (AMT-061) United States Open-label, single-arm, cohort study AAV5 2e13 46.7 (43-50) 66.7 36 66.7/33.3 Day 0 
HOPE-B/NCT03569891 (3) Etranacogene dezaparvovec (AMT-061) 8 countries#  Open-label, single-arm, cohort study 54 AAV5 2e13 41.5 (19-75) 25.9 26.5 81/19 Month 7 
NCT01687608 (1/2) BAX335 United States Open-label, dose-escalation, cohort study AAV8 2e11, 1e12, 3e12 30.5 (20-69) 12.5 86 NR NR 
NCT00979238 (1) scAAV2/8-LP1-hFIXco United States, United Kingdom Open-label, dose-escalation, cohort study 10 AAV8 2e11, 6e11, 2e12 36.3 (22-64) NR 128 100/0 NR 
101HEMB01/NCT02618915 (1/2) DTX101 United States, Bulgaria, United Kingdom Open-label, dose-escalation, cohort study 6 (3, 3) AAVrh10 1.6e12, 5e12 (50-84, 18-49) NR 12 NR Day 0 
NCT04135300 (1) BBM-H901 China Open-label, single-arm, cohort study 10 AAV843 5e12 NR 100 13 NR NR 
NCT00515710 (1/2) AAV2-hFIX16 United States Open-label, dose-escalation, cohort study AAV2 8e10, 4e11, 2e12 34 (20-63) NR 180 100/0 NR 
Trial name/NCT (phase)Gene therapy (prior names)SettingDesignN (n for individual dose cohorts)AAV vectorDose(s) (vg/kg)Age (y), mean (range)Non-White, %Duration (mo)Hemophilia severity (severe/moderately severe [%])Time at which ABR measurement started
HA 
Alta/NCT03061201 (1/2) Giroctocogene fitelparvovec (PF-07055480/SB-525) United States Open-label, dose-escalation, cohort study 11 AAV6 9e11, 2e12, 1e13, 3e13 30 (18-47) 18.2 62 100/0 Week 3 
GENEr8-1/NCT02576795 (1/2) Valoctocogene roxaparvovec (BMN-270) United Kingdom Open-label, dose-escalation, cohort study 13 (7, 6) AAV5 6e13
4e13 
30.4 (23-42)
31.3 (22-45) 
14.3
16.7 
72 100/0 Week 4 
GENEr8-1/NCT03370913 (3) Valoctocogene roxaparvovec (BMN-270) 13 countries  Open-label, single-arm, cohort study 134 AAV5 6e13 31.7 (18-70) 28.4 36 100/0 Week 5 
NCT03003533/NCT03432520 (1/2) Dirloctogene samoparvovec (SPK-8011) 5 countries  Open-label, dose-escalation, cohort study 24 AAV3 5e11
1e12
1.5e12
2e12 
32.8 (18-52) NR 60 94.4/5.6 Week 4 
NCT03734588 (1/2) SPK-8016 United States Open-label, single-arm, cohort study AAV-Spark 5e11 (18-63) NR 15 100/0 NR 
NCT03370172 (1/2) TAK-754 8 countries§  Open-label, dose-escalation, cohort study AAV8 2e12
6e12 
(18-75) NR 10 100/0 NR 
NCT03588299 (1/2) BAY 2599023 (AAVhu37.hFVIIIco) 6 countries||  Open-label, dose-escalation, cohort study AAVhu37 5e12, 1e13, 2e13, 4e13 NR NR 23 100/0 NR 
NCT03001830GO-8 (1/2) GO-8 (AAV8-HLP-hFVIII-V3) United States, United Kingdom Open-label, dose-escalation, cohort study 12 (1, 3, 3, 5) AAV8 6e11, 2e12, 4e12, 6e12 NR NR 60 100/0 NR 
HB 
BENEGENE-2/NCT02484092 (1/2) Fidanacogene elaparvovec (SPK-9001) United States, Australia Open-label, single-arm, cohort study 15 AAV-Spark100 5e11 35.6 (18-53) 14.3 12 60/40 Day 0 
BENEGENE-2/NCT03861273 (3) Fidanacogene elaparvovec (SPK-9001) 14 countries  Open-label, single-arm, cohort study 45 AAV-Spark100 5e11 29 (18-62) NR 15 NR Week 12 
B-LIEVE/NCT05164471 (1/2) Verbrinacogene setparvovec (FLT180a) United States, United Kingdom Open-label, single-arm, cohort study AAVS3 7.7e11 NR NR 12 NR NR 
B-AMAZE/NCT03369444 (1/2) Verbrinacogene setparvovec (FLT180a) United States, Ireland, Italy, United Kingdom Open-label, dose-escalation, cohort study 10 (2, 2, 4, 2) AAVS3 3.84e11, 6.4e11, 8.32e11,
1.28e12 
37.2 (25-67) 10 27.2 90/10 Day 15 
NCT02396342 (1/2) AMT-060 Denmark, Germany, The Netherlands Open-label, dose-escalation, cohort study 10 (5, 5) AAV5 5e12
2e13 
69 (35-72)
35 (33-46) 
0
20 
60 80/20
100/0 
NR 
HOPE-B/NCT03569891 (2b) Etranacogene dezaparvovec (AMT-061) United States Open-label, single-arm, cohort study AAV5 2e13 46.7 (43-50) 66.7 36 66.7/33.3 Day 0 
HOPE-B/NCT03569891 (3) Etranacogene dezaparvovec (AMT-061) 8 countries#  Open-label, single-arm, cohort study 54 AAV5 2e13 41.5 (19-75) 25.9 26.5 81/19 Month 7 
NCT01687608 (1/2) BAX335 United States Open-label, dose-escalation, cohort study AAV8 2e11, 1e12, 3e12 30.5 (20-69) 12.5 86 NR NR 
NCT00979238 (1) scAAV2/8-LP1-hFIXco United States, United Kingdom Open-label, dose-escalation, cohort study 10 AAV8 2e11, 6e11, 2e12 36.3 (22-64) NR 128 100/0 NR 
101HEMB01/NCT02618915 (1/2) DTX101 United States, Bulgaria, United Kingdom Open-label, dose-escalation, cohort study 6 (3, 3) AAVrh10 1.6e12, 5e12 (50-84, 18-49) NR 12 NR Day 0 
NCT04135300 (1) BBM-H901 China Open-label, single-arm, cohort study 10 AAV843 5e12 NR 100 13 NR NR 
NCT00515710 (1/2) AAV2-hFIX16 United States Open-label, dose-escalation, cohort study AAV2 8e10, 4e11, 2e12 34 (20-63) NR 180 100/0 NR 

NCT, National Clinical Trial; NR, not reported; vg, vector genomes.

For the dose-escalation studies, n for each dose cohort is specified in parentheses for the studies which have specified that data.

United States, Australia, Belgium, Brazil, France, Germany, Israel. Italy, Korea, South Africa, Spain, Taiwan, and United Kingdom.

United States, Australia, Canada, Israel, and Thailand.

§

United States, United Kingdom, Austria, France, Germany, Hungary, Italy, and Spain.

ǁ

United States, Bulgaria, France, Germany, The Netherlands, and United Kingdom.

United States, Australia, Brazil, Canada, France, Germany, Greece, Japan, Korea, Saudi Arabia, Sweden, Taiwan, Turkey, and United Kingdom.

#

United States, Belgium, Denmark, Germany, Ireland, The Netherlands, Sweden, and United Kingdom.

Efficacy of AAV-based gene therapy for HA

Of 8 studies,38,55,63,112,113 5 reported ABR data for pooled analysis. A random-effects model of 154 PwHA showed a PMD of −7.58 bleeding events per year (95% CI, −11.50 to −3.67; I2 = 43%; P = .12) in favor of the post–gene therapy period (Figure 2A). Three studies38,63,112 representing 143 PwHA reported AIR data with a PMD of −117.20 infusion per year (95% CI, −151.86 to −82.53; I2 = 83%; P < .01; Figure 2B) with significant between-study heterogeneity. There were insufficient data to complete a meta-analysis on annual factor concentrate use. Both studies reporting annual factor concentrate use showed a decrease after gene therapy, with the GENEr8-1 phase 3 trial for valoctocogene roxaparvovec showing a decrease from 3961 to 125 IU/kg per year63 and the phase 1/2 trial for GO-8 showing a decrease from 4097 to 1186 IU/kg per year.23 Measurement of factor levels was done with both OSA and CSA in 5 trials and was not specified in 2 trials. Mean factor levels measured by OSA at 12 months after gene therapy ranged from 10.4 IU/dL in the phase 1/2 trial for SPK-8016113 to 70.31 IU/dL in the 2 highest-dose cohorts (cohorts 3 and 4) in the phase 1/2 trial for valoctocogene roxaparvovec.112 Because of limited data, a meta-analysis of factor levels was not performed.

Figure 2.

Efficacy outcomes for HA. Forest plot of individual and PMD with 95% CI in (A) ABR and (B) AIR for AAV-based gene therapies for HA.

Figure 2.

Efficacy outcomes for HA. Forest plot of individual and PMD with 95% CI in (A) ABR and (B) AIR for AAV-based gene therapies for HA.

Close modal

Safety of AAV-based gene therapy for HA

Six studies reported AEs and 7 studies reported serious AEs of AAV-based gene therapy for HA. Overall, 99% of PwHA experienced an AE (95% CI, 49-100; Figure 3A) and 19% experienced a serious AE (95% CI, 10-31; Figure 3B). There was no evidence of significant between-study heterogeneity (I2 = 0% and P > .05 for both). ALT elevation was reported in 7 studies, which occurred in 71% (95% CI, 50-85) of PwHA, with evidence of significant heterogeneity across studies (I2 = 67%, P < .01; Figure 3C). On sensitivity analysis, there was evidence suggesting the existence of between-study heterogeneity after the removal of 2 studies99,113 with outlier results detected by z score (supplemental Table 2). Two studies reported anaphylaxis, which occurred in 2.2% of PwHA in the GENEr8-1 study of valoctocogene roxaparvovec63 and 0% in the phase 1/2 study of dirloctocogene samoparvovec.38 All studies reported no inhibitor formation or thrombosis.

Figure 3.

Safety outcomes for HA. Forest plot of individual and pooled proportion with 95% CI of patients who experienced (A) AE, (B) serious AE, and (C) ALT elevation for AAV-based gene therapies for HA.

Figure 3.

Safety outcomes for HA. Forest plot of individual and pooled proportion with 95% CI of patients who experienced (A) AE, (B) serious AE, and (C) ALT elevation for AAV-based gene therapies for HA.

Close modal

Efficacy of AAV-based gene therapy for HB

Eight studies8,22,26,28,33,69,73 representing 156 PwHB were included in the pooled analysis for ABR. The PMD for ABR throughout follow-up was −5.64 (95% CI, −8.61 to −2.68) bleeding events per year with significant between-study heterogeneity (I2 = 70%; P < .01; Figure 4A). On sensitivity analysis, removal of the 2 outlying studies28,73 on funnel plot suggested that there was evidence showing nonsignificant between-study heterogeneity for the remaining studies (supplemental Table 3). Five studies8,26,28,33,52 reporting AIR had a PMD of −58.92 (95% CI, −68.19 to −49.65) infusions per year without significant heterogeneity between studies (I2 = 53%; P = .07; Figure 4B). Data on annualized use of factor concentrate was available in 5 studies,22,26,33,69,73 showing a PMD of −2656.52 (95% CI, −3073.24 to −2239.79) IU/kg per year without significant heterogeneity (I2 = 0%; P = .56; Figure 4C). Two studies reporting annualized factor use in IU per year without participant weight showed a numerical decrease in annualized factor use. The HOPE-B phase 3 trial of etranacogene dezaparvovec showed a decrease from 257 338 to 8486 IU per year,8 and the phase 1/2 trial of BAX335 showed a decrease from 221 250 to 99 941 IU per year.52 Factor level measurement was reported with OSA alone in 7 studies, both OSA and CSA in 2 studies, and not reported in 3 studies. Factor level by OSA at 12 months after gene therapy administration was pooled for meta-analysis across 5 studies8,26,33,69 representing 126 PwHB with a mean FIX level of 28.72 IU/dL (95% CI, 18.78-38.66) with statically significant heterogeneity (I2 = 85%; P < .01; Figure 4D). On sensitivity analysis, after removing 2 outlying studies detected by z score, the phase 2b and 3 trials for etranacogene dezaparvovec,8,69 the I2 value of 0% suggested the nonsignificant between-study heterogeneity for the remaining studies (supplemental Table 3).

Figure 4.

Efficacy outcomes for HB. Forest plot of individual and PMD with 95% CI in (A) ABR, (B) AIR, (C) annualized factor use (IU/kg), and (D) FIX level at 12 months for AAV-based gene therapies for HB. MD, mean difference; MRAW, raw mean.

Figure 4.

Efficacy outcomes for HB. Forest plot of individual and PMD with 95% CI in (A) ABR, (B) AIR, (C) annualized factor use (IU/kg), and (D) FIX level at 12 months for AAV-based gene therapies for HB. MD, mean difference; MRAW, raw mean.

Close modal

Safety of AAV-based gene therapy for HB

Eleven trials reported AEs and serious AEs with 94% of PwHB experiencing an AE (95% CI, 68-99; Figure 5A) with statistically significant between-study heterogeneity (I2 = 45%; P = .04) and 21% experiencing a serious AE (95% CI, 10-37; Figure 5B) with nonsignificant between-study heterogeneity (I2 = 10%; P = .34). ALT elevation was reported in 10 studies and occurred in 32% of PwHB (95% CI, 19-49) with nonsignificant heterogeneity (I2 = 34%; P = .11; Figure 5C). Three studies reported no incidence of anaphylaxis. No study reported formation of an inhibitor or thrombosis.

Figure 5.

Safety outcomes for HB. Forest plot of individual and pooled proportion with 95% CI of patients who experienced (A) AE, (B) serious AE, and (C) ALT elevation for AAV-based gene therapies for HB.

Figure 5.

Safety outcomes for HB. Forest plot of individual and pooled proportion with 95% CI of patients who experienced (A) AE, (B) serious AE, and (C) ALT elevation for AAV-based gene therapies for HB.

Close modal

Durability of gene expression for HA and HB beyond 12 months

For trials reporting factor levels at 24 months after administration of gene therapy, we compared the highest previously reported factor level with the factor level at 24 months, weighted by size of study population. HA gene therapies fell to 55.8% of their peak FVIII level at 24 months. HB gene therapies fell to 95.7% of their peak FIX level at 24 months.

Risk-of-bias assessment

All trials followed a before-after or pre-post design and were assessed with the National Institutes of Health/National Heart, Lung, and Blood Institute Quality Assessment Tool for Before-After (Pre-Post) Studies with no control group. We assessed the plurality (10, 50.0%) of trials to have good quality; 6 (30.0%) trials were assessed to have fair quality; and 4 (20.0%) trials to have poor quality, primarily because of missing methodological information (Table 2).

Table 2.

Risk-of-bias assessment

Trial name/NCT (phase)Gene therapy (prior names)1. Study question2. Eligibility criteria and study population3. Study participants representative of clinical populations of interest4. All eligible participants enrolled5. Sample size6. Intervention clearly described7. Outcome measures clearly described, valid, and reliable8. Blinding of outcome assessors9. Follow-up rate10. Statistical analysis11. Multiple outcome measures12. Group-level interventions and individual-level outcome effortsQuality rating
HA 
Alta/NCT03061201 (1/2) Giroctocogene fitelparvovec (PF-07055480/SB-525) NR NR NA Fair 
GENEr8-1/NCT02576795 (1/2) Valoctocogene roxaparvovec (BMN-270) NR NR NR NR Fair 
GENEr8-1/NCT03370913 (3) Valoctocogene roxaparvovec (BMN-270) NR NR NR Good 
NCT03003533/NCT03432520 (1/2) Dirloctocogene samoparvovec (SPK-8011) NR NR NA Good 
NCT03734588 (1/2) SPK-8016 NR NR NR NA Fair 
NCT03370172 (1/2) TAK-754 NR NR NR NR NR Poor 
NCT03588299 (1/2) BAY 2599023 (AAVhu37.hFVIIIco) NR NR NR NA Poor 
NCT03001830GO-8 (1/2) GO-8 (AAV8-HLP-hFVIII-V3) NR NR NA Good 
HB 
BENEGENE-2/NCT02484092 (1/2) Fidanacogene elaparvovec (SPK-9001) NR NA Good 
BENEGENE-2/NCT03861273 (3) Fidanacogene elaparvovec (SPK-9001) NR NA Good 
B-LIEVE/NCT05164471 (1/2) Verbrinacogene setparvovec (FLT180a) NR NR NR NR NR NA Poor 
B-AMAZE/NCT03369444 (1/2) Verbrinacogene setparvovec (FLT180a) NR NR NR NR Good 
NCT02396342 (1/2) AMT-060 CD NA Good 
HOPE-B/NCT03569891 (2b) Etranacogene dezaparvovec (AMT-061) NR NR NR NA Fair 
HOPE-B/NCT03569891 (3) Etranacogene dezaparvovec (AMT-061) NR Good 
NCT01687608 (1/2) BAX335 NR CD NR NA Good 
NCT00979238 (1) scAAV2/8-LP1-hFIXco NR NR NR Fair 
101HEMB01/NCT02618915 (1/2) DTX101 NR NR NA Good 
NCT04135300 (1) BBM-H901 NR NR NR NR NR NR Poor 
NCT00515710 (1/2) AAV2-hFIX16 NR NR NA Fair 
Trial name/NCT (phase)Gene therapy (prior names)1. Study question2. Eligibility criteria and study population3. Study participants representative of clinical populations of interest4. All eligible participants enrolled5. Sample size6. Intervention clearly described7. Outcome measures clearly described, valid, and reliable8. Blinding of outcome assessors9. Follow-up rate10. Statistical analysis11. Multiple outcome measures12. Group-level interventions and individual-level outcome effortsQuality rating
HA 
Alta/NCT03061201 (1/2) Giroctocogene fitelparvovec (PF-07055480/SB-525) NR NR NA Fair 
GENEr8-1/NCT02576795 (1/2) Valoctocogene roxaparvovec (BMN-270) NR NR NR NR Fair 
GENEr8-1/NCT03370913 (3) Valoctocogene roxaparvovec (BMN-270) NR NR NR Good 
NCT03003533/NCT03432520 (1/2) Dirloctocogene samoparvovec (SPK-8011) NR NR NA Good 
NCT03734588 (1/2) SPK-8016 NR NR NR NA Fair 
NCT03370172 (1/2) TAK-754 NR NR NR NR NR Poor 
NCT03588299 (1/2) BAY 2599023 (AAVhu37.hFVIIIco) NR NR NR NA Poor 
NCT03001830GO-8 (1/2) GO-8 (AAV8-HLP-hFVIII-V3) NR NR NA Good 
HB 
BENEGENE-2/NCT02484092 (1/2) Fidanacogene elaparvovec (SPK-9001) NR NA Good 
BENEGENE-2/NCT03861273 (3) Fidanacogene elaparvovec (SPK-9001) NR NA Good 
B-LIEVE/NCT05164471 (1/2) Verbrinacogene setparvovec (FLT180a) NR NR NR NR NR NA Poor 
B-AMAZE/NCT03369444 (1/2) Verbrinacogene setparvovec (FLT180a) NR NR NR NR Good 
NCT02396342 (1/2) AMT-060 CD NA Good 
HOPE-B/NCT03569891 (2b) Etranacogene dezaparvovec (AMT-061) NR NR NR NA Fair 
HOPE-B/NCT03569891 (3) Etranacogene dezaparvovec (AMT-061) NR Good 
NCT01687608 (1/2) BAX335 NR CD NR NA Good 
NCT00979238 (1) scAAV2/8-LP1-hFIXco NR NR NR Fair 
101HEMB01/NCT02618915 (1/2) DTX101 NR NR NA Good 
NCT04135300 (1) BBM-H901 NR NR NR NR NR NR Poor 
NCT00515710 (1/2) AAV2-hFIX16 NR NR NA Fair 

CD, cannot determine; N, no; NA, not applicable; NCT, National Clinical Trial; NR, not reported; Y, yes.

Publication bias

On evaluation for publication bias for the primary outcome of ABR, funnel plots and Egger tests were used. The results indicated that nonsignificant heterogeneity was present for HA gene therapies (P = .0876; Figure 6A). For HB, the Egger test was significant (P = .0006), with the funnel plot showing asymmetry, especially for 2 studies28,73 with a larger absolute PMD and relatively larger standard error, which may overestimate the magnitude of the point estimate for ABR in HB gene therapies (Figure 6B; supplemental Table 3).

Figure 6.

Publication bias. Funnel plot for trials of AAV-based gene therapies for (A) HA and (B) HB.

Figure 6.

Publication bias. Funnel plot for trials of AAV-based gene therapies for (A) HA and (B) HB.

Close modal

We performed a systematic review and meta-analysis on the efficacy and safety of AAV-based gene therapies for HA and HB. We found that PwHA and PwHB had significantly lower annualized bleeding events and factor infusion requirements after gene therapy compared with factor prophylaxis before gene therapy. At 24 months, we observed that factor levels declined to 55.8% of their peak level among PwHA, whereas they remained durable among PwHB. Treatment was well tolerated. There was no inhibitor formation or thrombotic events reported among eligible studies.

AAV-based gene therapy has emerged as a promising treatment for PwHA and PwHB, offering advantages over prophylaxis with factor concentrate or emicizumab. As our results show, a single infusion of vector reduces bleeding and mitigates or eliminates the burden of frequent infusions compared with prophylaxis with factor concentrate. However, more work is needed to optimize gene therapy for hemophilia before it can be considered a treatment of choice for most patients.

First, most studies we identified excluded patients with neutralizing anticapsid antibodies or a history of inhibitors to FVIII or FIX, greatly limiting who is eligible to receive treatment. Efforts to expand eligibility for these therapies is paramount.

Second, improving the prevention, detection, and management of anticapsid immune responses is a priority. Such responses typically manifest as hepatic transaminase elevation. Prompt treatment, typically with corticosteroids, is necessary to minimize loss of factor expression.75,124 Our results suggest heterogeneity between gene therapy products with respect to the incidence of ALT elevation. Some of this heterogeneity may be due to protocol-specific factors. Protocols used different cutoffs for both grading ALT elevation (usually either 1.5- or twofold above baseline levels or upper limit of normal) and for initiating immunosuppression in response to ALT elevation. Likewise, some protocols used prophylactic prednisolone and tacrolimus22 in the initial post–gene therapy period to mitigate vector-related hepatotoxicity whereas others advised initiation of immunosuppression only in those who developed ALT elevation. These protocol differences and limited subject-level data preclude pooled analysis on the impacts of ALT elevation and use of immunosuppression on durability of factor expression and highlight the need for further research to optimize use of immunosuppression.

Higher rates of ALT elevation were observed in gene therapies for HA relative to HB, perhaps because of higher vector doses used in HA. In phase 1/2 studies reporting hepatotoxicity by dose cohorts, higher doses appeared to yield more hepatotoxicity.22,69 Higher vector doses were also associated with prolonged time to vector clearance from body fluids, such as semen.33 The impact of vector dose on the incidence and severity of other AEs merits further investigation.

Because the ultimate vision for gene therapy is a 1-time cure, the long-term durability of clotting factor expression is critical. Our results highlight what others have found, AAV-based gene therapy for HB appears to produce stable gene expression for at least 10 years whereas FVIII levels in PwHA tend to decline over time, at least with some products.108 Although gene therapy may reduce health care costs in the long-term, current pricing in the United States between $2 to $3 million may be cost-prohibitive for some patients based on their insurance coverage, geographic location, and health care system. Further study on duration of effect may yield a better understanding of the cost-effectiveness of gene therapy.125 Additionally, long-term data regarding safety and potential toxicities such as risk for insertional mutagenesis need to be further explored through long-term follow-up.126,127 

Our results are in general alignment with another recently published systematic review and meta-analysis on AAV-based gene therapy for hemophilia by Han et al,128 which also demonstrated significant reductions in ABR and AIR after vector infusion. However, we believe that our point estimates are more accurate because we combined successive publications of the same trial into 1 set of outcomes. In contrast, Han et al counted multiple publications of the same trial with the same participants as distinct studies with distinct outcomes, an error known as double-counting bias.129 

A key strength of our analysis is its completeness. By extracting data from peer-reviewed manuscripts, conference proceedings, and ClinicalTrials.gov, we were able to include data with the longest follow-up and most complete outcomes.

Our study also has limitations. First, all of the included studies followed a nonrandomized, single-group pre/post (before/after) design rather than a randomized controlled trial, although this is a typical and reasonable approach when recruitable participants are limited in rare diseases.130 This trial design limited our ability to directly compare gene therapies with other therapies of interest such as emicizumab and extended half-life factor prophylaxis. A second limitation is the intrinsic heterogeneity between different gene therapy products and certain aspects of their study designs. Nevertheless, the similar use of AAV vectors, study populations, pre/post study designs, and outcomes support the pooling of data in this context. The direction of treatment effect was uniformly in favor of gene therapy for the primary outcome (ABR), further supporting our use of meta-analysis. Finally, there were limitations to data availability. Some trials were only published as abstracts, or their latest results were published as abstracts with incomplete reporting of methods and outcomes. When possible, patient-level data were used, but they were not uniformly available.

In conclusion, our results demonstrate that AAV-based gene therapies for both HA and HB significantly reduce ABR, AIR, and factor use with achievement of hemostatic factor levels and an acceptable safety profile. FIX levels generally remained stable over 2 years, whereas FVIII levels showed a tendency to decline over time. The place of gene therapy in the evolving landscape of hemophilia treatment remains to be determined. Although uptake has been slow to date,131 AAV-based gene therapy represents an attractive option for patients who place a high value on freedom from regular treatment. Efforts to expand eligibility, minimize anticapsid immune responses, improve durability of factor expression, reduce costs, and expand access will only augment the potential of this game-changing therapy.

Contribution: S.R.D. and K.J. performed the literature search, data screening, data collection, quality appraisal of studies, and manuscript drafting; J.T. and Y.C. assisted with the statistical analysis, and reviewed and edited the manuscript; A.P. provided guidance during all phases of this project in addition to performing a thorough review of the manuscript; A.C. designed the study, provided guidance during all phases of the project, and wrote the manuscript; and all authors reviewed, edited, and approved the final version of the manuscript.

Conflict-of-interest disclosure: A.C. has served as a consultant for MingSight, Pfizer, Sanofi, and Synergy, and has received authorship royalties from UpToDate. A.P. has served on the advisory board for BioMarin and receives authorship royalties from UpToDate. The remaining authors declare no competing financial interests.

Correspondence: Saarang R. Deshpande, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104; email: [email protected].

1.
Iorio
A
,
Stonebraker
JS
,
Chambost
H
, et al
.
Establishing the prevalence and prevalence at birth of hemophilia in males: a meta-analytic approach using national registries
.
Ann Intern Med
.
2019
;
171
(
8
):
540
-
546
.
2.
Srivastava
A
,
Santagostino
E
,
Dougall
A
, et al
.
WFH guidelines for the management of hemophilia, 3rd edition [published correction appears in Haemophilia. 2021;27(4):699]
.
Haemophilia
.
2020
;
26
(
suppl 6
):
1
-
158
.
3.
Carcao
MD
.
The diagnosis and management of congenital hemophilia
.
Semin Thromb Hemost
.
2012
;
38
(
7
):
727
-
734
.
4.
Mahlangu
J
,
Oldenburg
J
,
Paz-Priel
I
, et al
.
Emicizumab prophylaxis in patients who have hemophilia A without inhibitors
.
N Engl J Med
.
2018
;
379
(
9
):
811
-
822
.
5.
Matsushita
T
,
Shapiro
A
,
Abraham
A
, et al
.
Phase 3 trial of concizumab in hemophilia with inhibitors
.
N Engl J Med
.
2023
;
389
(
9
):
783
-
794
.
6.
Nathwani
AC
.
Gene therapy for hemophilia
.
Hematology Am Soc Hematol Educ Program
.
2019
;
2019
(
1
):
1
-
8
.
7.
Ozelo
MC
,
Mahlangu
J
,
Pasi
KJ
, et al
.
Valoctocogene roxaparvovec gene therapy for hemophilia A
.
N Engl J Med
.
2022
;
386
(
11
):
1013
-
1025
.
8.
Pipe
SW
,
Leebeek
FWG
,
Recht
M
, et al
.
Gene therapy with etranacogene dezaparvovec for hemophilia B
.
N Engl J Med
.
2023
;
388
(
8
):
706
-
718
.
9.
Dhillon
S
.
Fidanacogene elaparvovec: first approval
.
Drugs
.
2024
;
84
(
4
):
479
-
486
.
10.
Deshpande
S
,
Joseph
K
,
Cuker
A
,
Pishko
A
. Systematic Reviews and Meta-Analyses on AAV-based Gene Therapy for Hemophilia A and B.
PROSPERO
;
2023
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=444873. Accessed 5 May 2024.
11.
Page
MJ
,
McKenzie
JE
,
Bossuyt
PM
, et al
.
The PRISMA 2020 statement: an updated guideline for reporting systematic reviews
.
Bmj
.
2021
;
372
(
8284
):
1-36
.
12.
National Institute of Health
. Study Quality Assessment Tools.
National Heart, Lung, and Blood Institute
;
2021
https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools. Accessed 5 May 2024.
13.
Copas
J
,
Dwan
K
,
Kirkham
J
,
Williamson
P
.
A model-based correction for outcome reporting bias in meta-analysis
.
Biostatistics
.
2014
;
15
(
2
):
370
-
383
.
14.
Higgins
JPT
,
Thompson
SG
,
Deeks
JJ
,
Altman
DG
.
Measuring inconsistency in meta-analyses
.
BMJ
.
2003
;
327
(
7414
):
557
-
560
.
15.
Cochran
WG
.
The combination of estimates from different experiments
.
Biometrics
.
1954
;
10
(
1
):
101
.
16.
Light
RJ
,
Pillemer
DB
.
Summing up: the science of reviewing research
.
Educ Res
.
1986
;
15
(
8
):
16
.
17.
Egger
M
,
Davey Smith
G
,
Schneider
M
,
Minder
C
.
Bias in meta-analysis detected by a simple, graphical test
.
BMJ
.
1997
;
315
(
7109
):
629
-
634
.
18.
Chowdary
P
,
Shapiro
S
,
Davidoff
AM
, et al
.
A single intravenous infusion of FLT180a results in factor IX activity levels of more than 40% and has the potential to provide a functional cure for patients with haemophilia B
.
Blood
.
2018
;
132
(
suppl 1
):
631
.
19.
Chowdary
P
,
Hamid
C
,
Slatter
D
, et al
.
A novel adeno associated virus (AAV) gene therapy (FLT180a) achieves normal FIX activity levels in severe hemophilia B (HB) patients (B-AMAZE Study)
.
Res Pract Thromb Haemost
.
2020
;
4
(
2
):
334
-
342
.
20.
Chowdary
P
,
Shapiro
S
,
Makris
M
, et al
. Follow-up on a novel adeno-associated virus (AAV) gene therapy (FLT180a) achieving normal FIX activity levels in severe hemophilia B (HB) patients (B-AMAZE Study). Paper presented at.
14th Annual Congress of EAHAD
;
3 February 2021
. Virtual Meeting.
21.
Chowdary
P
,
Shapiro
S
,
Makris
M
, et al
.
Factor IX expression within the normal range prevents spontaneous bleeds requiring treatment following FLT180a gene therapy in patients with severe hemophilia B: long-term follow-up study of the B-Amaze program
.
Blood
.
2021
;
138
(
suppl 1
):
3967
.
22.
Chowdary
P
,
Shapiro
S
,
Makris
M
, et al
.
Phase 1-2 trial of AAVS3 gene therapy in patients with hemophilia B
.
N Engl J Med
.
2022
;
387
(
3
):
237
-
247
.
23.
Chowdary
P
,
Reiss
U
,
Tuddenham
E
, et al
.
GO-8: stable expression of factor VIII over 5 years following adeno-associated gene transfer in subjects with hemophilia A using a novel human factor VIII variant
.
Blood
.
2023
;
142
(
suppl 1
):
3624
.
24.
Coppens
M
,
Pipe
SW
,
Miesbach
W
, et al
.
Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial
.
Lancet Haematol
.
2024
;
11
(
4
):
265
-
275
.
25.
Croteau
SE
,
Eyster
ME
,
Tran
H
, et al
.
Long-term durable FVIII expression with improvements in bleeding rates following AAV-mediated FVIII gene transfer for hemophilia A: multiyear follow-up on the phase I/II trial of SPK-8011
.
Blood
.
2022
;
140
(
suppl 1
):
1899
-
1901
.
26.
Cuker
A
,
Alzahrani
H
,
Astermark
J
, et al
. Efficacy and safety of fidanacogene elaparvovec in adults with moderately severe or severe hemophilia B: results from the phase 3 BENEGENE-2 gene therapy trial. Paper presented at.
Montreal, QC
:
ISTH Congress
;
24 June 2023
.
27.
Davidoff
A
,
Tuddenham
EG
,
Rangarajan
S
, et al
.
Stable factor IX activity following AAV-mediated gene transfer in patients with severe hemophilia B
.
Blood
.
2012
;
120
(
21
):
752
.
28.
Due
F
,
Li
H
,
Wu
X
, et al
.
Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial
.
Lancet Haematol
.
2022
;
9
(
8
):
e567
-
e576
.
29.
Escobar
M
,
Konkle
B
,
Ducore
J
, et al
.
BAX 335 hemophilia B gene therapy phase 1/2 clinical trial: long-term safety and efficacy follow-up
.
Blood
.
2022
;
140
(
suppl 1
):
10656
-
10657
.
30.
George
LA
,
Sullivan
SK
,
Giermasz
A
, et al
.
Spk-9001: adeno-associated virus mediated gene transfer for hemophilia B achieves sustained mean factor IX activity levels of >30% without immunosuppression
.
Blood
.
2016
;
128
(
22
):
3
.
31.
George
LA
,
Sullivan
S
,
Luk
A
, et al
.
Preliminary results of a phase 1/2 trial of SPK-9001, a hyperactive FIX variant delivered by a novel capsid, demonstrate consistent factor IX activity levels at the lowest dose cohort
.
Haemophilia
.
2016
;
22
(
S3
):
33
.
32.
George
LA
,
Ragni
MV
,
Samelson-Jones
BJ
, et al
.
SPK-8011: preliminary results from a phase 1/2 dose escalation trial of an investigational AAV-mediated gene therapy for hemophilia A
.
Blood
.
2017
;
130
(
S1
):
604
.
33.
George
LA
,
Sullivan
SK
,
Giermasz
A
, et al
.
Hemophilia B gene therapy with a high-specific-activity factor IX variant
.
N Engl J Med
.
2017
;
377
(
23
):
2215
-
2227
.
34.
George
LA
,
Sullivan
SK
,
Giermasz
A
, et al
.
Spk-9001: adeno-associated virus mediated gene transfer for hemophilia B - 1 year follow up and impact of baseline characteristics on transgene-derived factor IX activity and persistence
.
Blood
.
2017
;
130
(
S1
):
601
.
35.
George
LA
,
Sullivan
SK
,
Rasko
JE
, et al
.
Efficacy and safety in 15 hemophilia B patients treated with the AAV gene therapy vector fidanacogene elaparvovec and followed for at least 1 year
.
Blood
.
2019
;
134
(
suppl 1
):
3347
.
36.
George
LA
,
Eyster
E
,
Ragni
M
, et al
.
Phase I/II trial of SPK-8011: stable and durable FVIII expression for >2 years with significant ABR improvements in initial dose cohorts following AAV-mediated FVIII gene transfer for hemophilia A
.
Res Pract Thromb Haemost
.
2020
;
4
(
S1
):
10
.
37.
George
LA
,
Ragni
MV
,
Rasko
JEJ
, et al
.
Long-term follow-up of the first in human intravascular delivery of AAV for gene transfer: AAV2-hFIX16 for severe hemophilia B
.
Mol Ther
.
2020
;
28
(
9
):
2073
-
2082
.
38.
George
LA
,
Monahan
PE
,
Eyster
ME
, et al
.
Multiyear factor VIII expression after AAV gene transfer for hemophilia A
.
N Engl J Med
.
2021
;
385
(
21
):
1961
-
1973
.
39.
George
LA
,
Monahan
PE
,
Eyster
ME
, et al
.
Phase I/II trial of SPK-8011: stable and durable FVIII expression after AAV gene transfer for hemophilia A
.
Res Pract Thromb Haemost
.
2021
;
5
(
S2
):
92
.
40.
George
LA
,
Sullivan
SK
,
Rasko
JE
, et al
.
Evaluation of liver health after fidanacogene elaparvovec gene therapy: data from study participants with up to 5 years of follow-up
.
Res Pract Thromb Haemost
.
2021
;
5
(
S2
):
405
.
41.
Giermasz
A
,
Visweshwar
N
,
Harrington
T
, et al
.
Updated results of the Alta study, a phase 1/2 study of giroctocogene fitelparvovec (PF-07055480/SB-525) gene therapy in adults with severe hemophilia A
.
Blood
.
2022
;
140
(
suppl 1
):
7776
-
7777
.
42.
Gomez
E
,
Giermasz
A
,
Castaman
G
, et al
.
Etranacogene dezaparvovec (AAV5-Padua hFIX Variant, AMT-061), an enhanced vector for gene transfer in adults with severe or moderate-severe hemophilia B: 2.5 year data from a phase 2b trial
.
Res Pract Thromb Haemost
.
2021
;
5
(
S2
):
487
.
43.
Harrington
T
,
Giermasz
A
,
Visweshwar
N
, et al
. Four-year follow-up of the Alta study, a phase 1/2 study of giroctocogene fitelparvovec (PF-07055480/SB-525) gene therapy in adults with severe hemophilia A. Paper presented at.
San Diego, CA
:
ASH Annual Meeting & Exposition
;
11 December 2023
. Session 801.
44.
High
KA
,
George
LA
,
Eyster
ME
, et al
.
A phase 1/2 trial of investigational SPK-8011 in hemophilia A demonstrates durable expression and prevention of bleeds
.
Blood
.
2018
;
132
(
suppl 1
):
487
.
45.
Hui
DJ
,
Liu
Y
,
Patel
R
, et al
.
Spk-9001: adeno-associated virus mediated gene transfer for hemophilia B achieves sustained factor IX with minimal immune response
.
Blood
.
2017
;
130
(
S1
):
2056
.
46.
Itzler
R
,
Buckner
TW
,
Leebeek
FWG
, et al
.
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
.
Haemophilia
.
2024
;
30
(
3
):
709
-
719
.
47.
Itzler
R
,
Miller
J
,
Robson
R
, et al
. Improvements in health-related quality of life in adults with severe or moderately severe hemophilia B after receiving etranacogene dezaparvovec gene therapy. Paper presented at.
London, UK
:
ISTH Congress
;
9 July 2022
.
48.
Itzler
R
,
Miller
J
,
Robson
R
, et al
. Improvements in health-related quality of life in adults with severe or moderately severe hemophilia B after receiving etranacogene dezaparvovec gene therapy. Paper presented at.
Montreal, QC
:
ISTH Congress
;
24 June 2023
.
49.
Klamroth
R
,
Bonner
A
,
Gomez
K
, et al
.
Indirect treatment comparisons of the gene therapy etranacogene dezaparvovec versus extended half-life factor IX therapies for severe or moderately severe haemophilia B
.
Haemophilia
.
2024
;
30
(
1
):
75
-
86
.
50.
Konkle
BA
,
Stine
K
,
Visweshwar
N
, et al
. Initial results of the Alta study, a phase 1/2, open label, adaptive, dose-ranging study to assess the safety and tolerability of SB-525 gene therapy in adult subjects with hemophilia A. Paper presented at.
Melbourne, Australia
:
ISTH Congress
;
6 July 2019
.
51.
Konkle
BA
,
Stine
K
,
Visweshwar
N
, et al
.
Updated follow-up of the Alta study, a phase 1/2, open label, adaptive, dose-ranging study to assess the safety and tolerability of SB-525 gene therapy in adult patients with severe hemophilia A
.
Blood
.
2019
;
134
(
suppl 1
):
2060
.
52.
Konkle
BA
,
Walsh
CE
,
Escobar
MA
, et al
.
BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression
.
Blood
.
2021
;
137
(
6
):
763
-
774
.
53.
Laffan
M
,
Rangarajan
S
,
Lester
W
, et al
. Hemostatic results for up to 6 years following treatment with valoctocogene roxaparvovec, an AAV5-hFVIII-SQ gene therapy for severe hemophilia A. Paper presented at.
London, UK
:
ISTH Congres
;
9 July 2022
.
54.
Leavitt
AD
,
Konkle
BA
,
Stine
KC
, et al
.
Updated follow-up of the Alta study, a phase 1/2 study of giroctocogene fitelparvovec (SB-525) gene therapy in adults with severe hemophilia A
.
Blood
.
2020
;
136
(
suppl 1
):
12
.
55.
Leavitt
AD
,
Konkle
BA
,
Stine
KC
, et al
.
Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study
.
Blood
.
2024
;
143
(
9
):
796
-
806
.
56.
Leebeek
FW
,
Tangelder
M
,
Meijer
K
, et al
.
Interim results from a dose escalating study of AMT-060 (AAV5-hFIX) gene transfer in adult patients with severe hemophilia B
.
Blood
.
2016
;
128
(
22
):
2314
.
57.
Leebeek
FW
,
Meijer
K
,
Coppens
M
, et al
.
Stable elevations in FIX activity and reductions in annualized bleeding rate over up to 2 years of follow-up of adults with severe or moderate-severe hemophilia B treated with AMT-060 (AAV5-hFIX) gene therapy
.
Blood
.
2017
;
130
(
S1
):
602
.
58.
Leebeek
F
,
Meijer
K
,
Coppens
M
, et al
.
Reduction in annualized bleeding and factor IX consumption up to 2.5 years in adults with severe or moderate-severe hemophilia B treated with AMT-060 (AAV5-hFIX) gene therapy
.
Blood
.
2018
;
132
(
suppl 1
):
3476
.
59.
Leebeek
FW
,
Meijer
K
,
Coppens
M
, et al
.
AMT-060 gene therapy in adults with severe or moderate-severe hemophilia B confirm stable FIX expression and durable reductions in bleeding and factor IX consumption for up to 5 years
.
Blood
.
2020
;
136
(
suppl 1
):
26
.
60.
Leebeek
FW
,
Miesbach
W
,
Recht
M
, et al
.
Clinical outcomes in adults with hemophilia B with and without pre-existing neutralizing antibodies to AAV5: 6 month data from the phase 3 etranacogene dezaparvovec HOPE-B gene therapy trial
.
Res Pract Thromb Haemost
.
2021
;
5
(
S2
):
92
-
93
.
61.
Long
B
,
Kim
B
,
Wong
WY
, et al
.
Interim analysis of immunogenicity to the vector capsid and transgene-expressed human FVIII in a phase-1/2 clinical study of BMN 270, an AAV5-mediated gene therapy for hemophilia A
.
Blood
.
2017
;
130
(
S1
):
4611
.
62.
Long
BR
,
Veron
P
,
Kuranda
K
, et al
.
Early phase clinical immunogenicity of valoctocogene roxaparvovec, an AAV5-mediated gene therapy for hemophilia A
.
Mol Ther
.
2021
;
29
(
2
):
597
-
610
.
63.
Madan
B
,
Ozelo
MC
,
Raheja
P
, et al
.
Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A
.
J Thromb Haemost
.
2024
;
22
(
7
):
1880
-
1893
.
64.
Mahlangu
J
,
von Drygalski
A
,
Shapiro
S
. Efficacy and safety of valoctocogene roxaparvovec gene transfer for severe hemophilia A: results from the GENEr8-1 three year analysis. Paper presented at.
Frankfurt, Germany
:
GTH Congress
;
21 February 2023
.
65.
Miesbach
W
,
Meijer
K
,
Coppens
M
, et al
.
Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B
.
Blood
.
2018
;
131
(
9
):
1022
-
1031
.
66.
Miesbach
W
,
Meijer
K
,
Coppens
M
, et al
.
Stable FIX expression and durable reductions in bleeding and factor IX consumption for up to 4 years following AMT-060 gene therapy in adults with severe or moderate-severe hemophilia B
.
Blood
.
2019
;
134
(
suppl 1
):
2059
.
67.
Miesbach
W
,
Meijer
K
,
Coppens
M
, et al
.
Five year data confirms stable FIX expression and sustained reductions in bleeding and factor IX use following amt-060 gene therapy in adults with severe or moderate-severe hemophilia B
.
Res Pract Thromb Haemost
.
2021
;
5
(
S2
):
90
.
68.
Miesbach
W
,
Leebeek
FW
,
Recht
M
, et al
. Final analysis from the pivotal phase 3 HOPE-B gene therapy trial: stable steady-state efficacy and safety of etranacogene dezaparvovec in adults with severe or moderately severe hemophilia B. Paper presented at.
15th Annual Congress of EAHAD
;
2 February 2022
. Virtual Meeting.
69.
Miesbach
W
,
Recht
M
,
Key
NS
,
Sivamurthy
K
,
Monahan
PE
,
Pipe
SW
.
Durability of factor IX activity and bleeding rate in people with severe or moderately severe hemophilia B after 5 years of follow-up in the phase 1/2 study of AMT-060, and after 3 years of follow-up in the phase 2b and 2 years of follow-up in the phase 3 studies of etranacogene dezaparvovec (AMT-061)
.
Blood
.
2022
;
140
(
suppl 1
):
4913
-
4914
.
70.
Miesbach
W
,
Recht
M
,
Key
N
, et al
.
Durability of factor IX activity and bleeding rate in people with severe or moderately severe haemophilia B after long-term follow-up in the phase 1/2 study of AMT-060, and phase 2b and phase 3 studies of etranocogene dezaparvovec (AMT-061)
.
Hämostaseologie
.
2023
;
43
(
S1
):
46
-
47
.
71.
Miesbach
W
,
Croteau
SE
,
Eyster
E
, et al
.
Long-term FVIII expression with reduced bleeding following gene transfer for hemophilia A: follow-up on the dirloctocogene samoparvovec phase I/II trial
.
Hämostaseologie
.
2024
;
44
(
S1
):
80
-
81
.
72.
Nathwani
AC
,
Tuddenham
EG
,
Rangarajan
S
, et al
.
Adenovirus-associated virus vector-mediated gene transfer in hemophilia B
.
N Engl J Med
.
2011
;
365
(
25
):
2357
-
2365
.
73.
Nathwani
AC
,
Reiss
UM
,
Tuddenham
EG
, et al
.
Long-term safety and efficacy of factor IX gene therapy in hemophilia B
.
N Engl J Med
.
2014
;
371
(
21
):
1994
-
2004
.
74.
Nathwani
AC
,
Tuddenham
E
,
Chowdary
P
, et al
.
GO-8: preliminary results of a phase I/II dose escalation trial of gene therapy for hemophilia A using a novel human factor VIII variant
.
Blood
.
2018
;
132
(
suppl 1
):
489
.
75.
Nathwani
AC
,
Reiss
U
,
Tuddenham
E
, et al
.
Adeno-associated mediated gene transfer for hemophilia B: 8 year follow up and impact of removing "empty viral particles" on safety and efficacy of gene transfer
.
Blood
.
2018
;
132
(
suppl 1
):
491
.
76.
O’Mahony
B
,
Dunn
AL
,
Leavitt
AD
, et al
.
Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1
.
J Thromb Haemost
.
2023
;
21
(
12
):
3450
-
3462
.
77.
O'Mahony
B
,
Mahlangu
J
,
Peerlinck
K
, et al
.
Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1
.
Blood
.
2021
;
138
(
suppl 1
):
4916
.
78.
O’Mahony
B
,
Mahlangu
J
,
Peerlinck
K
, et al
. Impact of valoctocogene roxaparvovec gene transfer for severe haemophilia A on health related quality of life. Paper presented at.
15th Annual Congress of EAHAD
;
2 February 2022
. Virtual Meeting.
79.
Ozelo
MC
,
Pasi
KJ
,
Rangarajan
S
, et al
.
A first in-human four-year follow-up study of durable therapeutic efficacy and safety of AAV gene therapy with valoctocogene roxaparvovec for severe hemophilia A
.
Hematol Transfus Cell Ther
.
2020
;
42
(
S2
):
60
.
80.
Ozelo
MC
,
Mahlangu
J
,
Pasi
KJ
, et al
. Efficacy and safety of valoctocogene roxaparvovec adeno-associated virus gene transfer for severe hemophilia a: results from the phase 3 Gener8-1 trial. Paper presented at.
Philadelphia, PA
:
ISTH Congress
;
17 July 2021
.
81.
Ozelo
MC
,
Mahlangu
J
,
Madan
B
, et al
.
Bleeding, FVIII activity, and safety 3 years after gene transfer with valoctocogene roxaparvovec: results from Gener8-1
.
Hematol Transfus Cell Ther
.
2023
;
45
(
S4
):
451
-
452
.
82.
Pasi
KJ
. Interim results from a phase 1/2 AAV5-FVIII gene transfer in patients with severe hemophilia A. Paper presented at.
Berlin, Germany
:
ISTH Congress
;
10 July 2017
.
83.
Pasi
KJ
,
Rangarajan
S
,
Kim
B
, et al
.
Achievement of normal circulating factor VIII activity following BMN 270 AAV5-FVIII gene transfer: interim, long term efficacy and safety results from a phase 1/2 study in patients with severe hemophilia a
.
Blood
.
2017
;
130
(
S1
):
603
.
84.
Pasi
KJ
,
Rangarajan
S
,
Mitchell
N
, et al
. First-in-human evidence of durable therapeutic efficacy and safety of AAV gene therapy over three-years with valoctogene roxaparvovec for severe hemophilia A (BMN 270-201 study). Paper presented at.
Melbourne, Australia
:
ISTH Congress
;
8 July 2019
.
85.
Pasi
KJ
,
Rangarajan
S
,
Mitchell
N
, et al
.
Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for Hemophilia A
.
N Engl J Med
.
2020
;
382
(
1
):
29
-
40
.
86.
Pasi
KJ
,
Rangarajan
S
,
Robinson
TM
, et al
. Hemostatic response is maintained for up to 5 years following treatment with valoctocogene roxaparvovec, an AAV5-hFVIII-SQ gene therapy for severe hemophilia A. Paper presented at.
Philadelphia, PA
:
ISTH Congress
;
17 July 2021
.
87.
Pasi
KJ
,
Laffan
M
,
Rangarajan
S
, et al
.
Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A
.
Haemophilia
.
2021
;
27
(
6
):
947
-
956
.
88.
Pipe
SW
,
Stine
K
,
Rajasekhar
A
, et al
.
Single ascending dose-finding trial of DTX101 (AAVrh10FIX) in patients with moderate/severe hemophilia B that demonstrated meaningful but transient expression of human factor IX (hFIX)
.
Blood
.
2017
;
130
(
S1
):
3331
.
89.
Pipe
SW
,
Becka
M
,
Detering
E
,
Vanevski
K
,
Lissitchkov
T
.
First-in-human gene therapy study of AAVhu37 capsid vector technology in severe hemophilia A
.
Blood
.
2019
;
134
(
suppl 1
):
4630
.
90.
Pipe
SW
,
Giermasz
A
,
Castaman
G
, et al
.
One year data from a phase 2b trial of AMT-061 (AAV5-padua hfix variant), an enhanced vector for gene transfer in adults with severe or moderate-severe hemophilia B
.
Blood
.
2019
;
134
(
suppl 1
):
3348
.
91.
Pipe
SW
,
Miesbach
W
,
von Drygalski
A
, et al
. Recent progress in the development of AMT-061 (etranacogene dezaparvovec) for persons with severe or moderately severe hemophilia B. Paper presented at.
World Federation of Hemophilia Summit
;
14 June 2020
. Virtual Meeting.
92.
Pipe
SW
,
Recht
M
,
Key
NS
, et al
.
First data from the phase 3 HOPE-B gene therapy trial: efficacy and safety of etranacogene dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in adults with severe or moderate-severe hemophilia B treated irrespective of pre-existing anti-capsid neutralizing antibodies
.
Blood
.
2020
;
136
(
suppl 2
):
LBA-6
.
93.
Pipe
SW
,
Ferrante
F
,
Reis
M
, et al
.
First-in-human gene therapy study of AAVhu37 capsid vector technology in severe hemophilia A - BAY 2599023 has broad patient eligibility and stable and sustained long-term expression of FVIII
.
Blood
.
2020
;
136
(
suppl 1
):
44
-
45
.
94.
Pipe
SW
,
Hay
CRM
,
Sheehan
J
, et al
.
First-in-human gene therapy study of AAVhu37 capsid vector technology in severe hemophilia A: safety and FVIII activity results
.
Res Pract Thromb Haemost
.
2020
;
4
(
S1
):
27
-
28
.
95.
Pipe
SW
,
Recht
M
,
Key
NS
, et al
. Efficacy and safety of etranacogene dezaparvovec in adults with severe or moderate-severe hemophilia B: first data from the phase 3 HOPE-B gene therapy trial. Paper presented at.
14th Annual Congress of EAHAD
;
3 February 2021
. Virtual Meeting.
96.
Pipe
SW
,
Leebeek
FWG
,
Recht
M
, et al
. 26 week efficacy and safety of etranacogene dezaparvovec (AAV5-Padua HFIX variant; AMT-061) in adults with severe or moderate-severe hemophilia B treated in the Phase 3 HOPE-B clinical trial. Paper presented at.
EHA Congress
;
9 June 2021
. Virtual Meeting.
97.
Pipe
SW
,
Leebeek
FW
,
Recht
M
, et al
. 52 week efficacy and safety of etranacogene dezaparvovec in adults with severe or moderate-severe hemophilia B: data from the phase 3 HOPE-B gene therapy trial. Paper presented at.
Philadelphia, PA
:
ISTH Congress
;
17 July 2021
.
98.
Pipe
SW
,
Hay
C
,
Sheehan
J
, et al
.
Evolution of AAV vector gene therapy is ongoing in hemophilia. Will the unique features of BAY 2599023 address the outstanding needs?
.
Res Pract Thromb Haemost
.
2021
;
5
(
S2
):
490
.
99.
Pipe
SW
,
Sheehan
J
,
Coppens
M
, et al
.
First-in-human dose-finding study of AAVhu37 vector-based gene therapy: BAY 2599023 has stable and sustained expression of FVIII over 2 years
.
Blood
.
2021
;
138
(
suppl 1
):
3971
.
100.
Pipe
SW
,
Ozelo
M
,
Kenet
G
, et al
.
Relationship between endogenous, transgene FVIII expression and bleeding events following valoctocogene roxaparvovec gene transfer for severe hemophilia A: a post-hoc analysis of the GENEr8-1 phase 3 trial
.
Blood
.
2021
;
138
(
suppl 1
):
3972
.
101.
Pipe
SW
,
Leebeek
FW
,
Recht
M
, et al
.
Adults with severe or moderately severe hemophilia B receiving etranacogene dezaparvovec in the HOPE-B phase 3 clinical trial continue to experience a stable increase in mean Factor IX activity levels and durable hemostatic protection after 24 months’ follow-up
.
Blood
.
2022
;
140
(
suppl 1
):
4910
-
4912
.
102.
Pipe
SW
,
Leebeek
FW
,
Recht
M
, et al
.
Durability of bleeding protection and factor IX activity levels are demonstrated in individuals with and without adeno-associated virus serotype 5 neutralizing antibodies (titers <1:700) with comparable safety in the phase 3 HOPE-B clinical trial of etranacogene dezaparvovec gene therapy for hemophilia B
.
Blood
.
2022
;
140
(
suppl 1
):
4904
-
4906
.
103.
Pipe
SW
,
Leebeek
FW
,
Recht
M
, et al
. Phase 3 HOPE-B trial of etranacogene dezaparvovec in severe/moderately severe hemophilia B. Paper presented at.
Montreal, QC
:
ISTH Congress
;
24 June 2023
.
104.
Pipe
S
,
van der Valk
P
,
Verhamme
P
, et al
.
Long-term bleeding protection, sustained FIX activity, reduction of FIX consumption and safety of hemophilia B gene therapy: results from the HOPE-B trial 3 years after administration of a single dose of etranacogene dezaparvovec in adult patients with severe or moderately severe hemophilia B
.
Blood
.
2023
;
142
(
suppl 1
):
1055
.
105.
Pipe
S
,
van der Valk
P
,
Verhamme
P
, et al
.
Etranacogene dezaparvovec shows sustained efficacy and safety in adult patients with severe or moderately severe haemophilia B 3 years after administration in the HOPE-B trial
.
Hämostaseologie
.
2024
;
44
(
S1
):
35
-
36
.
106.
Ragni
MV
,
Evans
M
,
Croteau
SE
, et al
. Improved quality of life in people with hemophilia A following gene therapy with dirloctocogene sampoparvovec (SPK-8011). Paper presented at.
Montreal, QC
:
ISTH Congress
;
25 June 2023
.
107.
Rangarajan
S
,
Walsh
L
,
Lester
W
, et al
.
AAV5-factor VIII gene transfer in severe hemophilia A
.
N Engl J Med
.
2017
;
377
(
26
):
2519
-
2530
.
108.
Reiss
UM
,
Davidoff
AM
,
Tuddenham
EG
, et al
.
Stable therapeutic transgenic FIX levels for more than 10 years in subjects with severe hemophilia B who received scAAV2/8-LP1-Hfixco adeno-associated virus gene therapy
.
Blood
.
2023
;
142
(
suppl 1
):
1056
.
109.
Samelson-Jones
BJ
,
Sullivan
SK
,
Rasko
JE
, et al
.
Follow-up of more than 5 years in a cohort of patients with hemophilia B treated with fidanacogene elaparvovec adeno-associated virus gene therapy
.
Blood
.
2021
;
138
(
suppl 1
):
3975
.
110.
Samelson-Jones
BJ
,
Ragni
MV
,
Rasko
JE
, et al
. Improved joint health after gene therapy with dirloctocogene sampoparvovec (SPK-8011) in people with hemophilia A. Paper presented at.
Montreal, QC
:
ISTH Congress
;
25 June 2023
.
111.
Skinner
M
,
Chen
E
,
Ibrahim
Q
, et al
. Gene therapy in hemophilia A: the impact of valoctocogene roxaparvovec on patient outcomes - initial results from patient reported outcomes, burdens and experiences (PROBE) from Gener8-1 trial. Paper presented at.
Montreal, QC
:
ISTH Congress
;
25 June 2023
.
112.
Symington
E
,
Rangarajan
S
,
Lester
W
, et al
.
Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post-treatment
.
Haemophilia
.
2024
;
30
(
2
):
320
-
330
.
113.
Sullivan
SK
,
Barrett
JC
,
Drelich
DA
, et al
.
SPK-8016: preliminary results from a phase 1/2 clinical trial of gene therapy for hemophilia A [abstract]
.
Haemophilia
.
2021
;
27
:
129
.
114.
Sullivan
S
,
High
KA
,
George
LA
, et al
. AAV-mediated gene therapy for hemophilia B - expression at therapeutic levels with low vector doses. Paper presented at.
Copenhagen, Denmark
:
EHA Congress
;
11 June 2016
.
115.
Tuddenham
E
.
Gene therapy for haemophilia B
.
Haemophilia
.
2012
;
18
(
suppl 4
):
13
-
17
.
116.
Visweshwar
N
,
Harrington
TJ
,
Leavitt
AD
, et al
.
Updated results of the Alta study, a phase 1/2 study of giroctocogene fitelparvovec (PF-07055480/SB-525) gene therapy in adults with severe hemophilia A
.
Blood
.
2021
;
138
(
suppl 1
):
564
.
117.
von Drygalski
A
,
Giermasz
A
,
Castaman
G
, et al
.
Etranacogene dezaparvovec (AAV5-Padua hFIX variant), an enhanced vector for gene transfer in adults with severe or moderate-severe hemophilia B: two year data from a phase 2b trial
.
Blood
.
2020
;
136
(
suppl 1
):
13
.
118.
von Drygalski
A
,
Gomez
E
,
Giermasz
A
, et al
.
Stable and durable factor IX levels in patients with hemophilia B over 3 years after etranacogene dezaparvovec gene therapy
.
Blood Adv
.
2023
;
7
(
19
):
5671
-
5679
.
119.
von Mackensen
S
,
George
LA
,
Galvao
AM
, et al
. Preliminary results of SPK-9001 gene transfer demonstrate statistical improvements on the health related quality of life in adults with haemophilia B. Paper presented at.
Berlin, Germany
:
ISTH Congress
;
11 July 2017
.
120.
von Mackensen
S
. Health-related quality of life improvements in adult haemophilia B patients at one year follow-up after receiving SPK-9001 gene transfer. Paper presented at.
Melbourne, Australia
:
ISTH Congress
;
6 July 2019
.
121.
von Mackensen
S
,
Ducore
JM
,
George
LA
, et al
.
Health-related quality of life in adults with hemophilia B after receiving gene therapy with fidanacogene elaparvovec
.
Blood
.
2023
;
142
(
suppl 1
):
3628
.
122.
Yamaguti-Hayakawa
GG
,
Ricciardi
JB
,
Frade-Guanaes
J
, et al
. The impact of gene therapy on the musculoskeletal health of patients with severe hemophilia A. Paper presented at.
Montreal, QC
:
ISTH Congress
;
25 June 2023
.
123.
Young
G
,
Chowdary
P
,
Barton
S
, et al
. Results from B-LIEVE, a phase 1/2 dose-confirmation study of FLT180a AAV gene therapy in patients with hemophilia B. Paper presented at.
London, UK
:
ISTH Congress
;
24 June 2023
.
124.
Manno
CS
,
Pierce
GF
,
Arruda
VR
, et al
.
Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response
.
Nat Med
.
2006
;
12
(
3
):
342
-
347
.
125.
Bolous
NS
,
Chen
Y
,
Wang
H
, et al
.
The cost-effectiveness of gene therapy for severe hemophilia B: microsimulation study from the United States Perspective
.
Blood
.
2021
;
138
(
18
):
1677
-
1690
.
126.
Sidonio
RF Jr
,
Pipe
SW
,
Callaghan
MU
,
Valentino
LA
,
Monahan
PE
,
Croteau
SE
.
Discussing investigational AAV gene therapy with hemophilia patients: a guide
.
Blood Rev
.
2021
;
47
(
1
):
1-12
.
127.
Leebeek
FWG
,
Miesbach
W
.
Gene therapy for hemophilia: a review on clinical benefit, limitations and remaining issues
.
Blood
.
2021
;
138
(
11
):
923
-
931
.
128.
Han
Z
,
Yi
X
,
Li
J
,
Liao
D
,
Gao
G
,
Ai
J
.
Efficacy and safety of adeno-associated virus-based clinical gene therapy for hemophilia: a systematic review and meta-analysis
.
Hum Gene Ther
.
2024
;
35
(
3-4
):
93
-
103
.
129.
Senn
SJ
.
Overstating the evidence: double counting in meta-analysis and related problems
.
BMC Med Res Methodol
.
2009
;
9
(
1
):
1
-
7
.
130.
Auerswald
G
,
Šalek
SZ
,
Benson
G
, et al
.
Beyond patient benefit: clinical development in hemophilia
.
Hematology
.
2012
;
17
(
1
):
1
-
8
.
131.
Beasley
D
. Uptake of New Hemophilia Gene Therapies Slow as Field Assesses Options.
Reuters
;
2023
Accessed 14 August 2024. https://www.reuters.com/business/healthcare-pharmaceuticals/uptake-new-hemophilia-gene-therapies-slow-field-assesses-options-2023-12-15/.

Author notes

Data are available on request from the corresponding author, Saarang R. Deshpande ([email protected]).

The full-text version of this article contains a data supplement.

Supplemental data