• ClinicalTrials.gov Identifier:  NCT03569891¹
• Hope-B Trial, Phase III, Open-label, Single-dose

The clinical trial status is reported on ClinicalTrials.gov¹ as follows:

• Status: Completed
• Last Update Posted: 2025-05-04

Information on the approval status of etranacogene dezaparvovec was collected from References #2 and #3 and is summarised below:

• In November 2022, etranacogene dezaparvovec was approved in the United States for the treatment of haemophilia B.
• In December 2022, it received a positive opinion in the European Union for the treatment of haemophilia B.
• On February 28, 2023, the European Medicines Agency (EMA) granted conditional marketing authorization.

• Males ≥18 years with severe or moderate-severe HB (FIX≤2%)
• Pts. with/without pre-existing NAbs to AAV5⁴
• >150 previous EDs of treatment with FIX protein¹

• Previous gene therapy treatment

AAV5/ Insect cells, baculovirus expression system^{5 [Supplementary Appendix]}

Codon-opimized FIX-Padua variant⁵

• LP1 that is a smaller variant of the originally constructed APOE-HCR/hAAT enhancer/promoter^5, 6 
• LP1 is also used in AMT-060 vector (AAV5-wt FIX)⁷

Systemic

Data regarding the vector dose cohort was collected from reference #5:

• A total of 54 participants received etranacogene dezaparvovec (2e13 gc/kg)
• One participant prematurely discontinued treatment after an AE of hypersensitivity that occurred after a partial dose (approx. 10% of the full dose) had been received

Initially, follow-up durations were reported by different publications as follows:

• A 26-week follow-up period following a lead-in period of ≥64 weeks^{4, 8, 9}

Subsequently, long-term follow-up durations were reported in Reference #5 as follows:

• Participants were followed for 18 months after treatment to assess efficacy and safety
• Participants then entered a long-term follow-up phase extending up to 5 years after dosing

OS and CH  as reported here⁵

Early follow-up data on endogenous FIX activity at Week 26, in relation to pre-therapy NAb titers, were reported in References #4 and #8 as follows:

• One participant with a NAb titer of 3212.3 did not respond to treatment, and another participant with a titer of 198 received a partial dose and remained on prophylaxis
• No correlation between NAb titer and FIX activity was observed for titers up to 678.2 (n = 52; R² = 0.078)

Follow-up data on mean FIX transgene activity assessed by one-stage (OS) and chromogenic assay (CH) through month 18 were published in Reference #5 and are summarized as follows:    

• The mean FIX activity was 31.1% and 39.9% for participants with and without preexisting anti-AAV5 neutralizing antibodies, respectively, at 18 months after treatment
• At diagnosis, most participants (44; 81%) had FIX activity of <1%

Mean FIX activity levels over 4 years after gene therapy among AAV5 neutralizing antibody–negative (NAb–) participants (33/54), as reported in Reference #14, are summarized below:

Final analysis data from the 5-year follow-up on endogenous FIX activity were extracted from Reference #15 and are summarized in the table below:

Endogenous FIX activity data through four years after etranacogene dezaparvovec infusion in participants with preexisting AAV5 neutralizing antibodies (NAb+; n = 21) were extracted from the Results section of Reference #16 and are summarized below:

  ᵃ Sample availability:

• At Year 1, one participant had no sample and two samples were contaminated by exogenous FIX use.
• At Year 4, four participants had no sample, including the participant who underwent liver transplantation, and two samples were contaminated by exogenous FIX use.

Additional findings on endogenous FIX activity from Reference #16 are summarized as follows:

• Relationship to baseline AAV5 NAb titers
  • No clinically meaningful correlation was identified between baseline AAV5 NAb titers and median endogenous FIX activity during Months 7–48
• Nonresponders
  • The participant with the highest baseline NAb titer (3212) had uncontaminated FIX activity of 1.5 IU/dL at the central laboratory and 1 IU/dL at the local laboratory at Week 5
  • The participant who received approximately 10% of the planned dose had uncontaminated FIX activity of 1.7 IU/dL at the central laboratory and 1 IU/dL at the local laboratory at Week 11
  • Both participants were classified as nonresponders because their uncontaminated FIX activity remained ≤2 IU/dL and they continued regular FIX prophylaxis
• FIX activity in participants requiring corticosteroids for ALT elevation
  • Two participants had FIX activity of 16 and 5 IU/dL at or near corticosteroid initiation, respectively, and 13 IU/dL at Year 4 and 11 IU/dL at Month 42, respectively. The latter participant’s Year 4 value was contaminated by exogenous FIX use
  • A third participant had FIX activity of 16 IU/dL at or near corticosteroid initiation, 9.1 IU/dL at the end of tapering, 13 IU/dL at Month 24, and 4 IU/dL at Month 30. This participant resumed continuous FIX prophylaxis between Months 29 and 30, without recurrent ALT elevation
• Liver transplantation
  • One participant underwent liver transplantation at Month 28. His last uncontaminated transgene-derived FIX activity before transplantation was 37 IU/dL
  • Following transplantation, FIX was produced by the donor liver; subsequent efficacy data were therefore excluded from the gene therapy analysis

NAb, neutralizing antibody; FIX, factor IX; SD, standard deviation; ALT, alanine aminotransferase

Not reported

Early follow-up data on ABR were published in Reference #4 and are summarized as follows:

• Relative to lead–in, total bleeds were reduced by 83% and treated bleeds by 91% at Week 26

More detailed data on bleeding episodes during the lead-in phase compared to the post-treatment period were published in Reference #5 and are summarized as follows:

• The ABR for all bleeding episodes decreased after treatment
  • from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period
  • to 1.51 (95% CI, 0.81 to 2.82) in the post-treatment period
• The observed annualized bleeding rate ratio for the post-treatment period as compared with the lead-in period was 0.36 (95% Wald CI, 0.20 to 0.64; two-sided P<0.001)
• 14 participants (26%) had no bleeding episodes during the lead-in period, and this number increased to 34 pts. (63%) after treatment
• The rate ratios for the lead-in period as compared with the post-treatment period were 0.29 for spontaneous bleeding (i.e., a 71% reduction) and 0.22 for joint bleeding (i.e., a 78% reduction)     

Primary and secondary endpoints related to calculated ratios with respect to the observed ABRs were extracted from Table 2 (Reference #5) and are summarized as follows:

  ^a The upper limit of the confidence interval of the ABR ratio was compared with the noninferiority margin of 1.8. If the upper limit was less than 1.8, then noninferiority was declared
  ^b The width of the confidence interval has not been adjusted for multiplicity and may not be used in place of hypothesis testing

ABRs, including spontaneous, joint, and traumatic episodes, were extracted from Table 3 of Reference #5 and summarized in the table below:

  * The lead-in period equated to 33.1 person-years
  † Months 7–18 equated to 49.8 person-years
  ‡ The annualized bleeding rate and comparison of the annualized bleeding rate between the lead-in period and the post-treatment period were estimated from
  a negative binomial regression model involving repeated-measures generalized estimating equations; the paired design of the study was accounted for in the
  model with an offset parameter to account for the differential collection periods. Treatment period was included as a categorical covariate
  § The width of the confidence interval has not been adjusted for multiplicity and may not be used in place of hypothesis testing

ABR outcomes over 4 years after gene therapy in AAV5 neutralizing antibody-negative (NAb–) participants (33/54) were extracted from Reference #14 and are summarized below:

Final analysis data from the 5-year follow-up on ABR were extracted from Reference #15  and are summarized in the table below:

 
  Notes:

• ABR values represent adjusted annualized bleeding rates. Comparisons are between the lead-in period and months 7–60 after gene therapy
• Data are derived from the full analysis population (n = 54)

Unadjusted ABR data through four years after etranacogene dezaparvovec infusion in participants with preexisting AAV5 neutralizing antibodies (NAb+; n = 21) were extracted from Figures 3A and 3B of Reference #16  and are summarized below.

 ᵃFigure 3A labels the lead-in ABR for all bleeds as 4.47, whereas Figure 3B and the Results section report 4.64
  The Results section reports a 74.4% reduction. Values and percentage reductions above are reproduced as labeled in Figure 3A

 
  Notes:

• Values are ABRs; percentages in parentheses are reductions versus lead-in, as labeled in Figure 3B
• All participants assessed in Year 4 were free of spontaneous bleeds

Adjusted ABR findings from the Results section of Reference #16 are summarized as follows:

• Responder analysis
  • Adjusted ABR decreased from 3.05 (95% CI, 2.03–4.56) during lead-in to 0.52 (95% CI, 0.23–1.19) during Months 7–48 (P < 0.0001)
  • This analysis excluded the participant who received approximately 10% of the planned dose and the participant with the highest baseline AAV5 NAb titer (3212)
• Interpretation of adjusted subgroup results
  • These two nonresponders experienced six and five bleeding episodes, respectively, during Months 7–48 while receiving continuous FIX prophylaxis
  • The prespecified statistical rules generated aberrantly elevated adjusted ABRs for these participants, obscuring interpretation of adjusted results for the full NAb+ subgroup

  ABR, annualized bleeding rate; NAb, neutralizing antibody; CI, confidence interval; FIX, factor IX.

Data related to FIX usage and FIX infusion rates were published reference #5 and summarized as follows:

• A total of 52/54 participants (96%) discontinued FIX prophylaxis during the period from day 21 through month 18 after treatment
• Of the remaining 2 participants whose FIX activity was
  • <5% at month 18 and who did not discontinue FIX prophylaxis,
    • one received only approx. 10% of the dose,
    • and the other had the highest day-of-dosing AAV5 neutralizing antibody titer in the study (3212)
• During the lead-in period, participants used a mean of 257,338±149,013 IU of FIX/yr (range, 83,541 to 755,892)
• The mean use of FIX per participant decreased by 248,825 IU per year from the lead-in period to the post-treatment period (P<0.001)
• The annualized FIX infusion rate per participant  decreased
  • from 72.5 infusions (95% CI, 63.6 to 82.7) during the lead-in period
  • to 2.5 infusions (95% CI, 0.92 to 6.96) during months 7-18 after treatment (adjusted rate ratio, 0.03; P<0.001) 
• During months 7 through 18 after treatment, 15 participants received a total of 134 FIX infusions

Data on exogenous FIX use over 4 years after gene therapy among AAV5 neutralizing antibody–negative (NAb–) participants (33/54), as reported in Reference #14, are summarized below:

• Return to prophylaxis:
  • No AAV5 NAb– participant resumed continuous exogenous FIX prophylaxis over 4 years post gene therapy.
• Participants without exogenous FIX use:
  • ~80% per year required no exogenous FIX infusions post gene therapy (Figure 3)
• Bleeds requiring FIX treatment:
  • Lead-in: 82% of total bleeds required FIX treatment.
  • Post gene therapy (Years 1–4 combined): 37% of bleeds required exogenous FIX
• Exogenous FIX consumption (excluding invasive procedures):
  • Lead-in: 264,888 IU/year (SD 153,545)
  • Months 7–48: 1,878 IU/year (SD 3,337)
  • Mean reduction: 263,010 IU/year (SE 26,615); corresponding to 99% decrease (P < .0001)
     

Final analysis data from the 5-year follow-up on FIX consumption were extracted from Reference #15 and are summarized below:

• During months 7–60 after gene therapy, 51 participants (94%) discontinued and did not restart continuous FIX prophylaxis
• Two participants without a treatment response continued FIX prophylaxis:
  • One with a baseline AAV5 NAb titer of 3212.3
  • One who received ~10% of the planned dose
• One participant resumed FIX prophylaxis at 29 months post-gene therapy due to declining FIX activity (3.6 IU/dL) with bleeding events.
• Overall, 51 of 52 responders (98%) maintained durable protection from bleeding without continuous prophylaxis during months 7–60
• Mean annualized exogenous FIX consumption among all participants (excluding use for invasive procedures) decreased substantially following gene therapy:
  • 257,339 IU/year during the lead-in period
  • 10,924 IU/year during months 7–60 post–gene therapy
    → representing a 96% reduction (mean difference: −246,415 IU/year; 95% CI, −287,975 to −204,856)
• When excluding participants who continued or resumed prophylaxis, mean annualized FIX consumption during months 7–60 was 2,979 IU/year

Data on exogenous FIX use through four years after etranacogene dezaparvovec infusion in participants with preexisting AAV5 neutralizing antibodies (NAb+; n = 21) were extracted from Reference #16 and are summarized below. Annualized infusion rates were not reported; the available data describe annualized FIX consumption and freedom from FIX infusions as follows:

• Mean FIX consumption decreased by 90% versus lead-in (P < 0.0001) and remained stable over follow-up.
• Figure 4A shows significantly lower consumption in each of Years 1–4 versus lead-in (all P < 0.0001); exact annual means and SDs were not numerically labeled.

Additional findings on exogenous FIX use from Reference #16 are summarized as follows:

• Participants continuing or resuming prophylaxis
  • Most post-gene therapy exogenous FIX use was attributable to the two participants who remained on FIX prophylaxis and received 162,600 and 109,830 IU/year, respectively, over the four-year follow-up period.
  • Figure 4B shows the distribution of post-treatment FIX consumption among participants as follows:
    • 57% was attributable to the participant who received a partial gene therapy dose
    • 39% was attributable to the participant with an AAV5 NAb titer >3000
    • 4% was attributable to the other 19 NAb+ participants
  • One participant resumed prophylaxis in Year 3, with  annualized exogenous FIX consumption of:
    • 199,590 IU/year in Year 3
    • 256,175 IU/year in Year 4
  • No participant returned to prophylaxis in Year 4
• Freedom from FIX infusions
  • In Year 4, 13 of 18 participants (72%) who remained free from FIX prophylaxis received no exogenous FIX infusions
  • Eight participants received no exogenous FIX infusions throughout the entire post-treatment period

  FIX, factor IX; NAb, neutralizing antibody; SD, standard deviation; AIR, annualized infusion rate

Early follow-up (26 weeks) data on the IRRs for all patients and the subgroups with and without NAbs at Baseline (BL) were reported in References #8 and #9 as follows:

    † The presented percentage values (in parentheses) are not part of the published results and were calculated based on the number of affected patients
       as a proportion of the total number of patients in the corresponding group

• All IRRs were reported on the day of infusion and 8/9 IRRs resolved on the same day9

Additional data on the reported IRRs were published in Reference #5   and #9 and are summarized as follows:

Further IRR data for participants with preexisting AAV5 neutralizing antibodies (NAb+; n = 21) were extracted from Section 3.7 of Reference #16 and are summarized below:

• Incidence and baseline NAb titers
  • IRRs occurred in 5/21 participants (23.8%) with detectable AAV5 NAbs on the day of dosing
  • Four affected participants had AAV5 NAb titers ≥198, and one had a titer of 23
• Infusion discontinuation and subsequent outcome
  • The participant who discontinued infusion after receiving approximately 10% of the planned dose had an AAV5 NAb titer of 198.9 and experienced a moderate suspected hypersensitivity reaction
  • This participant did not respond to gene therapy and continued regular FIX prophylaxis
• Management
  • Management of other IRRs involved observation alone or temporary interruption followed by restarting the infusion at a slower rate, with or without an antihistamine and single-dose hydrocortisone

The NAb+ subgroup denominator in Reference #16 is 21, compared with 23 in the earlier reports summarized above

A detailed assessment data (left table) and early follow-up (right table) data on reported AEs were published in References #5 and #8 and are summarized below:

    a The determination of whether an adverse event was related to treatment was made by the investigators

Data on reported AEs over 4 years after gene therapy among AAV5 neutralizing antibody–negative (NAb–) participants (33/54), as reported in Reference #14, are summarized below:

• Total treatment-emergent AEs (Years 1–4): 455 events.
• Severity distribution:
  • Mild: 78%
  • Moderate: 19%
  • Severe: 3%
• Treatment-related AEs:
  • 22 of 33 participants experienced treatment-related AEs during the first 3 months post-infusion.
  • No treatment-related AEs were reported during months 3–42 of follow-up.
  • 1 participant reported 3 treatment-related AEs during months 43–48.
• Most frequent treatment-related AE:
  • Transient alanine aminotransferase (ALT) elevation in 6 participants (18%).
  • Occurred 22–71 days post infusion.
• ALT elevation characteristics:
  • Peak ALT levels:
    • ~2× ULN in 1 participant
    • 1–2× ULN in 3 participants
    • ~2× baseline ALT but within normal range in 2 participants
    • 5 of 6 participants with treatment-related ALT elevations received corticosteroid therapy.
  • Mean corticosteroid duration: 79.5 days (SD 30.3).
• Timing of treatment-related AEs:
  • Predominantly early after infusion, with very few events beyond year 1.

Further data on reported AEs over 4 years after gene therapy among AAV5 NAb– participants (33/54) were extracted from Figure 4 in Reference #14 and are summarized below.

Comprehensive data on AEs were extracted from Table 1 of the final study analysis (Reference #15) and are summarized in the table below:

    * Safety analysis population.
    † Total number of events; participants may have had more than one event
    ‡ Hepatic steatosis reported during long-term follow-up only

Additional safety findings relevant to treatment-related adverse events were extracted from Reference #15 and are summarized below:

• A total of 100 treatment-related AEs were reported in 39 participants over the 5-year follow-up period, distributed as follows:
  • Year 1: 91 events
  • Year 2: No treatment-related events reported
  • Year 3: 1 event
  • Year 4: 3 events
  • Year 5: 5 events
• The majority of treatment-related AEs occurred within the first 6 months after gene therapy
• 35 SAEs were reported during the 5-year follow-up; no SAEs were considered by the investigators to be related to treatment
• Of the 35 SAEs, 3 occurred during year 5 (hypertensive urgency, procedure-related bleeding, and cardiac amyloidosis that resulted in death)
• In addition, 1 participant died during the study from non–treatment-related cardiogenic shock at day 464 after gene therapy
• Early elevations in ALT levels were observed in 11 participants, defined as ≥2× baseline or greater than the upper limit of normal within <4 months after infusion
• No development of FIX inhibitors or thrombotic events was reported during the 5-year analysis period.
• The following neoplasms were reported in one participant each and were determined to be unrelated to treatment with etranacogene dezaparvovec:
  • Hepatocellular carcinoma (HCC)
  • Schwannoma
  • Myelodysplastic syndrome

Safety data through 48 months after etranacogene dezaparvovec infusion in participants with preexisting AAV5 neutralizing antibodies (NAb+; n = 21) were extracted from Section 3.6 and Table 2 of Reference #16 and are summarized below:

• Overall safety findings
  • All 21 participants experienced at least one AE
  • Of the 308 treatment-emergent AEs, 68.5% were mild, 17.9% were moderate, and 6.8% were severe
• Treatment-related AEs
  • Treatment-related AEs occurred in 15/21 participants (71.4%), comprising 36 events
  • Most treatment-related AEs occurred within the first three months after treatment

• Long-term follow-up
  • One participant resumed continuous FIX prophylaxis between Months 29 and 30 following a treatment-related event involving loss of transgene-derived FIX expression
  • No other treatment-related AEs, FIX inhibitor development, or thrombotic events were reported during Months 3–48

  AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; CRP, C-reactive protein; FIX, factor IX; NAb, neutralizing antibody

No glucocorticoid-related AEs were observed as shown in Table S7 published here⁵

Reported ALT elevations were extracted from Table S6 in Reference #5 and are summarized as follows:

• 11/54 participants (20%) had elevations in ALT levels that were classified most as mild or moderate AEs

Final analysis data on ALT elevations were extracted from Reference #15 and are summarized as follows:

• Early elevations in ALT levels were observed in 11 participants, defined as ≥2× baseline or above the upper limit of normal within <4 months post-infusion
• Of the participants with early ALT elevations:
  • 9 received systemic oral glucocorticoids
  • Mean treatment duration: 81.4 ± 28.6 days (range: 51–130 days)

Further ALT elevation data for participants with preexisting AAV5 neutralizing antibodies (NAb+; n = 21) were extracted from Section 3.8 of Reference #16 and are summarized below:

• Incidence and timing
  • Transient ALT elevations occurred in 3/21 participants (14.3%), all within the first three months after gene therapy
  • Elevations were first observed on Days 24, 28, and 35, respectively
• Magnitude and duration
  • Two participants had ALT levels 1–2 times the upper limit of normal
  • One participant had ALT levels >2 times baseline that remained within the normal range
  • Absolute peak ALT levels were not reported in the supplied section
  • The median maximum duration of ALT elevation was 17 days (range, 15–42 days)
• Corticosteroid treatment
  • All three participants received reactive corticosteroid treatment, initiated 0–10 days after ALT elevation
  • Median treatment duration, including tapering, was 83 days (range, 56–117 days)
• Long-term findings
  • One participant subsequently experienced declining FIX activity and resumed continuous FIX prophylaxis around Month 30, without recurrent ALT elevation
  • No signs of late or long-term hepatotoxicity were observed through four years of follow-up

  ALT, alanine aminotransferase; NAb, neutralizing antibody; FIX, factor IX

Not reported

Not reported

Data on the duration of steroid treatment were collected from Reference #5 and are summarized below as follows:

• 9 of 54 participants (17%) from the 11 participants with ALT elevations received and subsequently discontinued glucocorticoid treatment for the preservation of FIX Padua–expressing hepatocytes
• The mean duration of glucocorticoid use for elevated aminotransferase levels was 79.8±26.6 days (range, 51 to 130)
• All the participants discontinued immune suppression for elevations in aminotransferase levels between day 85 and day 170 after treatment

Statements and observations regarding the reduction or loss of FIX activity associated with ALT elevation were collected from reference #5 and are summarized as follows: 

• Only a minor reduction of transgene expression was observed in association with ALT elevations among participants treated with glucocorticoids
• Eleven participants (20%) had elevations in ALT levels that were reported as AEs; most were mild or moderate (Table S6)
• In 9 of these 11 participants, mean FIX activity was 22.2 ± 10.1% at peak, 17.1 ± 8.1% before glucocorticoid treatment, and 17.9 ± 10.6% at 2 weeks after glucocorticoid treatment
• The mean FIX activity in the 11 participants with elevated ALT levels was 21.6±11.8%, 20.3±11.5%, and 18.1±9.1% at 6, 12, and 18 months after treatment
• No participant resumed continuous FIX prophylaxis

Further statement regarding the reduction or loss of FIX activity associated with ALT elevation were extracted from Reference #15 and are summarized as follows:

• Participants with early ALT elevations generally showed lower mean FIX activity levels over time (remaining within therapeutic range) compared with those without ALT elevations

Reported findings on hepatocellular carcinoma (HCC) malignancy following vector administration, as described in the cited references, are summarized below:

• First reported case of HCC in a participant undergoing liver-directed AAV-based gene therapy affecting 1/54 pts. >65 years, with a history of hepatitis C, hepatitis B and evidence of non-alcoholic fatty liver changes on biopsy10 that are considered as multiple risk factors associated with the  development of liver cancer (References #5, #11,  and #12 )
• After analysis of a biopsy for integration of the AAV vector genome into the cells, no difference was seen between the healthy liver tissue and the liver cancer tissue (References #5 and #11)
• No other cases of HCC have been reported in uniQure clinical trials conducted in more than 100 patients in hemophilia B and other indications, with some patients dosed more than 10 years ago (References #12 and # 13)

Findings relevant to hepatocellular carcinoma surveillance and oncogenic risk assessment following vector administration, as reported in Reference #15, are summarized below:

• HCC developed in one participant and has been previously reported; tumor management and molecular characterization are described in the Supplementary Appendix (Figure S9 and Table S2)
• All three neoplasms (HCC, schwannoma, and myelodysplastic syndrome), each occurring in a single participant, were determined to be unrelated to treatment with etranacogene dezaparvovec based on:
  • Independent molecular characterization of tissue, including vector integration and genomic analysis, as assessed by the investigator
  • Confirmation through independent molecular medicine consultation
• During approximately 500 patient-years of monitored clinical study exposure across related hemophilia B gene therapy programs, no hepatocellular carcinoma with clonal expansion of AAV vector–integrated sequences has been observed
• At 5 years after infusion, no AAV-related oncogenicity was reported in the HOPE-B study
• Long-term surveillance for HCC is ongoing, and participants consenting to extended follow-up will be monitored for up to 15 years post-gene therapy

Further findings on malignancy and genotoxicity in participants with preexisting AAV5 neutralizing antibodies (NAb+) were extracted from Section 3.9 of Reference #16 and are summarized below:

• Myelodysplastic syndrome (MDS) was reported as a serious AE in one NAb+ participant during Year 4
• Molecular investigations showed:
  • No detectable AAV5 vector DNA in tumor or blood samples by polymerase chain reaction using vector-specific primers
  • No vector integration events in affected tissues by whole-genome or target enrichment sequencing
  • A premalignant genetic signature consistent with the development of MDS
• The MDS was considered unrelated to treatment
• No treatment-related oncogenicity was observed through four years after treatment

1. HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients. ClinicalTrials.gov identifier: NCT03569891. Link
2. Heo YA. Etranacogene Dezaparvovec: First Approval. Drugs. 2023 Mar;83(4):347-352. doi: 10.1007/s40265-023-01845-0. PMID: 36802324. Link
3. Hemgenix | European Medicines Agency - European Union. Link
4. Pipe, S.W., 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. ISTH Congress Abstracts, 2021. Thromb Haemost. 2021; 5 (Suppl 2). Link not available.
5. Pipe SW, Leebeek FWG, Recht M, Key NS, Castaman G, Miesbach W, et al. Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B. N Engl J Med. 2023 Feb 23;388(8):706-718. doi: 10.1056/NEJMoa2211644. PMID: 36812434. Link
6. Nathwani AC, Gray JT, Ng CY, Zhou J, Spence Y, Waddington SN, et al. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood. 2006 Apr 1;107(7):2653-2661. doi: 10.1182/blood-2005-10-4035. PMID: 16322469; PMCID: PMC1895379. Link
7. Miesbach W, Meijer K, Coppens M, Kampmann P, Klamroth R, Schutgens R, et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018 Mar 1;131(9):1022-1031. doi: 10.1182/blood-2017-09-804419. PMID: 29246900; PMCID: PMC5833265. Link
8. Leebeek, F.W., 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. ISTH Congress Abstracts, 2021. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). Link not available.
9. Recht, M., et al., Management of Infusion Reactions: Lessons from the Phase 3 HOPE-B Gene Therapy Trial of Etranacogene Dezaparvovec in Adults with Hemophilia B [abstract]. ISTH 2021 Congress, 2021. Res Pract Thromb Haemost. Link not available.
10. Schmidt, M., et al., Liver Safety Case Report from the Phase 3 HOPE-B Gene Therapy Trial in Adults with Hemophilia B. ISTH Congress Abstracts, 2021. Link not available.
11. BioMarin follows up on previously-reported serious adverse event in its phase I/II gene therapy clinical trial for haemophilia A. 2022, WFH World Federation of Hemophilia. Link
12. FDA puts uniQure’s gene therapy clinical programme, HOPE-B, on hold following submission of safety report. 2020: EHC European Haemophilia Consortium.  Link not available.
13. uniQure, uniQure Announces Findings from HCC Case Investigation in HOPE-B Trial for Gene Therapy. 2021, Source: uniQure press release dated March 26, 2021: NHF National Hemophilia Foundation. p. News. Link
14. Raheja P, O'Connell N, Verhamme P, Kampmann P, Lemons RS, Wang F, Gill S, Monahan PE, Le Quellec S, Leebeek FWG. Etranacogene dezaparvovec in people with hemophilia B and without adeno-associated virus serotype 5 neutralizing antibodies: a 4-year subgroup analysis of the Health Outcomes with Padua Gene; Evaluation in Hemophilia B (HOPE-B) trial. Res Pract Thromb Haemost. 2025 Dec 30;10(1):103321. doi: 10.1016/j.rpth.2025.103321. PMID: 41624239; PMCID: PMC12857339. Link
15. Pipe SW, Miesbach W, Recht M, Leebeek FWG, Key NS, Castaman G, Lattimore S, Coppens M, Le Quellec S, Mahajan V, Gill S, Drelich D, Monahan PE; HOPE-B Study Group Investigators. Final Analysis of a Study of Etranacogene Dezaparvovec for Hemophilia B. N Engl J Med. 2026 Jan 29;394(5):463-474. doi: 10.1056/NEJMoa2514332. Epub 2025 Dec 7. PMID: 41358585. Link
16. Klamroth R, Monahan PE, Van der Valk P, Quon D, Kazmi RS, Coppens M, O'Connell N, Pipe SW, von Drygalski A, Afzal S, Gabriel R, Youssar L, Gill S, Jansen N, Wang F, Le Quellec S, Hermans C. Etranacogene dezaparvovec in people with hemophilia B with preexisting adeno-associated virus 5 neutralizing antibodies: 4-year subgroup results from the HOPE-B trial. Res Pract Thromb Haemost. 2026 Jan 19;10(1):103360. doi: 10.1016/j.rpth.2026.103360. PMID: 41756540; PMCID: PMC12934310. Link

AAV, Adeno-associated virus; ABR, Annualized bleeding rate; AEs: adverse events; AIR, Annualized FVIII/FIX infusion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BL, baseline; CH, Chromogenic Assay; Co., cohort; DOACs, Direct oral anticoagulants; D, days; EDs, exposure days; FIX, factor IX; FIX-Padua, gain of function FIX variant; FVIII, factor VIII; gc, genome copies; HEK cells, human embryonic kidney cells; IQR, interquartile range; IRR, Infusion-related reaction; NAbs, neutralizing antibodies; OS, One-stage clotting assay; Pop., population; pt., patient/participant; pts., patients/participants; P1, Participant 1; PI, phase I; PBGD, porphobilinogen deaminase; PBMC, peripheral blood mononuclear cells; SAEs, serious adverse events; SFU, spot-forming units; TAC, tacrolimus; ULN, upper limit of normal; VCN, vector copy number; vg, vector genomes; W, weeks; WT, wild type; Y, year