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

• Active, not recruiting¹
• Last Update Posted: March 6, 2023

Information regarding the approval status of etranacogene dezaparvovec was collected from here^2, 3 and summarised as follows:

• November 2022, etranacogene dezaparvovec was approved in the USA for the treatment of haemophilia B
• In December 2022, etranacogene dezaparvovec also received a positive opinion in the EU for the treatment of haemophilia B
• It received a conditional marketing authorisation from the EMA on February 28, 2023.

• 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^6 , 5
• 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

• 26 weeks follow-up following a lead-in period of ≥6^{4 , 8, 9}
• Pts. were initially followed for 18 months after treatment for evaluation of efficacy and safety⁵
• They then entered a follow-up phase that extends through 5 years after dosing⁵

OS and CH  as reported here⁵

Early follow-up data on the mean FIX activity at week 26, in relation to pre-therapy NAbs titers, were reported in references #4 and #8 as follows:

• 1 pt. with a NAb titer of 3212.3 did not respond and an additional pt. (titer 198) received a partial dose and remained on prophylaxis
• no correlation with FIX activity was seen up to a titer of 678.2; n=52, R²=0.078

Follow-up data on mean FIX transgene activity through month 18 were published in reference #5 and are summarized as follows:    

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

Not reported

• Relative to lead–in, total bleeds were reduced by 83% and treated bleeds by 91% at W26⁴

Additional data on bleeding episodes during lead-in phase compared to 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 pts. (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)     

     ^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
 

     * 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

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

• A total of 52/54 pts. (96%) discontinued FIX prophylaxis during the period from day 21 through month 18 after treatment
• Of the remaining 2 pts. 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, pts. used a mean of 257,338±149,013 IU of FIX/yr (range, 83,541 to 755,892)
• The mean use of FIX per pt. 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 pt. 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.

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

• 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 #9 and #5 and are summarized as follows:

Early follow-up data (26 weeks) on reported AEs for the subgroups with and without NAbs at baseline were provided in reference #8 as follows:

A more detailed assessment of the reported AEs was published in reference #5 and is summarized as follows:

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

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

• 11/54 pts. (20%) had elevations in ALT levels that were reported as AEs most were mild or moderate as reported in Table S6 published here⁵

Not reported

Not reported

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

• 9/54 pts. (17%) from the 11 pts. 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 was79.8±26.6 days (range, 51 to 130)
• All the pts. 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 FVIII activity associated with ALT elevation were collected from reference #5 and are summarized as follows: 

• Only a minor reduction of the transgene expression might be associated with ALT elevation as the mean FIX activity among 9/11 pts. that were treated with glucocorticoids and peaked at 22.2±10.1% before glucocorticoid treatment, was 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 pts. with elevated ALT levels was 21.6±11.8%, 20.3±11.5%, and1 8.1±9.1% at 6, 12, and 18 months after treatment
• No pts. resumed continuous FIX prophylaxis

• First reported case of HCC in a pt. 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 biopsy^{8(8 -> 10)} that are considered as multiple risk factors associated with the  development of liver cancer^{5, 11, 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^{5, 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^12, 13

1. HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients. Available at: Study Details | HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients | ClinicalTrials.gov
2. FHeo YA. Etranacogene Dezaparvovec: First Approval. Drugs. 2023 Mar;83(4):347-352. doi: 10.1007/s40265-023-01845-0. PMID: 36802324. Etranacogene Dezaparvovec: First Approval - PubMed (nih.gov)
3. Hemgenix | European Medicines Agency - European Union. Available at: Hemgenix | European Medicines Agency (europa.eu)
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).
5. Pipe, S.W., et al., Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B. N Engl J Med, 2023. 388(8): p. 706-718. Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B - PubMed (nih.gov)
6. Nathwani, A.C., 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. 107(7): p. 2653-61. 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 | American Society of Hematology (ashpublications.org)
7. Miesbach, W., et al., Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood, 2018. 131(9): p. 1022-1031. Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B | Blood | American Society of Hematology (ashpublications.org)
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). 
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.
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.
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.BioMarin follows up on previously-reported serious adverse event in its phase I/II gene therapy clinical trial for haemophilia A – WFH - World Federation of Hemophilia
12. FDA puts uniQure’s gene therapy clinical programme, HOPE-B, on hold following submission of safety report. 2020: EHC European Haemophilia Consortium. European Haemophilia Consortium (EHC)
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. uniQure Announces Findings from HCC Case Investigation | NBDF (hemophilia.org)

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