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

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

• Males ≥18 years with severe or moderate-severe HB (FIX≤2%)
• Pts. with/without pre-existing NAbs (23/54) to AAV5²
• >150 previous EDs of treatment with FIX protein¹

• 1/54 (NAb titer 198) received a partial dose and was excluded from efficacy assessment³
• Previous gene therapy treatment

AAV5⁴, Insect cells, baculovirus expression system

Codon-opimized FIX-Padua variant^2-3, 4

• LP1 that is a smaller variant of the originally constructed APOE-HCR/hAAT enhancer/promoter⁵
• LP1 is also used in AMT-060 vector (AAV5-wt FIX)⁶

Systemic

2e13 (n = 54)^2-3, 4

• 26 weeks follow-up following a lead-in period of ≥6^2, 3, 4
• Pts. were initially followed for 18 months after treatment for evaluation of efficacy and safety⁷
• They then entered a follow-up phase that extends through 5 years after dosing⁷

OS and CH  as reported here⁷

• 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^2-3 
• no correlation with FIX activity was seen up to a titer of 678.2; n=52, R²=0.078^2-3     

    Follow-up data related to the mean FIX transgene activity were published here ⁷ and 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 W26²

Further data related to bleeding episodes during lead-in in comparison to post-treatment period were taken from here⁷ and 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
 

    Data related to FIX usage and FIX infusion rates were published here⁷ 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.

    All IRRs were reported on the day of infusion and 8/9 IRRs resolved on the same day⁴

    ^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 here ⁷

• 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 here ⁷

Not reported

Not reported

• Yes (duration of the steroid treatment was not reported here)³

More recent published data⁷ regarding the duration of the steroid treatment 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 F9 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

• No³
• As published here⁷, 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 biopsy⁸ that are considered as multiple risk factors associated with the  development of liver cancer^{7, 9-10}
• 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^{7, 9} 
• 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^10-11

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. 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). 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
3. 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). 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
4. 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. Management of Infusion Reactions: Lessons from the Phase 3 HOPE-B Gene Therapy Trial of Etranacogene Dezaparvovec in Adults with Hemophilia B - ISTH Congress Abstracts
5. 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)
6. 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)
7. 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)
8. 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. Liver Safety Case Report from the Phase 3 HOPE-B Gene Therapy Trial in Adults with Hemophilia B - ISTH Congress Abstracts
9. 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
10. 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)
11. 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; 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