Two Phase 1/2 clinical trials of etranacogene dezaparvovec are registered on ClinicalTrials.gov as follows:

• NCT03489291¹: Phase IIb, Open-label, Single-dose, Single-arm Study
• NCT05962398²:  Long-term safety and efficacy study in male adults with hemophilia B who were treated with etranacogene dezaparvovec (CSL222) in parent studies
  • CSL222_2001 (NCT03489291) or
  • CSL222_3001 (NCT0356989, Hope-B trial)

The status of both clinical trials is reported on ClinicalTrials.gov as follows:

• NCT03489291¹: Completed, Last Update Posted: 2024-06-28
• NCT05962398²: Enrolling by Invitation, Last Update Posted: 2025-07-18

• Individuals with detectable anti-AAV5 NAb (luciferase assay) included
• 3/3 subjects with positive NAb titers participants had no anti-AAV5 IgGantibodies at screening or baseline³
• Male ≥ 18 years with known severe FIX deficiency (< 1% of normal circulating FIX)
• >20 previous EDs of treatment with FIX protein

• ALT, AST and total bilirubin > 2 times UNL
• Previous gene therapy treatment
• Find full exclusion criteria listed on the supplemental data³

AAV5, Insect cells, baculovirus expression system³

Codon-opimized FIX-Padua³

• LP1 that is a smaller variant of the originally constructed APOE-HCR/hAAT enhancer/promoter⁴
• LP1 is also used in AMT-060 vector (AAV5-wt FIX)⁵

Systemic⁶

2e13 (n = 3)

Follow-up times were reported by different publications as follows:

• A planned 26-week interim assessment was reported in Reference #3
• The 1-year follow-up was subsequently reported in Reference #7
• The 3-year outcomes of the Phase 2b trial were published in Reference #8
• Final analyses of the Phase 2b study at 5 years post-treatment were reported in Reference #9

OS

Early outcomes related to FIX activity are taken from References #3  #7 and summarized as follows: 

Subsequently, 3-year outcomes on FIX activity following gene transfer were reported in Reference #8 and are summarized below:

Final results on endogenous FIX activity from the Phase IIb study, as reported in Reference #9, are summarized in the table below.

According Figure 1 included in that publication⁷:

• Peak in P1 and P3 (higher FIX levels) observed between W14 - W22 
• Peak in P2 (lower FIX levels) observed at W26

Early and intermediate outcomes on bleeding events and episodes, as reported in References #3, #7 and #8,, are summarized as follows:

• At 26³ and 52⁷  weeks, no bleeds were reported post-treatment
• As reported in the 3-year outcomes article (Reference #8):
  • Complete elimination of bleeds occurred in 2 of 3 participants
  • One participant required on-demand FIX replacement therapy after treatment per protocol:
    • Due to elective surgeries for 2 reported bleeding episodes
    • And twice for a single self-administered infusion due to an unreported reason

Final results on bleeding rates from the Phase IIb study, as reported in Reference #9, are summarized as follows:

• Cumulative mean ABRs:
  • 0.22 for Years 0–3
  • 0.17 for Years 0–4
  • 0.14 for Years 0–5

• Overall bleeding outcomes:
  • No bleeds reported after Year 2
  • No joint bleeds during the entire 5-year follow-up

• Individual participant data:
  • 2 participants: ABR = 0 over 5 years (100% reduction vs. baseline)
  • 1 participant (Participant 3): ABR = 0.42 at 5 years (92% reduction)
    • Experienced 2 bleeds in Year 2 (1 spontaneous, 1 traumatic),
      • both controlled with single self-administered on-demand FIX infusion
    • Required FIX for 3 hip surgeries (episodic use, not counted as bleeds)
    • Used 2 additional self-administered FIX infusions for unreported reasons

Early and intermediate outcomes on FIX use, as reported in References #6 and #8, are summarized as follows:

• As of 36 weeks, there was no requirement for FIX replacement aside from protocol-specified use for perioperative management in P3⁶
• The 3-year outcomes reported in this article⁸ revealed the following observations:
  • All participants discontinued FIX prophylaxis
  • One of three participants required on-demand FIX replacement therapy after treatment, as per protocol

Final results on exogenous FIX use from the Phase IIb study, as reported in Reference #9, are summarized as follows:

• Discontinuation of continuous FIX prophylaxis:
  • All 3 participants discontinued within 1–4 days after treatment.
• Decrease in mean annualized exogenous FIX use (excluding invasive procedures):
  • From 306 205 IU/y in the year before screening (per medical records).
  • To 605 IU/y over the entire 5-year study period.
  • And to 342 IU/y in the post-continuous prophylaxis period.
• Episodic FIX use (annualized mean):
  • 2 participants with ABR = 0 IU/y
  • 1 participant with 2 bleeding events: 1026 IU/y

More detailed data on exogenous FIX consumption, extracted from Table 2 of Reference #9, are presented in the table below.

Footnotes:

• Data collected retrospectively 1 year before screening from medical records.
• †Post-continuous FIX prophylaxis defined as a combination of 3 events:
  1. Study drug administered
  2. Uncontaminated FIX activity (after treatment) ≥5%
  3. No exogenous FIX used for ≥15 days after study drug administration

No infusion related reactions were reported

In early and intermediate outcomes, as reported in References #3 and #7, two AEs possibly related to etranacogene dezaparvovec, observed in P1, are summarized as follows:

• Self-limiting headache on day of dosing
• Mild elevation in CRP level (7.4 mg/L; reference range, 0-3 mg/L) on day 14 post treatment that resolved without intervention

Final results on adverse events (AEs) from the Phase IIb study, as reported in Reference #9, are summarized as follows:

• Overall AEs:
  • 84 treatment-emergent AEs (TEAEs) over 5 years.
  • 96% were mild or moderate (55 mild, 26 moderate, 3 severe)

• Treatment-related AEs (TRAEs):
  • Reported in 1 participant (P1 at Year 1 only):
    • Headache
    • Transient elevation of C-reactive protein (resolved without treatment).
  • No TRAEs or serious TRAEs were reported in Years 2–5

• Serious AEs (unrelated to treatment):
  • P3: worsening avascular necrosis in both hips
    • Underwent 3 hip surgeries
      • Femoral head decompression on Day 197
      • Arthroplasties on Day 720 and Day 1672
    • Received perioperative FIX infusions tailored to endogenous FIX levels per protocol

Not reported

Data on ALT elevations during the early and intermediate follow-up period after gene therapy were extracted from References  and are summarized as follows:  Data on ALT elevations during the early and intermediate follow-up period after gene therapy, as reported in References #3, #7, #8 and #9 are summarized as follows:

• 1/3 participants (P1): non-clinically significant elevations (44 IU/L at week 22)³
• No participants required steroids related to the treatment^{3, 7, 8, 9}

1/3 pts. (P2), non-clinically significant (43-48 IU/L at weeks 2 and 4)³

In 3/3 pts., no T-cell-mediated anti-AAV5 capsid responses were detected during W1 through W26³

Not applicable (resolved without steroid treatment)^3, 7

No^3, 7

Not reported

1. Dose Confirmation Trial of AAV5-hFIXco-Padua. Available at: Study Details | Dose Confirmation Trial of AAV5-hFIXco-Padua | ClinicalTrials.gov
2. An Extension Study Assessing the Long-term Safety and Efficacy of  Etranacogene Dezaparvovec (CSL222) Previously Administered to Adult Male Subjects With Hemophilia B. Available at: Study Details | NCT05962398 | Long-term Follow-up Study of Male Adults With Hemophilia B Previously Treated With Etranacogene Dezaparvovec (CSL222) | ClinicalTrials.gov
3. Von Drygalski, A., et al., Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B. Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B - PubMed (nih.gov)
4. 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)
5. 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 - PubMed (nih.gov)
6. Nathwani, A.C., Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program, 2019. 2019(1): p. 1-8. Gene therapy for hemophilia - PubMed (nih.gov)
7. Pipe, S., 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): p. 3348. 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 | American Society of Hematology (ashpublications.org)
8. von Drygalski, A., et al., Stable and durable factor IX levels in hemophilia B patients over 3 years post etranacogene dezaparvovec gene therapy. Blood Adv, 2022. Stable and durable factor IX levels in hemophilia B patients over 3 years post etranacogene dezaparvovec gene therapy | Blood Advances | American Society of Hematology (ashpublications.org)
9. von Drygalski A, Gomez E, Giermasz A, Castaman G, Key NS, Lattimore SU, Leebeek FWG, Miesbach WA, Recht M, Monahan PE, Le Quellec S, Pipe SW. Completion of phase 2b trial of etranacogene dezaparvovec gene therapy in patients with hemophilia B over 5 years. Blood Adv. 2025 Jul 22;9(14):3543-3552. doi: 10.1182/bloodadvances.2024015291. PMID: 40188458; PMCID: PMC12275190. Completion of phase 2b trial of etranacogene dezaparvovec gene therapy in patients with hemophilia B over 5 years - PubMed

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