Two clinical trials related to BBM-H901 are registered on ClinicalTrials.gov as follows:

• NCT04135300: Phase 1, open-label, non-randomized, uncontrolled, single-dose pilot study¹
  • A total of 10 Chinese adult patients with haemophilia B (aged >18 years) were enrolled and infused with BBM-H901²
• NCT05203679: Multi-center, Phase 1/2/3, single-arm, open-label, single-dose treatment clinical study^{3, 4}
  • The Phase 1/2 dose-escalation cohort enrolled 6 male participants³
  • The Phase 3 cohort enrolled 26 participants with haemophilia B in China⁴

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

• NCT04135300: Completed¹
• NCT05203679: Active, not recruting³

• Males ≥ 18 years of age;
• Have hemophilia B with ≤2 IU/dL (≤2 %) endogenous FIX activity levels;
• Have had ≥100 prior exposure days (EDs) to any recombinant and/or plasma-derived FIX protein products based on historical data from the subjects' records/histories;
• Low titre of neutralising antibodies (≤1:4) against vector capsid

• Have participated in a previous gene therapy research trial before screening, or in a clinical study with an investigational drug within 5 half-life of the investigational product, whichever is longer;

Details on the applied AAV capsid were extracted from the Supplementary Information in Reference #4 and are summarized below:

• Engineered liver-tropic AAV843 capsid, identified through screening of an AAV capsid gene–shuffled library constructed from AAV serotypes 1, 2, 3B, 4, 6, 7, 8, and 9
• Vector manufacturing platform: suspended HEK293 cells in a 200 L single-use bioreactor

FIX-Padua sequence in a double-stranded AAV (dsAAV) genome⁴

Expression cassette components were extracted from the information provided in Reference #4 and are summarized below:

• Codon-optimized cassette expressing FIX-Padua (R338L)
• LXP2.1 mini liver-specific promoter (188 bp) containing hepatocyte nuclear factor transcription elements, a TATA box, and specificity-protein-1 (SP1) elements
• Optimized F9 cDNA with removal of TCG and CGT codons (CpG-reducing) without altering the amino acid sequence
• Introduction of the Padua mutation (R338L) into the FIX coding sequence

Single intravenous infusion⁴

• Pilot study (Phase 1 | NCT04135300): 5 × 10¹² vg/kg — 10 participants²
• Phase 1/2 dose-escalation cohort (NCT05203679): 5 × 10¹² vg/kg — 6 participants⁴
• Phase 3 cohort (NCT05203679): 5 × 10¹² vg/kg — 26 participants⁴

Follow-up times were extracted from various publications and are summarized as follows:

• Pilot study (Phase 1, NCT04135300):
  • median follow-up 58 weeks (IQR 51.5 – 99.5 weeks)²
  • median (range) of 210 (159–270) weeks postgene therapy at the data cutoff date of 22 July 2024.
• Phase 3 study (NCT05203679): primary 52-week follow-up post-infusion for bleeding rate (ABR), FIX:C, safety endpoints⁴
• Registry / post-marketing / extension follow-up: According to sponsor/dissemination report, follow-up continues up to 5 years post-infusion in some participants⁵

Information on the clotting assays used in this trial was extracted from Reference #4 and is summarized below:

• OS clotting assay was used to measure FIX activity
• Two commercial OS methods were employed to ensure assay reliability and consistency across measurements: OS SynthASil and OS Actin FSL
• Chromogenic (CH) assay was not reported for this trial.

Long-term follow-up FIX activity level ranges for the Phase 1 Pilot Study (n = 10), assessed using the OS Actin-FSL method, are summarized in the table below based on the categorical data provided in Reference #4:

Mean, median and individual FIX activity levels for the Phase 1/2 Trial were extracted from Reference #4 and are summarized in the table below:

* IST: Participants on additional immune suppressive treatment in phase 1/2 study

FIX activity (IU/dL) levels for the Phase 3 Trial were extracted from Reference #4 and are summarized in the table below:

    Overall Table Annotations:

• All mean FIX activity levels shown here were assessed using the OS Actin-FSL assay, except at Week 52 where both OS Actin-FSL and OS SynthASil assays were applied
• The reported mean SynthASil : Actin-FSL activity ratio was 1.35 (SD 0.54)

Information on the early kinetics of FIX activity following BBM-H901 infusion was extracted from Reference #4. Based on the available time-course data, the mean time to peak FIX activity can be summarized as follows:

• Phase 3 cohort:
  • Mean time to peak FIX activity: ~6 days post-infusion, corresponding to the reported mean peak FIX:C level of 59.3 IU/dL on Day 6.
• Phase 1/2 cohort:
  • Not reported in Reference #4
• Phase 1 pilot cohort: 
  • Not reported in Reference #4 (long-term follow-up data do not include early peak kinetics) and in Reference #2.

ABR data related to the primary outcomes of the phase 3 study were reported in Reference #4 as follows:

• The mean ABR and its 95% CI within 52 weeks after BBM-H901 infusion was 0.60 (95% CI = 0.18–1.99)
• The upper limit of the 95% CI (1.99) was significantly lower than the predefined superiority margin of 5.0
  • which was based on the historical ABR assumed for patients receiving prophylactic treatment in China

ABR data from the phase 1/2 and phase 3 studies were extracted from Table 3 of Reference #4 and are summarized below

    a Time range of events collection was 52 weeks before enrollment and postvector infusion (initiated from 1 day after vector infusion)
    b The target joint was evaluated at the screen and the week 52 visit.
    c Time range of zero bleeding events calculation is 52 weeks before enrollment and postvector infusion (initiated from 1 day after vector infusion)
    d The two-sided P values were based on the Wilcoxon signed-rank test for pre- and post-treatment differences, and the exact P values were all less than 0.001

ABR–related data and reported bleeding events from the long-term follow-up of the phase 1 pilot study (Reference #4) are summarized as follows:

• Ten participants were enrolled and followed for a median of 210 weeks (range 159–270 weeks) after gene therapy
• Nine participants maintained FIX:C levels ≥10 IU/dl and remained free of bleeding events during long-term follow-up
• One participant had FIX:C of 2 IU/dl at 159 weeks and subsequently underwent total right knee arthroplasty
  • Prior to arthroplasty, this participant experienced two treated bleeding events after 52 weeks post-gene therapy
    • one left-knee bleed and one left-elbow bleed
    • both treated with 1,000 IU recombinant FIX
• Thus, during long-term follow-up beyond 52 weeks, only one participant experienced bleeding, with two total treated bleeding episodes reported

Data regarding FIX concentrate infusion rates and consumption in the phase 1/2 and phase 3 studies were obtained from Table 3 of Reference #4 and are summarized in the table below:

    ^a Time range of events collection was 52 weeks before enrollment and postvector infusion (initiated from 1 day after vector infusion)
    ^b The two-sided P values were based on the Wilcoxon signed-rank test for pre- and post-treatment differences, and the exact P values were all less than 0.001

In the phase 1/2 and phase 3 BBM-H901 studies reported in Reference #4, no IRRs were specifically documented or reported as a distinct category in the safety results

Data on vector-related adverse events (AEs) were extracted from Table 2 of Reference #4 and are summarized in the table below:

    ^a TEAE: treatment emergent adverse events

Additional safety findings on AEs from the BBM-H901 phase 1/2 and phase 3 studies were extracted from Reference #4 and are summarized below:

• No dose-limiting toxicities (DLTs) were observed in the phase 1/2 study during at least 10 weeks of follow-up.
• No grade 4 AEs, no SAEs, no FIX inhibitors, and no deaths were reported in either phase 1/2 or phase 3 studies.
  • Phase 1/2 overall AE profile
    • 82 AEs reported among 6 participants over 52 weeks
    • 6 participants (100%) experienced treatment-emergent AEs (TEAEs)
    • No TEAEs led to infusion interruption or drug discontinuation
      • BBM-H901–related TEAEs in phase 1/2 (n=6)
        • 3 participants (50%) experienced 6 TEAEs related to vector
        • Included:
          • elevated AST
          • elevated ALT
          • elevated γ-glutamyltransferase
          • pyrexia
          • palpitations
        • All were grade 1–2 and resolved
    • Transaminitis resolution in phase 1/2
      • two participants experienced grade 1 elevations
      • resolved spontaneously within 4–12 days
      • no additional intervention required
  • Phase 3 overall AE profile
    • 232 (100%) AEs reported in 26 participants over 52 weeks
    • 226 (97.4%) were TEAEs
    • 11 participants (42.3%) had AEs related to BBM-H901
    • Severity profile
      • AEs were predominantly grade 1–2
      • one grade 3 event occurred but was unrelated to BBM-H901
  • Most frequent BBM-H901–related AE in phase 3
    • Transaminitis (ALT ± AST elevation)
    • 9 episodes in 7 participants (26.9%)
    • All grade 1–2 by CTCAE criteria
  • Management of transaminitis
    • one participant required high-dose steroids and tacrolimus
    • remaining cases resolved without additional immunosuppression
• Immunosuppressive therapy use
  • phase 1/2: 3 of 6 participants (50%) required additional courses
  • phase 3: 3 of 26 participants (11.5%) required additional IST
• Vector shedding observed in plasma, urine, saliva, semen, and PBMCs, decreasing over time
  • Long-term follow-up (phase 1 pilot)
    • no BBM-H901–related AEs identified
    • no FIX inhibitors developed
    • no clinically substantial liver enzyme elevations

AEs judged as possibly or likely related to glucocorticoid use were extracted from Reference #4 and are summarized below:

• phase 1/2: 5 participants (83.3%) had steroid-related AEs
• phase 3: 23 participants (88.5%) had steroid-related AEs

Data on the durations, timings, and peak ALT level elevations were extracted from Reference #4 and are summarized as follows:

• Phase 1/2 study
  • ALT elevation occurred in 1 of 6 participants (16.7%)
  • Grade 1 ALT elevation
  • Timing: not explicitly stated in the main text
  • Duration: resolved spontaneously within 12 days
• Phase 3 study
  • ALT elevation occurred in 7 of 26 participants (26.9%)
  • A total of 9 episodes of transaminitis were observed (ALT alone or ALT+AST)
  • Duration of ALT elevation: 4–47 days
  • One key case without prophylactic prednisone:
    • ALT peak: 82 IU/L
    • Timing: week 9 post-treatment
    • Associated finding: concurrent decline in FIX:C
• Long-term follow-up (phase 1 pilot study)
  • No clinically substantial ALT elevations reported

Data on the durations, timings, and peaks of reported AST level elevations were extracted from Reference #4 and are summarized as follows:

• Phase 1/2 study
  • AST elevation occurred as part of one case of concurrent ALT/AST elevation
  • Grade: CTCAE grade 1
  • Resolution time: resolved spontaneously within 4 days
  • Peak AST values: not numerically reported
  • Timing details: not numerically specified
• Phase 3 study
  • Three episodes of concurrent ALT/AST elevation were reported
  • All were CTCAE grade 1–2
  • Peak AST values: not numerically reported
  • Timing of onset: not numerically specified
  • These occurred within the broader group of nine transaminitis episodes (ALT alone or ALT+AST)

No data on capsid-directed T cell activation were reported in Reference #4  for the phase 1/2 study, the phase 3 study, or the long-term follow-up phase 1 pilot study

Data on steroid use for immune response management were extracted from Reference #4 and are summarized as follows:

• Phase 1/2 study (n = 6)
  • Prophylactic prednisone
    • Administered to all participants.
    • Initiated 7 days before vector infusion
    • Mean (s.d.) duration: 72.8 (18.1) days
    • Median (range) duration: 65.5 days (62–113)
  • Additional steroid / immunosuppressive treatment
    • Three participants (50%) received additional immunosuppressive therapy due to declining FIX:C (not associated with transaminitis):
      • One participant:
        • Tacrolimus initiated at week 9, continued for 6 weeks (during prophylactic prednisone).
      • One participant:
        • Second course of prednisone initiated at week 31, tapered off by week 44 (≈ 13 weeks).
      • One participant:
        • Second course of prednisone initiated at week 35, tapered off by week 45 (≈ 10 weeks).
  • Transaminitis events in phase 1/2 resolved spontaneously and did not require steroid escalation.
• Phase 3 study (n = 26)
  • Prophylactic prednisone
    • Administered to 25 of 26 participants (96.2%).
    • Initiated 1 day before vector infusion.
    • Mean (s.d.) duration: 57.9 (6.4) days.
    • Median (range) duration: 58 days (32–71).
    • One participant did not receive prophylactic prednisone due to recent duodenal ulcer bleeding.
  • Steroid-responsive immune events requiring additional treatment
    • Participant without prophylactic prednisone:
      • Treated with methylprednisolone 500 mg/day for 3 days, followed by prednisone 50 mg/day plus tacrolimus 1.5 mg/day.
      • ALT elevation resolved, but FIX:C declined to baseline.
    • Two participants receiving prophylactic prednisone:
      • Participant 1:
        • Second prednisone course initiated at week 16, tapered off by week 29 (≈ 13 weeks).
      • Participant 2:
        • Second prednisone course initiated at week 11, tapered off by week 51 (≈ 40 weeks).
      • In both cases, FIX:C stabilized and remained >5 IU/dL at week 52.
  • Other participants with transaminitis did not require additional steroid or immunosuppressive therapy.
• Long-term follow-up (phase 1/2 and phase 1 pilot studies)
  • No new immune-mediated liver enzyme elevations reported.
  • No additional steroid-responsive immune events requiring treatment were described.

Data on reduction or loss of transgene expression associated with ALT elevations were extracted from Reference #4 and are summarized as follows:

• Phase 1/2 study
  • Two participants experienced transaminitis (ALT alone or ALT+AST)
  • Both ALT/AST elevations were grade 1 and resolved spontaneously (within 12 and 4 days, respectively)
  • No reduction or loss of FIX activity was explicitly attributed to ALT elevation
  • Participants who experienced declines in FIX:C requiring additional immunosuppressive therapy did not exhibit transaminitis
  • Overall, no clear association between ALT elevation and reduction of transgene expression was reported in the phase 1/2 study
• Phase 3 study
  • Key case with loss of transgene expression associated with ALT elevation:
    • One participant who did not receive prophylactic prednisone developed ALT elevation (peak 82 IU/L at week 9 post-treatment)
    • ALT elevation was accompanied by a decline in FIX:C
    • Despite resolution of ALT elevation after high-dose corticosteroid and tacrolimus treatment, FIX:C progressively decreased
    • FIX:C ultimately returned to baseline levels, and the participant resumed FIX prophylaxis after week 38
    • This represents a documented case of loss of transgene expression temporally associated with ALT elevation
  • Additional cases with ALT elevation and FIX:C decline:
    • Two participants receiving prophylactic prednisone experienced declining FIX:C accompanied by mild ALT increases (ALT ≤1.5× baseline and below ULN)
    • In both cases, second courses of prednisone were initiated
    • FIX:C stabilized at reduced but detectable levels at week 52 (13.9 IU/dL and 9.3 IU/dL, respectively)
    • These cases represent partial reduction, but not complete loss, of transgene expression associated with ALT trends
• Long-term follow-up (phase 1 pilot study)
  • No emerging safety concerns related to liver enzyme elevations
  • No additional cases of ALT-associated loss of FIX expression were reported

No cancer cases were reported following BBM-H901 administration across the phase 1/2 study, phase 3 study, or the long-term follow-up of the phase 1 pilot study in Reference #4

1. ClinicalTrials.gov registry — NCT04135300 (Phase 1 pilot study). Available at: Study Details | NCT04135300 | Gene Therapy for Chinese Hemophilia B | ClinicalTrials.gov
2. Xue F, Li H, Wu X, Liu W, Zhang F, Tang D, Chen Y, Wang W, Chi Y, Zheng J, Du Z, Jiang W, Zhong C, Wei J, Zhu P, Fu R, Liu X, Chen L, Pei X, Sun J, Cheng T, Yang R, Xiao X, Zhang L. 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 Jul;9(7):e504-e513. doi: 10.1016/S2352-3026(22)00113-2. Epub 2022 May 19. PMID: 35598604. 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 - PubMed
3. ClinicalTrials.gov registry — NCT05203679 (Phase 1/2/3, multicenter). Available at: Study Details | NCT05203679 | Evaluation of the Safety and Efficacy of Hemophilia B Gene Therapy Drug | ClinicalTrials.gov
4. Xue F, Ju M, Zhu T, Zhou Z, Sun J, Yang L, Yan Z, Zhou H, Du X, Zheng C, Zheng J, Wu X, Du Z, Jiang W, Yang C, Xiao X, Liu W, Yang R, Zhang L. Factor IX-Padua AAV gene therapy in hemophilia B: phases 1/2 and 3 trials. Nat Med. 2025 Nov 20. doi: 10.1038/s41591-025-04012-y. Epub ahead of print. PMID: 41266685. Factor IX-Padua AAV gene therapy in hemophilia B: phases 1/2 and 3 trials - PubMed
5. Unpublished sponsor report / web source — Dalnacogene Ponparvovec (BBM-H901) long-term follow-up data. DHG. Available at: https://www.dhg.de/fileadmin/dokumente/EHC/NTR-August-2025.pdf (accessed 26 November 2025).

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