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. Gene Therapy for Chinese Hemophilia B. ClinicalTrials.gov identifier: NCT04135300. Link
2. Xue F, Li H, Wu X, Liu W, Zhang F, Tang D, et al. 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. Link
3. Evaluation of the Safety and Efficacy of Hemophilia B Gene Therapy Drug. ClinicalTrials.gov identifier: NCT05203679. Link
4. Xue F, Ju M, Zhu T, Zhou Z, Sun J, Yang L, et al. Factor IX-Padua AAV gene therapy in hemophilia B: phases 1/2 and 3 trials. Nat Med. 2026 Jan;32(1):93-102. doi: 10.1038/s41591-025-04012-y. Epub 2025 Nov 20. PMID: 41266685; PMCID: PMC12823393. Link
5. Xue F, et al. Gene transfer with BBM-H901: results of long term follow up in Chinese Hemophilia B [abstract]. ISTH 2025 Congress, 2025. Abstract OC 69.2. European Haemophilia Consortium Novel Treatment Review. July 2025. Accessed November 26, 2025. Link

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