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

• ClinicalTrials.gov Identifier: NCT02484092 (A Phase 1/2, Open-Label, Non-Randomized, Dose-Escalation)¹
  • 15 men 18 years of age or older with severe to moderately severe hemophilia B were enrolled
• ClinicalTrials.gov Identifier: NCT03307980 (Long-term Safety and Efficacy Study and Dose-Escalation Substudy of PF 06838435 in Individuals With Hemophilia B)²
  • 14 of the participants entered the follow-up study, and 1 (P8) chose not to enroll for personal reasons

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

• NCT02484092¹: Completed; Last Update Posted: 2020-06-16
• NCT03307980²: Active, not recruiting; Last Update Posted: 2025-04-23

According to Supporting Document (Reference #3), Fidanacogene elaparvovec received FDA approval on May 20, 2024

• Male and ≥18 years of age have
• Hemophilia B with ≤2 IU/dL (≤2%) endogenous FIX activity levels as of the normal value
• Had ≥50 prior EDs to any FIX protein products

• Have anti-AAV-Spark100 neutralizing antibody titers ≥1:5 
• Participation in a previous gene therapy research trial within the last 52 weeks

Bioengineered capsid AAV-Spark100⁴/ HEK293 cells

Codon-opimized FIX-Padua⁴

The FIX expression cassette includes:

• APOE gene hepatic-control region (APOE-HCR) enhancer and the
• Liver-specific human α1 -antitrypsin (hAAT) promoter⁴

Systemic⁵

Infusion of single vector dose as follows:

• 5e11 (10) reported here⁴ and subsequently 
• 5e11 (15) reported here^1, 6 - 7

Early follow-up times were reported in the following references:

• 28 to 78 weeks (Reference #4)
• ≥ 52 weeks (References #6 and #7)

Long-term follow-up times were reported in Reference #8 and are summarized below:

• Median follow-up duration: 5.5 years (range: 3 to 6 years)
• 8 participants remained in the study at the time of data cutoff
• All 14 participants completed at least 3 years of follow-up

OS^4, 6

According to early follow-up data on FIX activity levels after gene therapy in References #4 and #6, the reported findings are summarized as follows:

• Data in Reference #4 were based on a mean follow-up of 49.0 ± 13.4 weeks (range, 28–78) among individual participants
  • Sustained steady-state factor IX–R338L expression was reached within 14 weeks after vector infusion
  • Among all participants, mean (± SD) steady-state vector-based FIX coagulant activity was 33.7 ± 18.5% of the normal value
• Data in Reference #6 were based on 15 patients infused with Fidanacogene elaparvovec, each with ≥1 year of follow-up
  • The mean (± SD) post-infusion steady-state FIX:C was 22.9% ± 9.9% at 1-year post vector infusion

Peak and steady-state vector-derived circulating FIX activity levels were determined in a time frame from W12 up to W52, as reported on clinicaltrials.gov¹, 
as follows:

• Mean (SD) peak FIX activity: 29.1 (11.63)
• steady-state level of 22.9 (9.89) % of normal

Long-term follow-up data on mean FIX activity levels across the indicated time periods (up to six years) for each participant were extracted from Table 2 in Reference #8 and are summarized as follows:

* Overall table annotations:

• Plus–minus values are means ±SD.
• The arithmetic mean FIX activity is shown for each period
• Participant 8 did not participate in long term follow-up
• Summary data include only valid measurements in participants who
  • had at least 96 hours of washout for plasma or recombinant FIX or
  • up to appr. 168 hours of washout for extended half-life recombinant FIX before FIX sample collection

† Glucocorticoids were used in the first year after treatment.

According to the long-term follow-up data on FIX activity levels in Reference #8, the reported findings are summarized as follows:

• Mean FIX levels were sustained within the mild hemophilia range.
  • In years 4 through 6, mean levels ranged from 7.4% to 44.2% (Table 2, summarized above).
• 95% confidence intervals (CI):
  • Difference between year 1 and years 2–3: −2.9 to 3.9 percentage points (among 14 participants).
  • Difference between year 1 and years 4–6: −7.6 to −0.4 percentage points (among 13 participants) (Table 2, summarized above).
• Participant 2 showed the largest decline in FIX activity:
  • 24.1% in Year 1 → 9.7% after 4.5 Years.
  • This decline occurred following a 6-month period of abnormal liver-function tests coinciding with heavy alcohol consumption.

Peaks not reported, possibly W28 based on Fig. 1⁴

Data on ABRs during early follow-up (28 to 78 weeks) were reported in Reference #4 and are summarized  as follows:

• The ABR mean was reduced from 11.1 events per year [range, 0 to 48] before vector administration to a mean rate of 0.4 events per year [range, 0 to 4] after vector administration
• That corresponds to 96% reduction of the mean bleeding rate per year

ABRs for the time period of six years and data concerning further characteristics of bleeding events were reported in Reference #7 as follows:
 

    ^a At enrollment in the phase 1/2a study, the majority of patients had target joints and/or joint arthropathy at baseline
    ^b All target joints or with known arthropathy
    ^c Occurred in joints in 2 patients who also had bleeds in the 1/2a study
    ^d In 1 pt., 6 of 10 bleeds were in target joints or joints with known arthropathy and 3 bleeds were in a wrist with known carpel tunnel syndrome
    ^e In the other pt., 3 bleeds occurred over 1.7 years in the same joint that was not a target joint and did not have known arthropathy
    ^f 4 were in joints; only 1 was not in a target joint or joint with known arthropathy

Long-term follow-up data on pre- and post-dosing annualized bleeding rates (ABRs) per patient, reported as treated bleeding events and mean ABRs, were extracted from Figure 2 (left panel) and Table S7 (right panel) in Reference #8 and are summarized below:

    * Participant 8 chose not to enroll for personal reasons

• Ten participants (67%) experienced no treated bleeding episodes during the 5-year follow-up period, beginning 1 year after treatment (see Table above, left, and Table below)
• The median annualized bleeding rate was 0.

Long-term follow-up data on ABRs for up to six years, reported as observed treated bleeding events, were extracted from Table 3 in Reference #8 and are summarized below:

• Five participants had bleeding events during the study (see Table above)
• The most common bleeding events were spontaneous bleeds into joints.

According to reported data on FIX concentrate use and annualized FIX infusion rate (AIR) in References #4 and #8, the relevant findings are summarized as follows:

• Reference #4
  • Mean FIX concentrate use decreased from 2908 IU/kg (range, 0–8090) in the 52 weeks before screening to 49.3 IU/kg (range, 0–376) after vector infusion.
• Reference #8
  • No participant resumed FIX prophylaxis
  • Mean baseline AIR among the 11 participants using prophylaxis in the year before treatment was 71.2 infusions per year
  • Mean AIR during year 1 after treatment was 1.1 infusions per year
  • AIR remained low during follow-up (Figure S6)

No SAEs occurred during or after vector infusion⁴

According to reported data on AEs possibly or likely related to the study vector in Reference #4, the findings are summarized as follows:

• 1/10 participants (P9) experienced transient grade 1 elevation of ALT level (to >2.5 X the ULN range) that was the only AE that was deemed to be likely related to the study vector
• P7 had an increase in liver-enzyme levels above baseline within the range of normal values that did not meet the criteria regarding toxic effects

AEs reported in participants during the phase 1–2a study during the first year after vector administration are summarized as follows, based on data extracted from Table S2 and other relevant statements in the Results section of Reference #8:

• Overall AEs: 14 of the 15 participants (93%) experienced adverse events during the first year after vector administration (Reference #8, Table S2)

SAEs during years 2 – 6 after vector administration, extracted from Table 1 in Reference #8, are shown below:

    * The investigator made the determination of whether an adverse event was related to fidanacogene elaparvovec.
    † This spontaneous bleeding event occurred in a nontarget joint:

• i.e., a joint without repeated bleeding and without symptoms of preexisting repeated bleeding and resulted in hospitalization
• FIX activity determined by the central laboratory was 12.5% on the day before the bleeding event

According to long-term follow-up data on AEs in Reference#8, the relevant findings are summarized as follows:

• Of the 14 participants who consented to long-term follow-up, none reported treatment-related AEs after year 1
• Nine SAEs were reported in 4 participants
• None were deemed related to the vector or vector-related therapy, and all occurred more than 1 year after administration (see Table above)
• No AEs resulted in discontinuation of participation in the study or in death
• No thrombotic events were reported, and no anti–FIX antibodies were detected

No AEs related to glucocorticoid in the 2/10 pts. that took prednisone observed (Rference #4)

According to reported data on elevations in hepatic transaminases after vector administration in References #4, #6, and #8, the findings are summarized as follows:

• 2 of 10 participants showed peak levels of approximately 70–140 U/L at weeks 5 and 9 (Reference #4, Figure 2)
• 3 of 15 participants were treated with corticosteroids for elevations in hepatic transaminases, although peak levels and timing were not reported (Reference #6)
• In Reference #8 (Figure 1), an ALT peak of approximately 150 U/L was observed in the third patient during the latter part of the first to second year

According to reported data on elevations in hepatic transaminases after vector administration in References #4, #6, and #8, the findings are summarized as follows:

• 2 of 10 participants showed peak levels of approximately 50–80 U/L at weeks 5 and 8 (Reference #4, Figure 2).
• 3 of 15 participants experienced hepatic enzyme elevations, but peak levels and timing were not reported (Reference #6).
• In Reference #8 (Figure 1), an AST peak of approximately 175 U/L was observed in the third patient during the latter part of the first to second year

According to reported data on capsid-directed T cell activation after vector administration in References #4, #6, and #8, the findings are summarized as follows:

• Reference #4
  • Participants P7 and P9 showed concomitant positive interferon-γ ELISpot responses to AAV-Spark100 capsid peptides during episodes of asymptomatic,
    transient ALT elevation that were managed with prednisone (Figure 2)
• Reference #6
  • Among fifteen participants, three experienced hepatic enzyme elevation; of these, two were positive for capsid-reactive T cells by interferon-γ ELISpot,
    although peak values and timings were not reported
• Reference #8
  • ELISpot results for Participants P7 and P9 showed positivity for AAV capsid antigen after week 2 and week 4, respectively (Figure S1)

Participants P7 and P9 received prednisone for a total of 130 and 119 days, respectively, as reported in the Supplementary Appendix Reference #4

Yes, in 1/2 pts. with ALT/AST elevations + T-cell response FIX coagulant activity declined from 48% to 30% on day 56 and to 18% on day 62⁴

According to reported data on cancer surveillance after vector administration in Reference #8, the findings are summarized as follows:

• No evidence of cancer was detected on surveillance liver ultrasounds obtained from year 1 onward
• No clinically relevant increases in alpha-fetoprotein levels were observed
• No cases of cancer were reported among treated participants
• Investigators emphasized the importance of continued long-term monitoring, as the interplay between liver disease progression and AAV gene therapy remains uncertain

1. A Gene Therapy Study for Hemophilia B. Available at: Study Details | A Gene Therapy Study for Hemophilia B | ClinicalTrials.gov
2. Long-term Safety and Efficacy Study and Dose-Escalation Substudy of PF 06838435 in Individuals With Hemophilia B. Available at: Study Details | NCT03307980 | Long-term Safety and Efficacy Study and Dose-Escalation Substudy of PF 06838435 in Individuals With Hemophilia B | ClinicalTrials.gov
3. FDA BLA Approval Document. Available at: April 25, 2024 Approval Letter - BEQVEZ (fda.gov)
4. George, L.A., et al., Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med, 2017. 377(23): p. 2215-2227. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant | NEJM
5. Nathwani, A.C., Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program, 2019. 2019(1): p. 1-8. Gene therapy for hemophilia - PMC (nih.gov) 
6. George, L.A., et al., Efficacy and Safety in 15 Hemophilia B Patients Treated with the AAV Gene Therapy Vector Fidanacogene Elaparvovec and Followed for at Least 1 Year. Blood, 2019. 134(Suppl. 1): p. 3347. Efficacy and Safety in 15 Hemophilia B Patients Treated with the AAV Gene Therapy Vector Fidanacogene Elaparvovec and Followed for at Least 1 Year | Blood | American Society of Hematology (ashpublications.org)
7. Rasko, J.E.J., et al., PATTERNS OF JOINT BLEEDS IN PATIENTS WITH HEMOPHILIA B FOLLOWING FIDANACOGENE ELAPARVOVEC ADENO-ASSOCIATED VIRUS GENE THERAPY. Haemophilia, 2023. 29. POSTER ABSTRACTS - Mulders - 2023 - Haemophilia - Wiley Online Library
8. Rasko JEJ, Samelson-Jones BJ, George LA, Giermasz A, Ducore JM, Teitel JM, McGuinn CE, High KA, de Jong YP, Chhabra A, O'Brien A, Smith LM, Winburn I, Rupon J. Fidanacogene Elaparvovec for Hemophilia B - A Multiyear Follow-up Study. N Engl J Med. 2025 Apr 17;392(15):1508-1517. doi: 10.1056/NEJMoa2307159. PMID: 40239068. Fidanacogene Elaparvovec for Hemophilia B - A Multiyear Follow-up Study - 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