• ClinicalTrials.gov Identifier:  NCT03061201¹
• Phase 1/2 open-label study (Alta study)^{2, 3, 4, 5, 6}

• Ongoing development, Active, not recruiting¹
• Last Update Posted: June 1, 2023¹

• Male ≥18 years of age with severe hemophilia A (past evidence of circulating FVIII activity of < 1% normal)
• Treated or exposed to FVIII concentrates or cryoprecipitate for at least 150 EDs

• Presence of NAbs to AAV6 capsid and/or inhibitor to FVIII
• History of hypersensitivity response to FVIII replacement therapy
• Liver dysfunction and Contraindication to steroids⁴

• AAV6^4, 6, 7, Baculovirus insect cell line⁷

    B domain deleted human FVIII transgene^4, 6, 8 

The SB-525 expression cassette includes a liver-specific promoter module with multi-factorial modifications and a synthetic polyA signal as regulatory vector elements⁷

    Systemic delivery through a single intravenous infusion (IV)²

Giroctocogene fitelparvovec was delivered via a single IV infusion to pts. in 4 cohorts (n=2 each², except Co. 4: n=5 ^{3, 6, 7, 8}) across 4 ascending doses as follows:

• Co. 1:    9e11 (2; participants 1 and 2) 
• Co. 2:    2e12 (2; participants 3 and 4)
• Co. 3:    1e13 (2; participants 5 and 6) 
• Co. 4:    3e13 (5; participants 7, 8, 9, 10, and 11)

• Lower dose cohorts: 52 weeks⁹
• Co. 4: 24 ³ and 44 weeks^8-9

According to the abstract submitted at the ASH Meeting 2021⁴, the follow-up for the participants was reported as follows:

• 95 - 195 weeks overall follow-up

According to the poster presented at the ASH Meeting 2022⁵, the follow-up for the participants was reported as follows:

• As of the cutoff date (September 6, 2022), participants in all cohorts had been followed for 153 to 263 weeks
• All participants have completed at least 35 months (Study Visit: Week 156)

According to the most recent publication⁶, the follow-up for the pts. was reported as follows: 

• follow-up ranged from ~114 weeks to 214 weeks
• One participant in Co. 3 (participant 6) missed a visit at week 5, was lost to follow-up ~35 weeks after dosing,
  and rejoined the study at ~130 weeks

OS³ and  CH^3, 9

• Co. 3 (1e13 vg/kg): stable and clinically relevant increases in FVIII activity³ 
• Early follow-up data on FVIII activity (IU/mL.) level in Co. 4 (3e13 vg/kg) were collected from the abstract³,  submitted at the
  ASH Meeting 2019 and summarized as follows:

• Two participants in Co. 4 (3e13 vg/kg) experienced transient chromogenic FVIII activity levels above the upper limit of normal (150%),
  with peak values of 169% and 187% at weeks 20 (P8) and 52 (P7)⁶
• Long-term follow-up data on FVIII activity (IU/mL) levels in Co. 4 (3e13 vg/kg) were collected from Table 4 of the poster presented at the
  ASH Meeting 2022⁵ and from the most recent publication⁶. The summarized data are as follows:

    ^a There was 1 participant each who was unable to attend visits at Weeks 52, 78, and 130
    ^b Three participants had not yet reached Week 182 at the time of the data cutoff
       BLQ=below limit of quantification (<1% for 1-Stage Assay and <3% for Chromogenic Assay); min = minimum, max = maximum
    ^c The indicated values represent a relative decrease of 40% in the mean FVIII activity level during year 2⁶

• All 5 participants in Co. 4 (3e13 vg/kg) had data available at Week 156⁵
  • 4/5 pts. had FVIII in the mild to normal range.
  • 1/4 pts. (P8) had FVIII activity levels below the lower level of quantification (<3%), as measured with CH and 3.3% measured with OS

• Factor response increasing to final endpoint³
• All participants in Co. 4 achieved peak FVIII levels in the normal range (>50%) by week 9⁶

ABR with the longest follow-up period for Co. 4 (3e13 vg/kg) was reported here⁵ as follows:

• Mean ABR was 0.0 for the first year post-infusion
• Mean overall ABR = 1.4 (n=5 participants with ≥2 years of follow-up

Long-term follow-up on ABR was reported in the poster presented at the ASH meeting 2022⁵, and summarized as follows:

• The mean annualized total bleeding rate [(number of all bleeding episodes starting 3 weeks after study drug infusion) / (observation period in years)] was 0 for the first-year post-infusion and 1.2 throughout the total duration of follow-up
  • 2 pts experienced an overall total of 18 bleeding events:
    • 1 participant (P9) (1 event): circumstances of bleed unknown; event occurred in a prior target joint on Study Day 471 (~Week 67).
    • 1 participant (P8) (17 events): 8 traumatic, 5 spontaneous, 4 unknown; no events occurred in known prior target joints; first occurrence on Study Day 474 (~Week 68).
    • No participants in Co. 4 have resumed prophylaxis

Treatment of bleeding episodes requiring the use of FVIII replacement therapy per patient was reported here as follows:

• In 2/2 participants each in cohorts 1 and 2
• 1 of 2 participants in cohort 3, and
• 2 of 5 participants in cohort 4.
• In Co. 3, the mean (SD) total ABR was 3.1 (4.4) vs a mean (SD) total ABR of 1.5 (2.1) in the year before vector infusion
• In Co. 3, one participant (P5) had 20 treated bleeding episodes in total
  • with the first bleeding episode (nontarget joint) occurring at week 12;
  • 9 bleeding episodes were in a target joint (knee), with the first target joint episode occurring at week 18.

Summarized data on annualized bleeding rates per cohort have been collected from here⁶ and are shown as follows:

* n indicates number of participants with bleeding events
† Defined as the number of bleeding episodes during the 12 months before screening
‡ Postinfusion rate = (number of bleed episodes starting 3 weeks after study drug infusion and until the start of prophylactic dosing
   of FVIII [or date of data cut or conclusion date]) / (observation period for the participant, in years)

No pts. in Co. 4 (3e13 vg/kg) have resumed prophylaxis with mean FVIII activity in the mild range through 104 weeks post-infusion⁴

At the time of data cutoff, statements  concerning infusions of FVIII products during the first year were collected from this source⁶ and summarized as follows:  

• In Co. 4 (3e13 vg/kg), there was a mean decrease of 98.6% in the AIR of exogenous FVIII compared to preinfusion levels
• None of the participants in Co. 3 (1e13 vg/kg) or Co. 4 (3e13 vg/kg) resumed prophylaxis
• In Co. 4 (3e13 vg/kg), there were no infusions of FVIII products during the first year
• The postinfusion mean (SD) AIR of FVIII therapy in Co. 4 (3e13 vg/kg) was 1.8 (3.5) at data cutoff

According to the submitted abstract and the presented poster at the ASH Meeting 2022⁵ , the following adverse events (AEs) were  reported ≈ 6 hours after giroctocogene fitelparvovec infusion:

• Treatment-related serious AEs were reported in 1/5 pts. in Co. 4 (3e13-vg/kg cohort), who experienced hypotension (grade 3) and fever (grade 2)
• The events fully resolved with treatment and did not delay post-infusion discharge the next day

According to sources^{5, 6}, in total, 103 treatment-emergent AEs (TEAEs) occurred across all cohorts

• 26 of these events were considered related to study treatment, and all participants reported at least one TEAE
• The most common treatment-related TEAEs were increases in ALT (13 events in 5 [46%] pts.) and AST levels (5 events in 3 [27%] pts.)
• A total of 5 SAEs were reported in 3/11 participants:
  • SAEs considered to be related to study treatment:
    • Two of these events were occurred in 1 participant (P7) in Co. 4
      • This participant (P7) experienced grade 3 hypotension and grade 2 pyrexia 6 hours after completion of dosing,
        which resolved within 24 hours after treatment with electrolytes, norepinephrine, ondansetron, glucose, and paracetamol
    • No hypotension events occurred in the 4 subsequent participants in Co. 4
  • SAEs not considered to be related to study treatment:
    • P3 in Co. 2 experienced SAEs of grade 3 cellulitis of the buttock and perineum
    • P4 in Co. 2 experienced an SAE of grade 2 burns to the right anterior foot
• No confirmed FVIII inhibitors, thrombotic events, hypersensitivity, or malignancy were detected in any participant during the analysis period

Data summarizing treatment-emergent AEs (TEAEs) and treatment-related TEAEs have been collected from this source6 and are presented below:

*Number of participants with at least 1 TEAE reported in the study population.
†For any AE, only the TEAEs reported by at least 2 participants are included in this table.
 Similarly, for any treatment-related AE, only the treatment-related TEAEs reported by at least 1 participant are included

    Not reported

Data regarding the elevation in ALT levels were reported in these sources^5, 6 as follows:

• Across all cohorts, 13 events were recorded in 5 (46%) participants with elevated ALT levels
• In Co. 4, 4 /5 participants had elevations in their ALT levels
• In Co. 4, the onset of initial ALT elevations ranged from week 2 to week 11
• According to Figure 1⁶, the ALT level peaks in the participants in Co. 4 ranged from 60 to 180 U/L

• In total, 5 events were recorded in 3 (27%) participants with elevated AST levels⁶
• According to Figure 1⁶, the ALT level peaks in the participants in Co. 4 ranged from around 30 to 80 U/L

    Not reported

• According to Fig. 1 in the recent publication⁶, all patients (4 out of 5) in Co. 4 who experienced ALT elevations were responsive to steroid treatment
• Courses of corticosteroid treatment resulting from ALT elevations were reported in the same publication⁶ as follows:
  • In Co. 4, the onset of initial ALT elevations ranged from week 2 to week 11
  • The duration of individual corticosteroid treatment courses ranged from 7 to 187 days, with an average duration of 65.7 days
  • At the investigator's discretion, not all steroid courses involved a full tapering regimen before discontinuation
  • The minimum observed duration for cases where steroids were tapered was 49 days
  • ALT elevations refractory to corticosteroid treatment were not observed

Statements and observations concerning reduction or loss of FVIII activity associated with ALT elevation were collected from here⁷ and summarized as follows:  

• No, durable FVIII activity demonstrated across the dose cohorts from W44 trough to W52 of follow-up
• No pts. treated with SB-525 experienced an ALT elevation associated with loss of FVIII expression

    No neoplastic events, abnormal AFP, and/or liver masses were reported⁴

1. A Study of Recombinant AAV2/​6 Human Factor 8 Gene Therapy SB-525 (PF-07055480) in Subjects With Severe Hemophilia A. Available at: Study Details | A Study of Recombinant AAV2/6 Human Factor 8 Gene Therapy SB-525 (PF-07055480) in Subjects With Severe Hemophilia A | ClinicalTrials.gov
2. Konkle, B.A., et al., Initial Results of the Alta Study, a Phase 1/2, Open Label, Adaptive, Dose- ranging Study to Assess the Safety and Tolerability of SB-525 Gene Therapy in Adult Subjects with Severe Hemophilia A. Res Pract Thromb Haemostasis, 2019. 3(S1): p. 80. ISTH Academy
3. Konkle, B.A., et al., Updated Follow-up of the Alta Study, a Phase 1/2, Open Label, Adaptive, Dose-Ranging Study to Assess the Safety and Tolerability of SB-525 Gene Therapy in Adult Patients with Severe Hemophilia A. Blood, 2019. 134(Suppl. 1): p. 2060. Updated Follow-up of the Alta Study, a Phase 1/2, Open Label, Adaptive, Dose-Ranging Study to Assess the Safety and Tolerability of SB-525 Gene Therapy in Adult Patients with Severe Hemophilia A | Blood | American Society of Hematology (ashpublications.org)
4. Visweshwar, N., et al. Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults With Severe Hemophilia A. 63rd Annual Meeting and Exposition of the American Society of Hematology. 2021. Atlanta, GA, and virtual. Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia a | Blood | American Society of Hematology (ashpublications.org)
5. Giermasz, A., et al., Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia Α. Blood, 2022. 140(1). ASH Meeting 2022 abstract: Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia Α | Blood | American Society of Hematology (ashpublications.org), ASH Meeting 2022 Poster: 5276d0a4-3a3c-40a1-9ef2-1ca5b25a917c (sangamo.com)
6. Leavitt AD, Konkle BA, Stine KC, Visweshwar N, Harrington TJ, Giermasz A, Arkin S, Fang A, Plonski F, Yver A, Ganne F, Agathon D, Resa MLA, Tseng LJ, Di Russo G, Cockroft BM, Cao L, Rupon J. Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study. Blood. 2024 Feb 29;143(9):796-806. doi: 10.1182/blood.2022018971. PMID: 37871576; PMCID: PMC10933705. Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study - PMC (nih.gov)
7. Peyvandi, F. and I. Garagiola, Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia, 2019. 25(5): p. 738-746. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia - PubMed (nih.gov)
8. Pfizer and Sangamo Announce Updated Phase 1/2 Results Showing Sustained Factor VIII Activity Levels and No Bleeding Events or Factor Usage in 3e13 vg/kg Cohort Following giroctocogene fitelparvovec (SB-525) Gene Therapy. 2020 Pfizer and Sangamo Announce Updated Phase1/2 Results Showing Sustained Factor VIII Activity Levels and No Bleeding Events or Factor Usage in 3e13 vg/kg Cohort Following giroctocogene fitelparvovec (SB-525) Gene Therapy | Pfizer.
9. Sangamo and Pfizer Announce Updated Phase 1/2 Results Showing Sustained Increased Factor VIII Activity Through 44 Weeks Following SB-525 Gene Therapy Treatment.  December 7, 2019]; Sangamo and Pfizer Announce Updated Phase 1/2 Results Showing Sustained Increased Factor VIII Activity Through 44 Weeks Following SB-525 Gene Therapy Treatment.

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