• ClinicalTrials.gov Identifier:  NCT03061201 NCT03061201
• Phase 1/2 open-label study (Alta study) ^22-23

• Ongoing development, Active, not recruiting ^*
• Last Update Posted: June 1, 2023 ^*

• 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 steroids ⁵⁰

• AAV6 ^{43, 50}, Baculovirus insect cell line ⁴³ 

    B domain deleted human FVIII transgene ^{36, 50}

The SB-525 expression cassette includes a liver-specific promoter module with multi-factorial modifications and a synthetic polyA signal as regulatory vector elements ⁴⁸

    Systemic delivery through a single intravenous infusion (IV) ²²

Giroctocogene fitelparvovec was delivered via a single IV infusion to pts. in 4 cohorts (n=2 each ²², except Co. 4: n=5 ^23, 48, 86) across 4 ascending doses as follows:

• Co. 1:    9e11 (2) 
• Co. 2:    2e12 (2)
• Co. 3:    1e13 (2) 
• Co. 4:    3e13 (5)

• Lower dose cohorts: 52 weeks ⁴⁸
• Co. 4: 24 ²³ and 44 weeks ^36, 48

According to the abstract submitted at the ASH Meeting 2021 ⁵⁰, the follow-up for the pts. was reported as follows:

• 95 - 195 weeks overall follow-up

According to the poster presented at the ASH Meeting 2022 ⁸⁶, the follow-up for the pts. was reported as follows:

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

OS ²³ and  CH ^23, 48

•     Co. 3 (1e13 vg/kg): stable and clinically relevant increases in FVIII activity ²³ 
•     Early follow-up data on FVIII activity (IU/mL.) level in Co. 4 were collected from the abstract ²³,  submitted at the ASH Meeting 2019 and summarized as follows:

• Long-term follow-up data on FVIII activity (IU/mL.) level were collected from Table 4 in the poster ⁸⁶ , presented at the ASH Meeting 2022 and summarized 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, max=minimum, maximum> < 1% for OS and < 3% for CH); min, max=minimum, maximum

    All 5 participants had data available at Week 156

• 4/5 pts. had FVIII in the mild to normal range.
• 1/4 pts. (#02) 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 endpoint ²³

ABR with the longest follow-up period for Co. 4 (3e13 vg/kg) was reported here ⁵⁰ 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 in 2022, 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 (#03) (1 event): circumstances of bleed unknown; event occurred in a prior target joint on Study Day 471 (~Week 67).
    • 1 participant (#02) (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

No pts. in Co. 4 (3e13 vg/kg) have resumed prophylaxis with mean FVIII activity in the mild range through 104 weeks post-infusion ⁵⁰

Infusion-related reactions, occurring within a day of dosing, were reported here ⁵⁰ for pts. in Co. 4 (n = 5) as follows:

According to the submitted abstract and the presented poster at the ASH Meeting 2022 ⁸⁶ IRRs were reported as follows:

• 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) with onset ≈6 h after giroctocogene fitelparvovec infusion
• The events fully resolved with treatment and did not delay post-infusion discharge the next day

A total of 103 treatment-emergent AEs occurred in 11 pts. ⁵⁰ and 26 treatment-related AEs that occurred in 6 pts. were reported here ⁵⁰ as follows:

    Treatment-related AEs were collected additionally from Table 3 ⁸⁶ in the poster presented at the ASH Meeting 2022 and summarized as follows:

    ^a 1 pt. experienced grade 3 hypotension that was considered related to study drug and resolved with treatment

    Not reported

• Co. 1-3: No ALT elevations requiring > 7 days corticosteroid treatment ^22-23
• 3/5 pts. in Co. 3 had ALT elevations that responded to corticosteroids ^{23,  36}
• Co. 4 (3e13 vg/kg):  4/5 pts treated with corticosteroids for ALT elevations ^36, 86
• The median duration for managing elevations in ALT with a tapering course of corticosteroids was 56 days (range, 7–135 days) ⁸⁶

Not reported

    Not reported

    Co. 4 (3e13 vg/kg): 3/3 ALT elevations responded to steroids within 1 week ^22-23            

Statements and observations concerning reduction or loss of FVIII activity associated with ALT elevation were collected from here ⁴⁸ 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 reported ⁵⁰

  *   ClinicalTrials.gov
22. 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             
23. 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) 
36. Sangamo and Pfizer, 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
43. 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) 
48. 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
50. 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)
86. 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)

AAV, Adeno-associated virus; AEs, Adverse events; 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