• ClinicalTrials.gov Identifier: NCT04370054¹
• Phase III AFFINE trial (NCT04370054)^1, 2

• Active, not recruiting
• Last Update Posted: 2024-07-24

• Males who have been followed on routine Factor VIII prophylaxis therapy during the lead-in study (C0371004) and have > = 150 documented exposure days to a Factor VIII protein product
• Moderately severe to severe hemophilia A (Factor VIII activity < =1%)
• Suspension of FVIII prophylaxis therapy post study drug infusion

• Anti-AAV6 neutralizing antibodies
• History of inhibitor to Factor VIII
• Laboratory values at screening visit that are abnormal or outside acceptable study limits

AAV6³, Baculovirus insect cell line³

 B domain deleted human FVIII transgene⁴

The SB-525 expression cassette includes a liver-specific promoter module with multi-factorial modifications and a synthetic polyA signal as regulatory vector elements⁵

    Systemic delivery through a single intravenous infusion (IV)⁴

Single dose cohort: 3e13 (76)¹

From Week 12 to at least 15 months²

Not yet reported

84% of participants maintained FVIII activity above 5% at 15 months post-infusion, with most participants  exhibiting levels of 15% or higher (Reference #2)

FVIII activity data from a case report describing follow-up through Day 736 in one patient who received a single infusion of giroctocogene fitelparvovec at 3 × 10¹³ vg/kg in the phase 3 AFFINE study were extracted from Reference #6 and are summarized below:

Additional findings on FVIII activity from Reference #6 are summarized as follows:

• FVIII activity increased above the normal range within the first three months after infusion
• During the first year, FVIII activity declined when corticosteroids were tapered or discontinued and partially recovered following their reintroduction
• Following discontinuation of the third corticosteroid course on Day 333, FVIII activity continued to decline substantially, prompting initiation of mycophenolate mofetil on Day 350
• FVIII activity and FVIII antigen were below the limit of detection from Day 487 onward
• During edoxaban treatment, plasma samples were treated with DOAC-Stop before testing
• Following initiation of emicizumab on Day 462, FVIII activity was measured exclusively using a bovine chromogenic assay

Not yet reported

Statements about the ABR after gene therapy, compared to the pre-infusion period, were collected from here² and summarized as follows:   

• From week 12 at least 15 months [15–44 months]):
  • Giroctocogene fitelparvovec demonstrated statistically significant 74% reduction in mean total ABR compared to the pre-infusion
    period (1.24 vs. 4.73) following a single 3e13 vg/kg dose
  • The mean treated ABR showed a statistically significant 98.3% reduction from 4.08 in the pre-infusion period to 0.07 post-infusion

Not yet reported

Not yet reported

Adverse event and safety data from a case report describing follow-up through Day 736 in one patient who received a single infusion of giroctocogene fitelparvovec at 3 × 10¹³ vector genomes/kg in the phase 3 AFFINE study were extracted from Reference #6 and are summarized below:

• FVIII inhibitor development
  • The patient had no previous history of FVIII inhibitors despite extensive exposure to FVIII products
  • Retrospective testing identified the first positive inhibitor measurement on Day 333 (0.6 BU)
  • An inhibitor was detected at the scheduled Day 368 visit (2.7 BU), progressing to a high titer on Day 452 (5.3 BU)
  • The inhibitor titer peaked at 647.9 BU on Day 592 and subsequently declined to 333.2 BU on Day 736
  • FVIII activity and FVIII antigen were below the limit of detection from Day 487 onward
  • Laboratory investigations identified type 2 inhibition kinetics. The authors could not definitively classify the inhibitor as an autoantibody or alloantibody
• Transaminase elevations
  • Recurrent mild-to-moderate transaminase elevations occurred during the first year, with peak ALT and AST levels of 315 U/L and 189 U/L, respectively
  • Three tapering courses of prednisone were administered, beginning on Day 26
  • Episodes were associated with declining FVIII activity during corticosteroid tapering or discontinuation, partially reversed following corticosteroid reintroduction
  • Liver enzymes remained within normal limits from Day 487 onward
• Elevated FVIII activity
  • FVIII activity rose above the normal range during the first three months, peaking on Day 75 at 625 IU/dL by OS and 442 IU/dL by CH
  • Protocol-directed edoxaban prophylaxis was administered from Day 54 to Day 328
• Corticosteroid-related adverse effects
  • Weight gain, irritability, and insomnia were reported
  • Concerns about corticosteroid adverse effects prompted initiation of mycophenolate mofetil on Day 350 following a further decline in FVIII activity
• Other clinical findings
  • Recurrent joint aches suggested possible microbleeds, which were not confirmed by ultrasound. Symptoms resolved following initiation of emicizumab on Day 462
  • No bleeding events were reported after gene therapy through the latest follow-up

The publication describes events occurring after gene therapy but does not provide a formal event-by-event classification of their relationship to the study agent

BU, Bethesda units; ALT, alanine aminotransferase; AST, aspartate aminotransferase; OS, one-stage assay; CH, chromogenic assay

Not yet reported

Not yet reported

Not yet reported

Not yet reported

Not yet reported

Not yet reported

Not yet reported

1. Study to Evaluate the Efficacy and Safety of PF-07055480 / Giroctocogene Fitelparvovec Gene Therapy in Moderately Severe to Severe Hemophilia A Adults (AFFINE). ClinicalTrials.gov identifier: NCT04370054. Link
2. Philippidis A. Pfizer Marks Phase III Success in Hemophilia A, then Layoffs after Failure in DMD. Hum Gene Ther. 2024 Sep;35(17-18):578-581. doi: 10.1089/hum.2024.378422.tlg. Epub 2024 Sep 13. PMID: 39284162. Link
3. Peyvandi F, Garagiola I. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia. 2019 Sep;25(5):738-746. doi: 10.1111/hae.13816. Epub 2019 Jul 8. PMID: 31282050. Link
4. Leavitt AD, Konkle BA, Stine KC, Visweshwar N, Harrington TJ, Giermasz A, et al. 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. Link
5. 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. Link
6. Matino D, Ligia S, Nazy I, Kwok S, Moffat K, Carlino S, Iorio A. A case report of high-titer FVIII inhibitor development after AAV-mediated gene therapy in hemophilia A. Blood Vessel Thromb Hemost. 2026 Apr 20;3(2):100170. doi: 10.1016/j.bvth.2026.100170. PMID: 42206011; PMCID: PMC13208095. 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