Summary Information For: AAV6, FVIII-BDD, Giroctocogene Fitelparvovec (SB-525), NCT03061201 ²²⁻²³ˑ ³⁶
AAV6, FVIII-BDD, Giroctocogene Fitelparvovec (SB-525), NCT03061201 ²²⁻²³ˑ ³⁶
Haemophilia A
Pfizer/Sangamo
General Study Information
  • 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 234886) 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 3648

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 2348

Efficacy details
  •     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:

Mean FVIII activity (IU/mL.) levels measured by OS and CH as reported here 23 for the high dose cohort Co.4 (3e13 vg/kg)

Study week

2

4

8

12

16

20

24

28

Participants, n

3

4

4

2

2

1

1

1

OS FVIII mean (SD)

   19.47   (6.70)

   47.38    (15.81)

   90.93    (39.28)

    147.20     (28.99)

224.70 (33.38)

      250.70        (NA)

   213.10     (NA)

           266.90            (NA)

CH FVIII mean (SD)

  13.27   (6.52)

   31.15    (12.76)

  61.48    (26.13)

       96.30         (18.67)

 134.40  (8.06)

         169.10          (NA)

       130.60        (NA)

           165.60            (NA)

 

  • 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:

 

Long-term follow-up FVIII activity (IU/mL.) level measured by OS and CH up to week 182 post infusion

Study week

12

24

52

78

104

130

156

182

Participants, n

5

5

4a

4a

5

4a

5

2b

OS FVIII mean (min, max)

110.9 (82.7, 167.7)

107.5 (30.5, 212.6)

66.4 (12.0, 191.3)

65.7 (3.8, 144.2)

38.9 (4.1, 99.1

54.1 (5.4, 164.5)

40.5 (3.3, 129.0)

66.0 (18.2, 113.9)

CH FVIII mean (min, max)

71.7 (51.8, 109.5)

68.9 (20.4, 123.8)

42.6  (7.8, 122.3)

48.9 (BLQ, 114.7

25.4 (BLQ, 71.6)

34.7 (BLQ, 113.2)

25.5 (BLQ, 91.1)

37.7 (11.3, 64.0)


    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

Safety Details

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

IRR Event

Affected pts.

IRR grade

Tachycardia

2/5 pts.

grade 1

Pyrexia

3/5 pts.

grades 1 and 2

Hypotension

1/5 pts.

grade 3

 

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:

 

No. pts

No. of AEs

No. pts

No. of AEs

No. pts

No. of AEs

Any treatment- related event

2

5

4

21

6

26

Grade 3/4 AE

0

0

a

1

1

1

ALT increased

2

3

3

10

5

13

AST increased

1

2

2

3

3

5

Pyrexia

0

0

3

3

3

3

Tachycardia

0

0

2

2

2

2

Myalgia

0

0

1

1

1

1

Hypotension

0

0

1

1

1

1


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

 

Co. 2 (2e12 vg/kg, n = 2)

Co. 4 (3e13 vg/kg, n = 5)

All pts. (N = 11)

MedDRA Preferred Term

n

No. of Events

n

No. of Events

n

No. of Events

Any treatment- related event

2

5

4

22

6

27

Grade 3/4 AE

0

0

1a

1

1

1

ALT increased

2

3

3

10

5

13

AST increased

1

2

2

3

3

5

Pyrexia

0

0

3

3

3

3

Tachycardia

0

0

2

2

2

2

Myalgia

0

0

1

1

1

1

Hypotension

0

0

1

1

1

1

Fatigue

0

0

1

1

1

1

FVIII level increased

0

0

1

1

1

1


    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 3686
  • 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

References:

  *   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

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