Summary Information For: AAVS3, FIX-Padua, FLT180a, NCT03369444 [16, 17]
AAVS3, FIX-Padua, FLT180a, NCT03369444 [16, 17]
Haemophilia B
Freeline Therapeutics
General Study Information
  • ClinicalTrials.gov Identifier: NCT03369444
  • A Phase I/II, Open Label, Ascending Single Dose Safety Study
  • Terminated due to challenges during the COVID-19 pandemic and a change in requirements of data to be submitted for marketing authorization *
  • Last Update Posted: December 2, 2022 *
  • Adults males, ≥ 18 years of age
  • Severe FIX deficiency with plasma FIX activity of<1% of normal o rmoderately severe FIX deficiency with plasma FIX activity level ≥1% and ≤2%
  • At least 150 exposure days to FIX concentrates
  • Patients at high risk of thromboembolic events

AAVS3, Mammalian cell manufacturing (iCELLis®17

FIX-Padua 16

  • New small liverÔÇÉ specific promoter referred to as FRE1 16 or HLP2 43
  • An optimized 44 truncated FIX intron 1 43

Systemic 29

Initially, dose levels in the 4 dose cohorts were reported here 17 as follows: 

  • Co. 1: 4.5e11 (2)
  • Co. 2: 7.5e11 (2)
  • Co. 3: 9.5e11 (4)
  • Co. 4: 1.5e12 (2)

Subsequently, dose levels were adjusted according to changed vector genome titer assay and reference standard 41 as follows :

  • Co. 1: 3.84e11 (2)
  • Co. 2: 6.4e11 (2)
  • Co. 3: 8.32xe11 (4)
  • Co. 4: 1.28xe12 (2)

Initially, follow-up times were reported here 17 as follows: 

  • Co. 1: 66-78 weeks
  • Co. 2: 26 weeks
  • Co. 3: 3  weeks
  • Co. 4: 26weeks

Subsequently, here 41 as follows:

  • Co. 1 - Co. 4: ≥ 16 weeks

OS 16, FIX:C levels assessed by chromogenic assay were 2-fold lower 16

Efficacy details
  • Steady state FIX:C levels in Co. 1 were 42.5 ± 6 % using an OS clotting assay 16

Following data regarding the mean FIX activity at W3 and W104 were taken from here 40 and summarized as follows:

  • At W3, FIX activity levels in Co. 1- Co. 4 were in the range of 24% to 168 %
  • Pts. in Co. 1 (4.5e11vg/Kg), have stable, therapeutic, FIX activity levels through W104

Mean FIX activities over the course of time were reported by these two publications  1740 as follows:

Cohort

N

week 3

week 26

week 52

week 78

Co. 1 (4.5e11 vg/kg)

2

25 % 17; 24.5% 40

40 % 17, 40

37.5 % 17, 40

43.5 % 17, 40

Co. 2 (7.5e11 vg/kg)

2

25.5% 17, 40

32.0% 17, 40

31.0% 40

-

Co. 3 (9.5e11 vg/kg)

4

109.0 % 17; 100.5 40

98.0 % 40

-

-

Co. 4 (1.5e12 vg/kg)

2

130 % 17, 40

160 % 17, 40

-

-

 

Not reported

Co. 1 (low dose): no spontaneous bleeding episodes in 2/2 pts. 16

No need of FIX concentrate infusions over 12 months follow up following gene transfer16

Safety Details

No evidence of infusion-related reactions 17, 41

  • No serious AEs following gene transfer 16
  • The most common drug related SAE was transient transaminitis (in 4 pts.) requiring supplemental immunosuppression 40
  • Observed FIX activities levels above 150% were individually assessed for risk of thrombosis, and one patient is being treated with DOACs 41

Not reported

  • Co. 1: Liver enzymes within the normal range 16
  • Co. 1-4: Transaminitis in 2 pts. (magnitude and cohort not reported) 17
  • Co. 1: Liver enzymes within the normal range 16
  • Co. 1-4: Transaminitis in 2 patients (magnitude and cohort not reported) 17

Not reported 16

  • Co. 1: Prophylactic steroids W4-12 16
  • Co. 2-4: Prophylactic steroids + TAC 17
  • Not reported 16
  • Co. 1: No 16 
  • Co. 1-4: Yes, in 2 pts. (magnitude and cohort not reported) transaminitis associated with decreased FIX expression 17

Not reported

References:

  *   ClinicalTrials.gov
16. Chowdary, P., et al., FLT180a: Next Generation AAV Vector for Haemophilia B - Long Term, Follow- up and In- depth Analysis of Transgenic
       FIX Using One- stage, Chromogenic and Global Assays. Res Pract Thromb Haemostasis, 2019. 3(S1): p. 307.ISTH Academy
17. Freeline. Corporate presentation. 2020 [cited 2020 06 May]; Available from: PowerPoint Presentation (azureedge.net)
29. Manno, C.S., et al., AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood, 2003. 101(8): p. 2963-72.
       AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B - PubMed (nih.gov)
40. Chowdary, P., et al., A Novel Adeno Associated Virus (AAV) Gene Therapy (FLT180a) Achieves Normal FIX Activity Levels in Severe Hemophilia B
      (HB) Patients (B-AMAZE Study). ISTH 2020 Congress, 2020. Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia Gene Therapy.
      A Novel Adeno Associated Virus (AAV) Gene Therapy (FLT180a) Achieves Normal FIX Activity Levels in Severe Hemophilia B (HB) Patients
      (B-AMAZE Study) - ISTH Congress Abstracts

41. Chowdary, P., et al., Factor IX Expression within the Normal Range Prevents Spontaneous Bleeds Requiring Treatment Following FLT180a Gene
       Therapy in Patients with Severe Hemophilia B: Long-Term Follow-up Study of the B-Amaze Program. ASH Annual Meeting 2021, 2021.
       Oral and Poster Abstracts. Factor IX Expression within the Normal Range Prevents Spontaneous Bleeds Requiring Treatment Following FLT180a
       Gene Therapy in Patients with Severe Hemophilia B: Long-Term Follow-up Study of the B-Amaze Program - ScienceDirect

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)
44. Freeline. B-AMAZE Phase 1/2 Study of FLT180a in Haemophilia B. 2020; Available from: PowerPoint Presentation (freeline.life)

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

See All Trials