Summary Information For: AAV5, FIX-WT, AMT-060, uniQure, NCT02396342 ¹¹⁻¹³ˑ ⁵⁸
AAV5, FIX-WT, AMT-060, uniQure, NCT02396342 ¹¹⁻¹³ˑ ⁵⁸
Haemophilia B
uniQure
General Study Information
  • ClinicalTrials.gov Identifier: NCT02396342 
  • A Phase 1/2 Open-Label, Single-Dose, Dose-ascending Study

Completed *, Last Update Posted: April 23, 2021 *

  • Male, Age ≥ 18 years, pts. with congenital hemophilia B 
  • FIX deficiency with plasma FIX activity level < 1%
  • Moderately severe FIX deficiency with plasma FIX activity level ≥ 1% and ≤ 2% 
  • > 150 previous EDs of treatment with FIX protein
  • NAbs against AAV5 at Visit 1
  • A sample is considered positive at 29% inhibition of transduction (sample vs negative control) 
  • Previous arterial or venous thrombotic event
  • Previous gene therapy treatment

AAV5/ Insect cells, baculovirus expression system

Codon-optimized FIX-WT 11

The FIX expression is driven by the liver-specific enhancer/promoter construct referred to as LP1 that is based on 11, 42:

  • The APOE gene hepatic-control region (APOE-HCR) and
  • The human α1 -antitrypsin (hAAT) promoter                              

Systemic 28

Data regarding the dose-cohorts were reported by these publications 11, 12,13, 58  as follows:

  • Co. 1: 5e12 (5)
  • Co. 2: 2e13 (5)

3 - 5 years 11, 1213, 58

OS

Efficacy details
  • Mean steady-state FIX activity across all 10 pts. in both cohorts  was in the range of 1.3 -12.7 IU/dl according table 3 here 11 

Mean yearly FIX activities through 5 years were reported publications 111213, 58

Year

1

2

3

4

5

Co. 1 (5e12 gc/kg)

4.4 ᵃ

6.8

7.3

7.0

5.2

Co. 2 (2e13 gc/kg)

7.1

8.4

7.9

7.4   

7.2

​​​    ​a P3 continued with prophylaxis after AMT-060 treatment so that only limited samples uncontaminated by exogenous FIX were available 11

Stable activity with no peak 11

Data regarding the annualized bleeding rate were extracted from Figure 3B 11 and are summarized as follows:

Annualized Bleeds in the year before and after vector infusion and reduction of the ABR (%) to year prior treatment

Median Age

median age, 69 years

median age, 35 years

Cohort

Co. 1 (5e12 gc/kg)

Co. 2 (2e13 gc/kg)

  Year pre-/ post treatment

pre

post

Percent of Reduction (%)

pre

post

Percent of Reduction (%)

total bleeds

14.5

7.5

48

4.0

2.0

49

spontaneous bleeds

9.8

4.6

53

3.0

0.9

70

 

  •  At year 3 the mean ABR was 1.7 for Co. 1 and 0.7 for Co. 2 12
  • At year 4 the mean ABR was 3.3 for Co. 1 and 0.0 for Co. 2 corresponding to 77% and 100% reduction of mean ABR to the year prior to treatment 13
  • At year 5 the mean ABR was 6.5 for Co. 1 and 0.0 for Co. 2 corresponding to 55% and 100% reduction of mean ABR to the year prior to treatment 58

Data regarding the annualized FIX usage were extracted from Figure 3A 11 and are summarized as follows:

Annualized FIX usage (IU) in the year before and after vector infusion and % of reduction of the FIX use to year prior treatment

Median Age

median age, 69 years

median age, 35 years

Cohort

Co. 1 (5e12 gc/kg)

Co. 2 (2e13 gc/kg)

  Year pre-/ post treatment

pre

post

Percent of Reduction (%)

pre

post

Percent of Reduction (%)

Annualized FIX usage (IU)

1,774,000

331,208

81%

866,000

232,299

73%

 

  • The total annualized reduction of exogenous FIX use after AMT-060 treatment was 79% overall (81% in Co. 1 and 73% in Co. 2) 11
  • FIX replacement therapy consumption declined 84% (Co. 1) and 99% (Co. 2) during year 5 post AMT-60 infusion 58    
  • All participants who discontinued prophylaxis remain prophylaxis-free through 5 years 58
Safety Details
  • Gene transfer was well tolerated with no severe TRAEs 11
  • No infusion related reactions were reported

 

A total of 14 treatment-related adverse events (TRAEs) classified as possibly/
probably related to treatment by the reporting investigator
11

 

Co. 1 (5e12 gc/kg)

Co. 2 (2e13 gc/kg) ᵇ

TRAE

No. of events (No. of pts.)

No. of events (No. of pts.)

Any TRAEs

4 (3)

10 (3)

Liver enzymes increased

1 (1)

3 (2)

Pyrexia

1 (1)

2 (2)

Anxiety

1 (1)

1 (1)

Drug ineffective ᵃ

1 (1)

0

Palpitations

0

1 (1)

Prostatitis

0

1 (1)

Rash

0

1 (1)


    a    Because this was an early trial of gene therapy, lack of efficacy was included as an adverse event of special notification and therefore was automatically reported.    
    b    P6 in Co. 2 (2e13 gc/kg) experienced 7 TRAEs (2 instances of increases in liver enzymes, pyrexia, anxiety, palpitations,  headache, and rash).
     

  • No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation 58

Not reported

1/5 pts. in Co. 2 and 2/5 pts. in Co. 3 with peak levels in the range of 61-85 U/L at W6-W16 11

No

0/10

Yes, 2 - 10 weeks

No

Not reported

References:

* ClinicalTrials.gov
11. Miesbach, W., et al., Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood, 2018. 131(9): p. 1022-1031.
       Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B | Blood | American Society of Hematology (ashpublications.org)
12. Miesbach, W., et al., Stable FIX Expression and Durable Reductions in Bleeding and Factor IX Consumption for up to 4 Years Following AMT-060 Gene Therapy
       in Adults with Severe or Moderate-Severe Hemophilia B. Blood, 2019. 134(Suppl 1): p. 2059.
       Stable FIX Expression and Durable Reductions in Bleeding and Factor IX Consumption for up to 4 Years Following AMT-060 Gene Therapy in Adults with Severe
       or Moderate-Severe Hemophilia B | Blood | American Society of Hematology (ashpublications.org)

13. Leebeek, F.W., et al., AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B Confirm Stable FIX Expression and Durable Reductions in
      Bleeding and Factor IX Consumption for up to 5 Years. Blood, 2020. 136(Supplement 1): p. 26.
      AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B Confirm Stable FIX Expression and Durable Reductions in Bleeding and Factor IX
      Consumption for up to 5 Years | Blood | American Society of Hematology (ashpublications.org)

28. Nathwani, A.C., Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program, 2019. 2019(1): p. 1-8.
       Gene therapy for hemophilia | Hematology, ASH Education Program | American Society of Hematology (ashpublications.org)
42. Nathwani, A.C., et al., Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood, 2006. 107(7): p. 2653-61.
       Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver | Blood | American Society of Hematology (ashpublications.org)
58. Miesbach, W., et al., Five Year Data Confirms Stable FIX Expression and Sustained Reductions in Bleeding and Factor IX Use Following AMT-060 Gene Therapy in
      Adults with Severe or Moderate-severe Hemophilia B [abstract]. ISTH 2021 Congress, 2021. Five Year Data Confirms Stable FIX Expression and Sustained Reductions
      in Bleeding and Factor IX Use Following AMT-060 Gene Therapy in Adults with Severe or Moderate-severe Hemophilia B - ISTH Congress Abstracts

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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