• ClinicalTrials.gov Identifier: NCT02396342¹
• A Phase 1/2 Open-Label, Single-Dose, Dose-ascending Study

Completed¹, Last Update Posted: April 23, 2021¹

• 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-WT²

The FIX expression is driven by the liver-specific enhancer/promoter construct referred to as LP1 that is based on^2-3:

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

Systemic⁴

Data regarding the dose-cohorts were reported by these publications^{2, 5, 6, 7}  as follows:

• Co. 1: 5e12 (5)
• Co. 2: 2e13 (5)

3 - 5 years^{2, 5, 6, 7}

OS

• According to Table 3 in reference # 2, the mean steady-state FIX activity across all 10 patients in both cohorts ranged from 1.3 to 12.7 IU/dL during the first year
• Data documenting the course of mean FIX activity over a 5-year period following vector infusion are presented in references #2, #5, #6, and #7 and are summarized in the table below as follows:

​​    ^​a P3 continued with prophylaxis after AMT-060 treatment so that only limited samples uncontaminated by exogenous FIX were available²

Stable activity with no peak²

Data on the annualized bleeding rate were extracted from Figure 3B of reference #2 and are summarized as follows:

Follow-up data on the ABRs from year 3 to year 5 were published in references #5, #6 and #7 and are summarized as follows:

• At year 3 the mean ABR was 1.7 for Co. 1 and 0.7 for Co. 2⁵
• 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 treatment⁶
• 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 treatment⁷

Data regarding the annualized FIX usage were extracted from Figure 3A of reference #2 and are summarized as follows:

Follow-up data on the annualized FIX usage from year 3 to year 5 were published in references #5, #6 and #7 and are summarized as follows:

• The total annualized reduction of exogenous FIX use after AMT-060 treatment was 79% overall (81% in Co. 1 and 73% in Co. 2)2
• FIX replacement therapy consumption declined 84% (Co. 1) and 99% (Co. 2) during year 5 post AMT-60 infusion7
• All participants who discontinued prophylaxis remain prophylaxis-free through 5 years7

• Gene transfer was well tolerated with no severe TRAEs²
• No infusion related reactions were reported

Treatment-related adverse events (TRAEs) were reported in reference  #2 and are summarized as follows:

    ^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 activation⁷

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-W16²

No

0/10

Yes, 2 - 10 weeks

No

Not reported

1. Trial of AAV5-hFIX in Severe or Moderately Hemophilia B. Available at: Study Details | Trial of AAV5-hFIX in Severe or Moderately Severe Hemophilia B | ClinicalTrials.gov
2. 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)
3. 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)
4. 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)
5. 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)
6. 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)
7. 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.

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; TRAEs, treatment-related adverse events; ULN, upper limit of normal; VCN, vector copy number; vg, vector genomes; W, weeks; WT, wild type; Y, year