Hemophilia B is a monogenic X-linked recessive coagulation disorder, which causes a deficiency of coagulation factor IX (FIX) and affects ∼25 000 individuals globally. Factor IX concentrate can be administered on demand or prophylactically, which provides some pros and cons, as Dr. Frank Leebeek and others have noted. On-demand therapy at the time of a bleed is effective at stopping individual hemorrhages. Prophylaxis, by infusion of FIX concentrate given up to 3 times weekly, does not completely prevent bleeding occurrence. Low trough plasma levels may not optimally protect against bleeds.

Gene transfer potentially offers constant and sustained endogenous production of functional FIX. It is particularly attractive for the treatment of hemophilia because even a modest rise in clotting factor activity can change the bleeding phenotype and substantially reduce the bleeding risk. However, knowledge on durability of gene transfer is limited. In this study, AMT-060, an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wild-type human FIX gene and liver-specific promoter, was investigated in patients with severe/moderate-severe hemophilia B.

The aim of this Phase 1/2 study was to provide follow-up data for up to 3.5 years post-AMT-060. Adult males, split into 2 cohorts with 5 subjects in each, with pre-existing FIX activity ≤2% and a severe bleeding phenotype, received 1 of 2 different single intravenous infusions of AMT-060: 5 x 1012 gc/kg or 2 × 1013 gc/kg. The assessments included FIX activity, FIX replacement use, annualized bleeding rate (ABR), treatment-related adverse events (TRAE), vector shedding, and immunological and inflammatory biomarkers up to 3.5 years (Cohort 1) or 3 years (Cohort 2).

As of May 2019, mean FIX activity was 5.1% and 7.5% over 3.5 and 3 years of follow-up for Cohorts 1 and 2, respectively. Eight of 9 participants using prophylaxis at baseline were able to discontinue use of FIX prophylaxis. Mean ABR decreased from 14.4 pre-AMT-060 to 5.1 (range 1.7-7.6) over 3.5 years of follow-up (Cohort 1), and from 4.0 pre-AMT-060 to 1.0 (range 0.6-1.4) over 3 years of follow-up (Cohort 2). No patients developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. Most TRAE were reported in the first 3.5 months after treatment, including 3 patients who experienced transient mild elevations in alanine aminotransferase, which resolved after a short course of corticosteroids, without reductions in FIX activity. One mild TRAE of joint swelling was reported in the last year of follow-up.

As Dr. Leebeek stated, “Our current data indicate an ongoing long-term stable endogenous FIX activity and reductions in ABR and FIX replacement use following a single treatment with AMT-060, with no additional safety concerns. This has important implications for patients with hemophilia in whom the bleeding is minimized by a single gene transfer treatment.” The results and findings support the ongoing Phase 3 study of the enhanced construct, AMT-061, which encodes the highly active Padua FIX variant.

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