Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B

Abstract

Gene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay, and all 10 were enrolled. A single dose of 5 × 10 or 2 × 10 genome copies of AMT-060/kilogram was administered to 5 participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8% to 4.6% (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts, and 8 of 9 participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n = 1) and higher-dose (n = 2) cohorts were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids. This trial was registered at www.clinicaltrials.gov as #NCT02396342; EudraCT #2013-005579-42.

The 1st WFH Gene Therapy Round Table: Understanding the landscape and challenges of gene therapy for haemophilia around the world

“…Some discrepancies between assays and assay reagents notwithstanding, it was agreed that the haemophilia community should establish a minimally acceptable factor level and a minimum durability of treatment, for gene therapy to be considered successful. Several studies have demonstrated that a reduction in bleeding and factor use can be achieved with FIX expression levels of <10%; however, a minimal acceptable level still needs to be determined. Subsequent to the round table, the FDA issued draft guidelines specifying that factor levels may be utilized as the primary endpoint for breakthrough therapy approval, but ABR was proposed as the primary endpoint for the regular approval process .…”

“…Recently, we have seen the introduction of non‐factor therapies, including gene therapy, reach late phase clinical trials and the market . There are currently several ongoing clinical trials for both FVIII and FIX gene therapy, and barring unforeseen safety or efficacy issues, it is expected that at least 1‐2 will obtain regulatory approval in the next few years.…”

Hemophilia gene therapy is effective and safe

“…1 Importantly, hemoglobin appears to be the strongest predictor of CBF and OEF in this report and across all studies, potentially calling into question current transfusion practice guidelines that only consider posttransfusion hemoglobin S levels. ASE and other advanced neurovascular imaging techniques will be essential to determine the optimal hemoglobin level for cerebral protection in SCD patients and the role of hemoglobin S in cerebrovascular toxicity.…”

Haemophilia gene therapy: From trailblazer to gamechanger

“…106 When a higher dose was given (2 × 10 13 vg/kg) to another patient cohort, the FIX expression levels improved to almost 7%. Approximately 4% of FIX expression levels was achieved in the patients that received a dose of 5 × 10 12 vg/kg of the AMT-060 vector.…”