Phase 3 studies are continuing in the enhanced Padua FIX variant AMT-061 for hemophilia B.
AMT-060 was shown to produce stable Factor IX (FIX) expression and sustained reductions in bleeding in hemophilia B in 5-year data presented at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Congress.1
Patients in cohort 1 that received a 5 x 1012 gc/kg dose of AMT-060 had a mean FIX activity of 5.2% through 5 years compared with patients in cohort 2, who received a 2 x 1013 gc/kg dose and had a mean FIX activity of 7.2% through 5 years. Additionally, during the last 12 and 6 months of observation, cohort 1 had a mean annualized bleeding rate (ABR) of 6.5 and cohort 2 had a mean ABR of 0.0, representing a 55% and 100% reduction in ABR compared with the year before treatment, respectively.
“Gene therapy in hemophilia aims to provide long-term therapeutic benefit from a single administration,” Investigator Wolfgang Miesbach, MD, University Hospital Frankfurt, and colleagues wrote. “Sustained endogenous FIX activity and reductions in ABR and use of FIX replacement were maintained through 5 years following a single administration of AMT-060, with no additional safety concerns.”
Miesbach and colleagues worked to evaluate the safety and efficacy of AMT-060, an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human FIX gene and liver-specific promoter. The phase 1/2 study (NCT02396342) enrolled 10 male participants with moderate to severe hemophilia B, FIX activity of at most 2%, and a severe bleeding phenotype. These participants received a single intravenous infusion of AMT-060 at the 2 doses with 5 participants in each cohort.
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Investigators assessed FIX activity, ABR, FIX replacement use, and treatment-related adverse events (AEs). Cohort 1 had mean FIX activity rates of 4.4%, 6.8%, 7.3%, 7.0%, and 5.2% at years 1 to 5, respectively. Cohort 2 had mean FIX activity rates of 7.1%, 8.4%, 7.9%, 7.4%, and 7.2% at years 1 to 5, respectively. FIX replacement therapy consumption declined by 84% in cohort 1 and 99% in cohort 2 by 5 years. No participants who discontinued prophylaxis resumed its use.
No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. Treatment-related AEs mostly occurred in the first 3.5 months after treatment. These included 3 cases of transient mild alanine aminotransferase. UniQure will present final 5-year data at a later date. Study participants will also be able to enroll in a long-term follow-up study over an additional 5 years.
The phase III HOPE-B trial (NCT03569891) of the enhanced construct of AMT-060 with the Padua variant of the FIX gene, etranacogene dezaparvovec (AMT-061) is ongoing. UniQure recently announced data from the trial that showed that participants treated with AMT-061 sustained increases in FIX activity.2
FIX activity increased from 39.0% of normal mean FIX activity at 26-weeks of follow-up to 41.5% of normal mean FIX activity at 52 weeks. A single dose of the treatment was prospectively found to significantly reduce ABR requiring treatment by 80%, from 3.39 per year at baseline to 0.68 per year at 52 weeks (P <.0001). The annualized rate of spontaneous bleeding requiring treatment was also significantly reduced by 85% from 1.16 bleeds per year at baseline to 0.18 bleeds per year at 52 weeks (P <.0001).
FIX replacement therapy use was reduced by 96% in all patients during the interventional period, and 52 patients (96%) discontinued the therapy entirely. Of the 2 non-responders, 1 received a partial dose due to an infusion reaction and the second had an unusually high pre-existing NAb titer of 3212.
“The 52-week data show mean FIX activity in the normal range and increase our confidence in the potential durability and long-term benefits of etranacogene dezaparvovec, bringing us one step closer to our goal of delivering this groundbreaking therapy to fulfill an unmet medical need for patients living with hemophilia B,” Ricardo Dolmetch, PhD, president, research and development, uniQure, said in a statement.2