HOPE-B: Study Design of a Phase III trial of an Investigational Gene Therapy AMT-061 in Subjects with Severe or Moderately Severe Hemophilia B

Scientific Research Question: Somatic gene therapy for hemophilia B offers the potential to ameliorate disease severity through continuous endogenous production of FIX protein with a single treatment. Robust preliminary efficacy and safety results have been obtained in 10 subjects with hemophilia B after treatment with AMT-060, an adeno-associated virus (AAV) serotype 5 vector containing a wildtype factor (F) IX gene, in an ongoing Phase I/II trial. At 1.5 years after a single dose of 2x10¹³ gc/kg (n = 5), stable FIX activity (mean of 7.2%) was observed, without immune-mediated loss of FIX activity or inhibitor development. AMT-060 was modified to encode the highly active Padua variant of FIX (AMT-061), which is expected to increase the activity-to-protein ratio by approximately 7-9 fold. The purpose of this Phase III trial is to demonstrate the efficacy of AMT-061 in terms of endogenous FIX activity and annualized bleeding rate, and to describe its safety profile in patients with hemophilia B.

Methodology: Open-label, single-dose, multi-center trial, with sites planned in the United States, the Netherlands, Germany, Denmark, Italy, Ireland, and other European countries. Participants will be adult males with FIX ≤ 2%, utilizing routine FIX prophylaxis, without history of FIX inhibitors, active hepatitis B or C, or uncontrolled HIV. Pre-existing AAV5 neutralizing antibodies (nAbs) will be assessed but not used as an exclusion criterion. Eligible patients will enter a prospective lead-in phase, during which FIX use and bleeding episodes will be documented. At the completion of the lead-in phase, patient eligibility will be re-confirmed and participants re-consented prior to receiving the single dose of AMT-061. Post-treatment, patients will be followed for 5 years.

Findings: Assessments during the post-treatment follow-up phases will include FIX activity, bleeds, use of FIX replacement, adverse events, FIX inhibitors, transaminases, and AAV5 nAbs. Patient reported outcome questionnaires and joint status will also periodically be determined

Conclusions: The modification of AMT-060 to AMT-061 with a highly active FIX variant (FIX Padua) is anticipated to achieve comparable levels of FIX protein but result in higher FIX activity, while preserving the safety profile and absence of T-cell activation observed with AMT-060. By not excluding patients from participating in the study based on nAb status, safety and efficacy can be evaluated in a broader population of patients.