UniQure Hope B Clinical Trial: Etranacogene dezaparvovec (AAV5-FIX-Padua Gene Therapy) Showed Substantial Improvement in Bleeding in Subjects with Hemophilia B

 Etranacogene dezaparvovec For Treatment of Hemophilia B (Highlights)

Data from the HOPE-B pivotal study showed that participants continued to demonstrate durable, sustained increases in Factor IX (FIX) activity at 52-weeks post-infusion with a mean FIX activity of 41.5 percent of normal, as measured by a one-stage APTT-based clotting assay, compared to a mean FIX activity of 39.0 percent of normal at 26-weeks of follow-up. There continued to be no clinically significant correlation between pre-existing neutralizing antibodies to AAV5 (NAbs) and FIX activity in patients with NAb titers up to 678.2, a range expected to include more than 93 percent of the general population. 

During the 52-week period, a single dose of etranacogene dezaparvovec significantly reduced the annualized rate of bleeding requiring treatment by 80 percent from a prospectively collected 3.39 at baseline to 0.68 bleeding episodes per year (p-value <0.0001). The annualized rate of spontaneous bleeding requiring treatment was also significantly reduced by 85 percent from a prospectively collected 1.16 at baseline to 0.18 bleeds per year during the 52-week period (p-value <0.0001). 

Usage of FIX replacement therapy (IU/year and infusions/year) in all patients declined 96 percent during the 52-week period, with 52 of 54 patients (96 percent) successfully discontinuing their prophylactic infusions. As previously announced, of the two non-responders, one patient only received a partial dose (less than 10 percent of the dosage) due to an infusion reaction and a second patient had an unusually high pre-existing NAb titer of 3,212, which is expected in less than 1 percent of the general population.

Introduction to Hemophilia B

Hemophilia B, also called factor IX (FIX) deficiency or Christmas disease, is a genetic disorder caused by missing or defective factor IX, a clotting protein. Hemophilia is an inherited disorder that is passed down from parents to children. About 1/3 of cases are also caused by a spontaneous mutation, a change in a gene. Hemophilia occurs in approximately 1 in 5,000 live births. There are about 20,000 people with hemophilia in the US.

In subjects with Hemophilia B, a deficiency of factor IX results in prolonged bleeding episodes. Based on the factor IX activity, the hemophilia B can be classified into: 

a) Mild Hemophilia B, the factor IX activity ranges from 6 to 49% of the normal reference range. 

b) Moderate Hemophilia B, the factor IX activity ranges from 1 to 5% of the normal reference range

c) Severe Hemophilia B, the factor IX activity is less than 1%

Treatment Platform

Etranacogene dezaparvovec consists of an AAV5 viral vector carrying a gene cassette with the patent-protected Padua variant of Factor IX (FIX-Padua). FIX-Padua is a natural variant of FIX that have higher FIX activity than wild-type FIX.

Regulatory Status

Etranacogene dezaparvovec has been granted Breakthrough Therapy Designation by the United States Food and Drug Administration and access to Priority Medicine (PRIME) regulatory initiative by the European Medicines Agency. 

HOPE-B Pivotal Phase 3 Clinical Studies : Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients (NCT03569891)
This is an open-label, single-dose, multi-center, multinational trial to demonstrate the efficacy of AMT-061 and to further describe its safety profile.

The study drug is identified as AAV5-hFIXco-Padua (AMT- 061). AMT-061 is a recombinant adeno-associated viral vector of serotype 5 (AAV5) containing the Padua variant of a codon-optimized human FIX complementary deoxyribonucleic acid (cDNA) under the control of a liver-specific promoter. The pharmaceutical form of AMT-061 is a solution for intravenous infusion administered at a dose of 2 x 10^13 gc/kg.
Subjects will receive a single infusion of AAV5-hFIXco-Padua (AMT- 061) at baseline. After study drug administration (post study drug), subjects will be monitored for tolerance to the study drug and detection of potential immediate AEs at the clinical trial site for a few hours after dosing.

Primary Outcome Measures:

• Factor IX activity levels [ Time Frame: 26 weeks ]. Assessment of factor IX activity after a single dose of AMT-061

Secondary Outcome Measures:

• Annualized bleeding rate (ABR) [ Time Frame: 52 weeks ]. Comparison of ABR between prophylaxis used in the lead-in and after administration of AMT-061
• Use of factor IX replacement therapy [ Time Frame: 52 weeks ]. Patients will record all use of prophylactic factor IX replacement therapy in an e-diary, including the reason for factor IX use, date, and time of infusion, and total dose
• Adverse events[ Time Frame: 5 years ]. Follow up and assess any adverse events reported for safety

Demographics of Study Population From Phase III HOPE B Clinical Study

Patients in the Phase III HOPE-B clinical study were initially enrolled into a prospective, observational lead-in period of at least six months during which bleeding events and FIX replacement therapy usage were monitored. All patients required prophylactic routine FIX replacement prior to entering the clinical trial.