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)

Etranacogene dezaparvovec is AAV5 gene therapy for the treatment of Hemophilia B 
- In HOPE-B open Label Phase III study, 54 patients met primary endpoint with mean Factor IX activity of 37% of normal at 26 weeks 
- Patients achieved significant increases in Factor IX activity irrespective of pre-existing neutralizing antibodies, potentially supporting broad patient access
- Increases in Factor IX activity were sustained for up to 18 months with near elimination of bleeding
Mean annualized usage of FIX replacement therapy declined by 96 percent after dosing compared to the observational lead-in period ~
- Etranacogene dezaparvovec was well-tolerated with no treatment-related serious adverse events
- Uniqure & CSL Behring entered into a licensing agreement providing CSL Behring with exclusive global rights

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. 
More than 80 percent of the 54 patients treated in the open-label study had severe hemophilia with endogenous FIX activity at ≤1%. Forty-three percent of patients in the study had NAbs to AAV5 up to a maximum titer of over 3,200. Fifty-four patients reported 123 bleeds during the lead-in phase of the study, even while they remained on prophylactic replacement therapy.

Efficacy Endpoint
  • FIX activity increased rapidly after dosing to a mean of 37.2 percent at 26 weeks from a baseline of less than 2 percent, meeting the first primary endpoint of the study. For those patients with follow-up beyond 26 weeks, similar FIX expression was sustained including one patient who has reached 18 months of follow-up.
  • No correlation between pre-existing NAbs and FIX activity was found in patients with NAb titers up to 678.2, a range expected to include more than 95 percent of the general population; a single patient with a higher NAb titer of 3,212.3 did not show an increase in FIX activity.


  • The number of bleeds requiring treatment decreased by 91 percent after the one-time administration of etranacogene dezaparvovec, with 87 percent of patients reporting no such bleeds after dosing. Total reported bleeds, which includes suspected bleeds that did not require treatment and bleeds associated with trauma and unrelated medical procedures, decreased by 83 percent. 
  • Usage of FIX replacement therapy in all patients declined 96 percent, with 52 of 54 patients (98 percent) successfully discontinuing their prophylactic infusions.
  • Of the two non-responders, one patient received only a partial dose (less than 10 percent of the dosage) due to an infusion reaction during administration. The second patient had a pre-existing NAb titer of 3,212. It is expected that less than 1 percent of the general population have a pre-existing NAb titer of more than 3,000.
Safety Endpoints
  • Etranacogene dezaparvovec was generally well-tolerated with no treatment-related serious adverse events.
  • Most adverse events were classified as mild (81.5 percent). Most common treatment-related events included transaminase elevation treated with steroids per protocol (9 pts; 17 percent), infusion-related reactions (7 pts; 13 percent), headache (7 pts; 13 percent) and influenza-like symptoms (7 pts; 13 percent).
  • Liver enzyme elevations resolved with a tapering course of corticosteroids, and FIX activity remained in the mild range (8-39 percent) in the steroid treated patients.
  • While administration was discontinued in one patient experiencing an infusion reaction, administration was completed successfully in the remaining six patients who experienced an infusion reaction.
  • No inhibitors to FIX were reported.
  • No relationship between safety and NAbs titers was observed.

Results from Phase IIb Study Showed Durable Expression of Factor IX Up to Two Years and Reduction of Prophylactic FIX infusion 
The Phase IIb study of etranacogene dezaparvovec is an open-label, single-dose, single-arm, multi-center trial being conducted in the United States. Three patients with severe hemophilia (endogenous Factor IX (FIX) activity less than or equal to one percent) were enrolled in the study and received a single intravenous infusion of 2x10^13 gc/kg. 

A two-year follow-up data showed that all three patients have sustained FIX activity at therapeutic levels after the one-time administration of etranacogene dezaparvovec. Mean FIX activity for the three patients at two years after administration was 44.2% of normal (compared to 41% of normal at 52 weeks), with the first patient achieving FIX activity of 44.7% of normal, the second patient achieving FIX activity of 51.6% of normal and the third patient achieving FIX activity of 36.3% of normal.

At two years after dosing, two of the three participants remain free from bleeds and use of FIX replacement therapy. A single bleed has been reported in one participant, who has used a total of two FIX infusions (excluding surgery). All patients have remained free of prophylaxis in the two years since receiving etranacogene dezaparvovec.

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