Uniqure announced positive top-line data from its pivotal, Phase III HOPE-B gene therapy trial of etranacogene dezaparvovec, an adeno-associated virus five (AAV5)-based gene therapy for the treatment of patients with severe and moderately severe hemophilia B. These clinical data were published as a late-breaking abstract, one of only six accepted for presentation at the 62nd Annual Meeting of the American Society of Hematology (ASH) and will be featured as an oral presentation in the conference on December 8, 2020.
The pivotal HOPE-B clinical trial was an open-label, single-dose, single-arm, multi-national trial in adult males with severe or moderately severe hemophilia. All patients required prophylactic routine FIX replacement prior to entering the clinical trial, and patients were not excluded from the trial based on pre-existing neutralizing antibodies (NAbs) to AAV5.
The patients in the 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. Fifty-four patients received a single intravenous infusion of etranacogene dezaparvovec gene therapy at 2×1013 gc/kg, including 23 patients who had pre-existing NAbs to AAV5. The primary endpoint was assessment of factor IX activity after a single dose etranacogene dezaparvovec.
FIX activity in the 54 patients increased rapidly after dosing from ≤2% to a mean of 37.2% at 26 weeks, meeting the primary endpoint. 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% of the general population; one patient with a NAb titer of 3,212.3 did not show an increase in FIX activity.
During the 26-week period after dosing, 72% of patients (39/54) reported no bleeding events. Fifteen patients reported a total of 21 bleeds. Mean annualized usage of FIX replacement therapy, a secondary endpoint in the clinical trial, declined by 96 percent.
Etranacogene dezaparvovec was generally well-tolerated, with no treatment-related serious adverse events. The most common adverse events were classified as mild and included the following: transaminase elevation, infusion-related reactions, headache and influenza-like symptoms. Liver enzyme elevations resolved with a tapering course of corticosteroids and FIX activity remained in the mild range in the steroid treated patients. No relationship between safety and NAbs titers was observed.
Based on this data, uniQure plans to hold a pre-BLA meeting with the FDA and to complete the last patient’s 52-week follow-up visit in the first quarter of 2021.
About Etranacogene dezaparvovec
Etranacogene dezaparvovec consists of an AAV5 viral vector carrying a gene cassette with the patent-protected Padua variant of Factor IX (FIX-Padua). Etranacogene dezaparvovec aims to restore the function of blood clotting on a long-term and potentially curative basis. It works by delivering the functional gene for hFIX directly into patients’ liver cells.
Etranacogene dezaparvovec has been granted Breakthrough Therapy Designation by the U.S. FDA and access to Priority Medicine (PRIME) regulatory initiative by the European Medicines Agency.
uniQure and CSL Behring entered into a licensing agreement in June of 2020 providing CSL Behring with exclusive global rights to etranacogene dezaparvovec. This licensing agreement is subject to antitrust regulatory review in the United States, Australia and the United Kingdom that is currently ongoing.
About Hemophilia B
Hemophilia B is a rare inherited disease characterized by insufficient blood clotting. Patients with severe hemophilia B have levels of zero or less than 1% of human blood clotting Factor IX (hFIX) and therefore require FIX replacement therapy to prevent persistent episodes of internal and external bleeding. These episodes can lead to long-term damage to the joints and can be fatal if the bleed occurs in the brain.