uniQure Announces Positive Top-Line Data From the HOPE-B Pivotal Trial of  Gene Therapy 

uniQure N.V. recently announced positive top-line data from its pivotal, Phase 3 HOPE-B gene therapy trial of etranacogene dezaparvovec, an investigational adeno-associated virus five (AAV5)-based gene therapy for the treatment of patients with severe and moderately severe hemophilia B. This is the first data set to be reported from a Phase 3 gene therapy study in hemophilia B and, with 54 patients, the largest set of patients receiving a single gene therapy investigational product to be reported to date. These clinical data were published today as a late-breaking abstract, one of only six accepted for presentation at the 62^nd 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 abstract is available here.

“We are extremely pleased that these top-line pivotal data show that a single administration of etranacogene dezaparvovec gene therapy led to sustained increases of Factor IX (FIX) to functionally curative levels capable of eliminating the need for regular infusions to control and prevent bleeding episodes,” saidd Ricardo Dolmetsch, PhD, President of Research and Development at uniQure. “Most impressively, these data also demonstrate the potential to achieve clinical benefit in patients with a range of pre-existing neutralizing antibodies representative of the general population. The ability to dose a gene therapy in patients with pre-existing neutralizing antibodies has not been demonstrated for any other gene therapy and illustrates the potentially unique ability of our AAV5 platform to address the needs of a broad set of patients living with hemophilia B and other disorders.”

The pivotal, Phase 3 HOPE-B clinical trial of etranacogene dezaparvovec is 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.

Patients in the HOPE-B clinical study were initially enrolled into a prospective, observational lead-in period of at least 6 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. Patients are then evaluated to assess FIX activity determined by a one-stage assay performed at a central laboratory, annualized bleeding rates and usage of Factor IX replacement therapy. Patients will be monitored for 5 years to evaluate the safety of 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 first 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%.

Etranacogene dezaparvovec was generally well-tolerated with no treatment-related serious adverse events. Most adverse events were classified as mild (81.5%). Most common events included transaminase elevation treated with steroids per protocol (9 pts; 17%), infusion-related reactions (7 pts; 13%), headache (7 pts; 13%) and influenza-like symptoms (7 pts; 13%). 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.

“We believe that etranacogene dezaparvovec has the potential to be a first- and best-in-class gene therapy for patients with hemophilia B,” said Matt Kapusta, Chief Executive Officer of uniQure. “We are very pleased to have met the 26-week FIX primary endpoint and to feature these promising data at the upcoming ASH conference. Based on interactions with the FDA and EMA, we plan to incorporate FIX activity and bleeding rates at 52 weeks as additional co-primary endpoints in the study. We look forward to holding our pre-BLA meeting with the FDA and completing the last patient’s 52-week follow-up visit in the first quarter of 2021.”

Etranacogene dezaparvovec consists of an AAV5 viral vector carrying a gene cassette with the patent-protected Padua variant of Factor IX (FIX-Padua). uniQure holds multiple issued patents in the US and Canada broadly covering methods of treating bleeding disorders, including hemophilia B, using AAV gene therapy with the FIX-Padua variant. Etranacogene dezaparvovec has been granted Breakthrough Therapy Designation by the US FDA and access to Priority Medicine (PRIME) regulatory initiative by the European Medicines Agency. In June 2020, the company and CSL Behring entered into a licensing agreement providing CSL Behring with exclusive global rights to etranacogene dezaparvovec. This licensing agreement is subject to antitrust regulatory review in the US, Australia, and the UK that is currently ongoing.

AAV5-based gene therapies have been demonstrated to be safe and well tolerated in a multitude of clinical trials, including five uniQure trials conducted in nearly 80 patients in hemophilia B and other indications. No patient treated in clinical trials with the uniQure’s AAV5 gene therapies has experienced any confirmed cytotoxic T-cell-mediated immune response to the capsid. Additionally, preclinical and clinical data show that AAV5-based gene therapies may be viable treatments in patients with pre-existing antibodies to AAV5, thereby potentially increasing patient eligibility for treatment compared to other gene therapy product candidates.

uniQure is delivering on the promise of gene therapy – single treatments with potentially curative results. We are leveraging our modular and validated technology platform to rapidly advance a pipeline of proprietary gene therapies to treat patients with hemophilia B, Huntington’s disease, Fabry disease, spinocerebellar ataxia Type 3 and other diseases. For more information, visit www.uniQure.com.