FDA filing for uniQure, CSL's haemophilia B gene therapy planned for early 2022

At the company's R&D event on Tuesday, uniQure disclosed updated results from the Phase III HOPE-B trial showing that its adeno-associated virus five (AAV5)-based gene therapy etranacogene dezaparvovec allowed patients with haemophilia B to maintain Factor IX (FIX) activity at near-normal levels after one year. The company noted that based on recent FDA feedback, a final analysis of HOPE-B is now planned at 18 months to support marketing authorisation applications, with a US filing expected to be submitted in the first quarter of 2022.  

The single-arm trial had been slapped with an FDA clinical hold late last year due to safety concerns after a participant was diagnosed with hepatocellular carcinoma, but the hold was lifted in April. HOPE-B included 54 adult males with severe or moderately severe haemophilia B who received a single intravenous infusion of etranacogene dezaparvovec at a dose of 2 x 1013 gc/kg. The primary endpoint was FIX activity at 26 weeks, which uniQure previously said had been achieved, while secondary goals assessed annualised bleeding rate (ABR) and use of FIX replacement therapy, both at one year.

FIX activity at 41.5% of normal

In the latest analysis, the company said mean FIX activity at 52-weeks post-infusion was 41.5% of normal, compared to 39% of normal at 26 weeks. It noted that results also continued to show no clinically significant link between pre-existing neutralising antibodies to AAV5 (NAbs) and FIX activity for most patients.

The majority of subjects did not report bleeding after treatment. A single dose of etranacogene dezaparvovec reduced ABR requiring treatment by 80% at 52 weeks, to 0.68 bleeding episodes per year. Over the same period, the gene therapy also significantly lowered the annualised rate of spontaneous bleeds requiring treatment by 85%, to 0.18 episodes per year. The company said 52 of the 54 patients also no longer needed prophylactic infusions of replacement therapy. For the two non-responders, it noted that one patient had only received a partial dose due to an infusion reaction, while the second had an unusually high pre-existing NAb titre.

Safety-wise, the company said etranacogene dezaparvovec continues to be "generally well-tolerated," with no treatment-related serious adverse events and no inhibitors to FIX reported. The HOPE-B findings are due to be presented at the International Society on Thrombosis and Haemostasis (ISTH) annual meeting next month.

FDA requires longer data readout

Meanwhile, uniQure and partner CSL Behring have had recent talks with the FDA during which the agency confirmed that in order to judge the durability of the treatment effect, it wants to see data from patients followed for at least a 52-week period starting from when they achieved steady-state FIX levels, rather than when the gene therapy was administered. According to uniQure, all HOPE-B patients achieved steady-state FIX activity by 26 weeks.

"As a result, [we] will now conduct as the sole primary endpoint a non-inferiority analysis of ABR at 78 weeks after the administration," the company said, noting that all patients should have completed their 78-week follow-up visits by the end of the third quarter of 2021, to allow a potential regulatory filing early next year.

Bags epilepsy gene therapy with Corlieve buy

Separately, uniQure also announced Tuesday that it entered into a definitive agreement to acquire Corlieve Therapeutics and its gene therapy programme to treat temporal lobe epilepsy (TLE). The candidate therapy, dubbed AMT-260, is based on miRNA silencing technology to target suppression of aberrantly expressed kainate receptors in the hippocampus of patients with TLE.

As part of the deal, which is expected to close in the third quarter, uniQure will pay €46.3 million upfront in cash, with Corlieve shareholders also eligible for additional payments of which up to 25% will be payable in uniQure ordinary shares. These include up to €43.7 million in development milestones through Phase I/II and €160 million in milestones associated with Phase III development and the approvals of AMT-260 in the US and EU. 

Corlieve has an established license agreement with REGENXBIO that includes an exclusive license to AAV9 for the specific genetic target of AMT-260. Under that deal, REGENXBIO received equity in Corlieve and is eligible to receive milestone payments and royalties on net sales of AMT-260, uniQure said.

New CFO named

Meanwhile, uniQure also recently disclosed in a US Securities and Exchange Commission filing that its chief accounting officer Christian Klemt has been named chief financial officer, and that he will continue to serve as general manager of the company's Amsterdam site. Matthew Kapusta, who has been uniQure's CEO since December 2016, had been doing double duty as chief financial officer until this month.

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