RARE Daily

UniQure and CSL Behring Report Pivotal Study of Hemophilia B Gene Therapy Hits Primary Endpoint

December 9, 2021

CSL Behring and UniQure said their experimental gene therapy for the treatment of patients with severe to moderately severe hemophilia B achieved the pre-specified primary endpoint of non-inferiority in annualized bleeding rate (ABR) 18-months following administration compared to baseline Factor IX (FIX) prophylactic therapy in the pivotal phase 3 trial.

Photo: Ricardo Dolmetsch, president of research and development at UniQure

The study also successfully achieved a secondary endpoint demonstrating statistical superiority in reduction of ABR compared to baseline FIX prophylactic therapy.

Hemophilia B is a rare bleeding disorder caused by mutations in the F9 gene resulting in insufficient levels of the blood clotting protein factor IX. Symptoms can range from mild to severe depending on the level of factor IX in the blood and can range from prolonged bleeding after injury to frequent spontaneous bleeds into the muscles and joints and organs in severe cases that cause pain and other problems. Bleeding in the brain can lead to death if untreated.

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 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. In June 2020, UniQure and CSL Behring entered into a licensing agreement providing CSL Behring with exclusive global rights to etranacogene dezaparvovec.

The primary endpoint in the pivotal study was 52-week ABR after achievement of stable FIX expression compared with the six-month lead-in period, considering all bleeds regardless of investigator adjudication as true bleeds. For this endpoint, ABR was measured from month seven to month 18 after infusion, ensuring the observation period represented likely steady-state FIX transgene expression. Secondary endpoints included assessment of FIX activity and statistical superiority of ABR after dosing.

“We are very pleased with these top-line results from what is the largest and first pivotal trial of a gene therapy for patients with hemophilia B,” said Ricardo Dolmetsch, president of research and development at UniQure. “The HOPE-B data not only achieved the pre-specified primary endpoint of non-inferiority in annualized bleeding rate following 12 months or more of stable FIX expression, but also the secondary endpoint of superiority in reduction of annualized bleeding, while continuing to demonstrate durability and stability in FIX levels and other benefits to this point in the study.”

A total of 54 patients received a single dose of etranacogene dezaparvovec in the pivotal trial, with 53 patients completing at least 18 months of follow-up.

ABR for all bleeds after stable FIX expression, assessed at 18 months, was 1.51 compared with the ABR of 4.19 for the lead-in period of at least six months, achieving the primary non-inferiority endpoint and a secondary superiority endpoint in the HOPE-B trial. ABR for investigator-adjudicated FIX-treated bleeds was 0.83 compared with lead-in ABR of 3.65.

Data from the HOPE-B pivotal trial showed that patients continued to demonstrate durable, sustained increases in FIX activity at 18 months post-infusion with a mean FIX activity of 36.9 percent of normal as measured by a one-stage APTT-based clotting assay, compared to mean FIX activity of 39.0 percent of normal at six months post-infusion.

Etranacogene dezaparvovec was generally well-tolerated with more than 80 percent of adverse events considered mild. One death resulting from urosepsis and cardiogenic shock in a 77-year-old patient at 65-weeks following dosing was considered unrelated to treatment by investigators and the company sponsor. A serious adverse event of hepatocellular carcinoma (HCC) was identified in one patient. Independent molecular characterization and vector integration analysis of the HCC and adjacent tissue supported the conclusion by the investigator and company sponsor that the HCC was unrelated to treatment with etranacogene dezaparvovec. No inhibitors to FIX were reported.

CSL Behring plans to submit regulatory applications for marketing approval of etranacogene dezaparvovec in the United States and European Union in the first half of 2022.

Author: Rare Daily Staff

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