uniQure and CSL Behring recently announced that etranacogene dezaparvovec, an investigational hemophilia B gene therapy currently in clinical trials, has achieved a primary endpoint of “non-inferiority” in annualized bleeding rate (ABR) 18-months post administration. The non-inferiority component of a clinical trial measures whether the investigational therapy is not worse/less efficacious than a currently available product. In this case, etranacogene dezaparvovec is being compared to baseline factor IX prophylactic replacement therapy as part of the phase III HOPE-B pivotal trial.

The investigational therapy consists of adeno-associated virus serotype 5 (AAV5), which function as a delivery vector carrying a gene cassette with the Padua variant of factor IX (FIX). AAV5 is a variant of the type of the adeno-associated virus (AAVs) vectors that are being investigated in other gene therapy trials.

HOPE-B is investigating etranacogene dezaparvovec in patients with severe and moderately severe hemophilia B. To date, 54 patients have received a single dose of the therapy, 53 of which have completed at least 18 months of follow-up. According to a new press release, ABR for all bleeds after stable FIX expression, assessed at 18 months, was 1.51compared with the ABR of 4.19 for the lead-in period of at least six months. Trial data also 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% of normal, compared to mean FIX activity of 39.0% of normal at six months post-infusion.

The companies also reported that etranacogene dezaparvovec was generally well-tolerated with over 80% of adverse events “considered mild.” One death resulting from urosepsis, a spreading infection originating in the urinary tract, and cardiogenic shock in a 77-year-old patient at 65-weeks following dosing was determined to be unrelated to treatment by investigators and the company sponsor. In addition, no inhibitors to FIX were reported.

In December 2020, a serious adverse event of hepatocellular carcinoma (HCC), a common form of liver cancer, was identified in one patient in this trial. It prompted a clinical hold by U.S. Food and Drug Administration (FDA) and an investigation into the case, which was conducted earlier this year. The hold was subsequently removed after the FDA determined that uniQure satisfactorily addressed all issues raised by the agency that were related to the HCC case.

This new press release further addresses the HCC case, stating that “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.”

“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.” stated Ricardo Dolmetsch, PhD, president of research and development at uniQure.

“On behalf of uniQure, we extend our heartfelt gratitude to all the HOPE-B clinical trial patients and their families, as well as the trial investigators. We now look forward to collaborating with CSL Behring on completing the regulatory submissions that we hope will advance etranacogene dezaparvovec one step closer to reaching hemophilia B patients around the world.”

In the spring of 2021, uniQure and CSL Behring began a commercialization and licensing agreement which provides the latter company with exclusive global rights to etranacogene dezaparvovec.

“These encouraging results illustrate the potential that gene therapy has to be a long-term treatment option for patients living with hemophilia B and we look forward to sharing more detailed data with the medical community in the near future,” stated Brahm Goldstein, MD, MCR, Vice President, Research and Development, Hematology at CSL Behring. “This milestone advances our efforts towards expected regulatory submissions in first half of 2022.”

Source: UniQure and CSL press releases, both dated December 9, 2021