CSL Reports Positive Final Analysis of Pivotal HOPE-B Study of Gene Therapy in Hemophilia B

CSL Behring reported positive long-term results from the phase 3 HOPE-B clinical trial evaluating etranacogene dezaparvovec, an investigational AAV5-based gene therapy for people living with hemophilia B, a life-threatening bleeding disorder.

Photo: Brahm Goldstein, vice president, Hematology Research and Development at CSL Behring

Following a single infusion of the gene therapy, participants experienced a stable and durable increase in mean Factor IX (FIX) activity and hemostatic protection at 18 months. The final data, from the largest gene therapy study in hemophilia B, were presented as part of the latest clinical trial results session at the European Association of Haemophilia and Allied Disorders 2022 Annual Meeting.

“The final 18-month results from the pivotal HOPE-B study continue to establish the durability of etranacogene dezaparvovec gene therapy, which produced Factor IX levels that remained stable and consistent over the course of the study, while also significantly reducing the rate of annual bleeds after a single infusion,” said Wolfgang Miesbach, head of the Department of Coagulation Disorders and the Comprehensive Care Centre from the University Hospital of Frankfurt, Germany, and an investigator for the HOPE-B trial. “Hemophilia B, like many other genetic diseases, is an ideal target for gene therapy because the disease stems from a single faulty gene, making its replacement with a fully functional F9 gene a robust therapeutic intervention.”

Hemophilia B is a life-threatening degenerative disease. People with the condition are particularly vulnerable to bleeds in their muscles, internal organs, and joints, leading to pain, swelling, and joint damage. Current treatment includes life-long prophylactic infusions of FIX to temporarily replace or supplement low levels of the blood-clotting factor. This can reduce joint bleeding events, prevent life-threatening bleeds, and preserve joint function. However, infusions can be cumbersome, painful and veins can fibrose over time, making ongoing treatment difficult. A person’s immune system may also generate inhibitors against the replacement factor, negating its benefit. In addition, many people receiving prophylaxis are forced to plan their lives around the highs and lows of their FIX levels, which rise immediately after an infusion but drop over time—leaving them especially vulnerable to bleeds and pain in the days before their next infusion. Prophylactic FIX replacement therapy also sometimes fails to control unobservable micro-bleeds in the joints, meaning that the degeneration can continue despite regular infusions. Missing an infusion may also the increase their likelihood of a life-threatening bleed or even premature death.

Etranacogene dezaparvovec (also known as CSL222, previously known as AMT-061) uses a specific type of AAV, called AAV5, as its delivery vehicle. The AAV5 vector carries the Padua gene variant of Factor IX (FIX-Padua), which generates FIX proteins that are 5x-8x more active than normal. Preclinical and clinical data show that AAV5-based gene therapies may be clinically effective in up to 95 percent of hemophilia B patients with pre-existing antibodies to AAV vectors, thereby potentially increasing patient eligibility for treatment compared to other AAV gene therapy product candidates.

The phase 3, open label, single-dose, single arm HOPE-B trial, which included 54 male participants with severe or moderately severe hemophilia B, demonstrated that etranacogene dezaparvovec produced mean FIX activity of 39.0 IU/dL at six months and 36.9 IU/dL at 18 months post infusion. After the six-month lead-in period post-infusion, the adjusted annualized bleeding rate (ABR) (1.51) for all bleeds was reduced by 64 percent and all FIX-treated bleeds was reduced by 77 percent over months seven to 18. In addition, 98 percent of subjects treated with a full dose of etranacogene dezaparvovec discontinued use of prophylaxis, with an overall 97 percent reduction in mean unadjusted annualized FIX consumption of 257338.8 IU/yr/participant to 8486.6 IU/yr/participant (from lead-in period to months 13-18).

“Nearly all patients treated with gene therapy in this study were able to discontinue use of prophylaxis. The treatment was also effective in people who have pre-existing neutralizing antibodies, which would typically disqualify someone from this kind of treatment,” said Steven Pipe, professor of Pediatrics and Pathology and pediatric medical director of the Hemophilia and Coagulation Disorders Program at the University of Michigan, and the principal investigator of the HOPE-B trial.

Etranacogene dezaparvovec is generally well-tolerated with most adverse events (80.4 percent) 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 was determined, by independent molecular tumor characterization and vector integration analysis, to be unrelated to treatment with etranacogene dezaparvovec. No inhibitors to FIX were reported.

“With this positive data and accelerated regulatory review pathways in the U.S. and in Europe, we look forward to expanding on the foundational work done by our partner, uniQure and working closely with regulatory authorities to bring the potentially life-changing benefits of gene therapy to the hemophilia B community,” said Brahm Goldstein, vice president, Hematology Research and Development at CSL Behring.

The multi-year clinical development for etranacogene dezaparvovec is being jointly led by CSL Behring and uniQure (Nasdaq: QURE). CSL Behring acquired global rights to commercialize etranacogene dezaparvovec in May 2021.

Author: Rare Daily Staff