Gene Therapy Shows 5-Year Success
Etranacogene Dezaparvovec Shows Sustained Efficacy and Safety in Hemophilia B Over 5 Years
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Long-Term Follow-Up Demonstrates Significant Improvements in FIX Activity and Bleeding Rates
San Diego, CA – A Phase 2b trial investigating the gene therapy etranacogene dezaparvovec (AMT-061) in adults with severe hemophilia B has reported sustained efficacy and a favorable safety profile over a five-year follow-up period. The study, published in Blood Advances, found that participants maintained significantly elevated levels of Factor IX (FIX) activity and experienced a dramatic reduction in bleeding events, leading to the discontinuation of prophylactic FIX concentrate use.
Study Design and Patient Population
The trial enrolled three adult participants diagnosed with hemophilia B, characterized by FIX activity levels of 2% or less. A key inclusion criterion was the presence of pre-existing neutralizing antibodies against adeno-associated virus serotype 5 (AAV5), with a mean titer of 25 at the time of dosing. Participants underwent FIX recovery assessments prior to receiving the gene therapy.
The primary endpoint of the study was the achievement of FIX activity of 5 IU/dL or higher at six weeks post-treatment. Secondary endpoints focused on the long-term impact of the therapy, including bleeding frequency, the need for FIX concentrate use, and the occurrence of adverse events over a five-year observation period.
To comprehensively assess the therapy’s effects, FIX levels were monitored weekly for the first six weeks, then biweekly until week 26. Subsequent assessments were conducted monthly up to month 12, and twice-yearly thereafter, up to month 60. Quality of life was evaluated using the Hem-A-QoL questionnaire.
Key Findings: Sustained Efficacy and Safety
The five-year follow-up data revealed compelling results:
Sustained FIX Activity: Mean FIX activity levels rose to 40.8 IU/dL at year one and remained robust, averaging 45.7 IU/dL at year five. Notably, two participants achieved FIX activity levels within the non-hemophilic range (≥ 40 IU/dL).
Reduced Bleeding: The mean annualized bleeding rate (ABR) significantly decreased to 0.14 over the cumulative five-year follow-up period. Two participants remained entirely free of bleeds throughout the entire study duration. Discontinuation of Prophylaxis: All participants were able to discontinue their regular FIX prophylaxis following treatment with etranacogene dezaparvovec.Onyl one participant required episodic FIX replacement therapy for elective surgeries, and two isolated bleeding episodes were managed with this approach. Favorable Safety Profile: Throughout the five-year observation period, no participants experienced clinically significant elevations in liver enzymes, required steroid treatment, developed FIX inhibitors, or suffered thrombotic complications. No late-emergent safety events were observed.
clinical Implications and Future Directions
The findings suggest that etranacogene dezaparvovec offers a durable and safe treatment option for adults with hemophilia B, even those with pre-existing AAV5 neutralizing antibodies. The ability of participants to cease prophylactic treatment and maintain normal or near-normal FIX activity levels represents a significant advancement in hemophilia care.
“Five years after administration, etranacogene dezaparvovec was effective in adults with hemophilia B with a favorable safety profile,” stated the study authors. “Participants are eligible to participate in an extension study for 10-year additional follow-up.”
limitations and Ongoing Research
While the study demonstrates promising long-term outcomes, the small sample size of three participants limits the generalizability of the findings. The researchers acknowledge the need for longer-term follow-up studies to further confirm the durability and safety of the treatment. All participants have enrolled in an extension study to provide an additional 10 years of data.
the study was supported by CSL behring. Lead author Annette von Drygalski, MD, from the Division of Hematology/Oncology, Department of Medicine, University of California San Diego, has disclosed various consulting and advisory roles with several pharmaceutical companies, including CSL Behring, and is a cofounder and board member of Hematherix LLC. Additional disclosures are detailed in the original publication.