Review: One-Shot Etranacogene Dezaparvovec Represents Game-Changing Gene Therapy for Hemophilia B

The gene therapy etranacogene dezaparvovec (Hemgenix; uniQure/CSL Behring) was approved by the FDA in 2022 to treat hemophilia B, and it does its work remarkably well, according to a review summarizing the nonclinical studies and clinical development that made clearance possible.¹

Just as significant, the authors wrote in Blood Advances, is that etranacogene dezaparvovec—a one-time infusion treatment—and the science behind it represent progression in treating not only hemophilia, but potentially medical conditions ranging from plasma protein deficiencies to metabolic and lysosomal storage disorders.

Etranacogene dezaparvovec enables the body to continuously produce factor IX, the protein that is deficient in hemophilia B, by using a noninfectious viral vector, an adeno-associated virus (AAV) called AAV5. AAV5 gets the Padua gene variant of Factor IX (FIX) to targeted cells in the liver, where it remains to generate FIX proteins that are 5 to 8 times more active than normal.

Gene therapy specifically for hemophilia has been explored clinically for more than 2 decades, they explained, and simultaneously, researchers have been working more generally on liver-directed, AAV-mediated gene therapies.

Fifty-two of 54—“a remarkable 96%”—of the participants (all adults) in an ongoing, multinational phase 3 trial who received etranacogene dezaparvovec were able to cease prophylaxis with FIX. This was “not surprising, given a mean FIX level at 18 months after infusion of 37%,” the authors reported. The trial is designed to follow participants for 5 years.

Efficacy results demonstrated a decrease in annualized bleeding rate from 4.19 during the run-in period to 1.9 during month 7 to month 18 after vector infusion. This was the study’s primary end point, and the criteria for etranacogene dezaparvovec’s noninferiority compared with FIX prophylaxis were met.

Clinically and statistically significant, too, were key secondary end points. The annualized infusion rate, for instance, declined by 97%, and the plasma FIX activity level at 18 months after infusion had a least squares mean increase of 34.3 percentage points compared with baseline.

Still, decreasing the variability in FIX levels, either “through a gene editing approach at the endogenous genomic location or via readministration to achieve optimal levels, is a key factor that needs to be addressed in future research,” the authors stated.

A news release issued by CSL Behring in June 2023, when the therapy became commerically available, noted that patients with hemophilia B who have the opportunity to use etranacogene dezaparvovec—“a long-awaited advancement”—will likely be able to live their lives “without frequent bleeds or the burden of regular infusions.”²

A relative handful of gene therapies that treat hemophilia A and B, certain other blood disorders, some cancers, and other conditions are approved and available, and others are accessible only through clinical trials, according to the Mayo Clinic.³ Among the major barriers they identify to gene therapies becoming more reliable treatment options are finding consistent ways to insert genetic materials into cells, pinpointing the correct cells or genes, keeping the risks of adverse effects to a reasonable level, and, of course, cost.

The authors of the Blood Advances review note that significant challenges remain that are specific to gene therapy’s use in hemophilia.¹ Extending its reach to broader populations, especially to children, critically involves durability of transgene expression. “Although no indication of waning transgene expression in adult patients who have been treated with an AAV has been recorded in hemophilia B studies, a decrease in FIX levels in younger pediatric patients due to liver growth would be expected with a (predominantly) nonintegrating vector,” they pointed out.

Developing effective gene therapies for pediatric use, they therefore concluded, “is likely to include integrative and/or redosable vectors.”

References

1. Anguela XM, High KA. Hemophilia B and gene therapy: a new chapter with etranacogene dezaparvovec. Blood Adv. 2024;8(7):1796-1803. doi:10.1182/bloodadvances.2023010511

2. CSL Behring announces the first patient has received FDA-approved Hemgenix (etranacogene dezaparvovec-drlb) for hemophilia B. News release. CSL Behring. June 20, 2023. Accessed May 1, 2024. https://www.prnewswire.com/news-releases/csl-behring-announces-the-first-patient-has-received-fda-approved-hemgenix-etranacogene-dezaparvovec-drlb-for-hemophilia-b-301854676.html

3. Gene therapy. Mayo Clinic. April 23, 2024. Accessed May 1, 2024. https://www.mayoclinic.org/tests-procedures/gene-therapy/about/pac-20384619