Novel gene therapy reduces bleeding events, need for factor IX infusions in hemophilia B
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A single infusion of verbrinacogene setparvovec resulted in normal factor IX levels among all 10 men who received the investigational gene therapy for moderate to severe hemophilia B, study results showed.
Data from the analysis revealed verbrinacogene setparvovec (Freeline Therapeutics) had a dose-dependent effect on maintaining normal factor IX levels while substantially reducing patients’ mean annualized bleeding rate and need for treatment with donor-derived factor IX concentrate.
Background
The current standard of care for patients with severe hemophilia B involves lifelong prophylactic therapy via regular IV infusions of factor IX concentrate, according to the study’s investigators. The use of more advanced factor-replacement therapies with longer half-lives that require less frequent infusions has been a “major advance” in care over the last decade, they added.
“However, factor prophylaxis remains an invasive, expensive and burdensome lifelong treatment approach that cannot completely prevent long-term complications,” Pratima Chowdary, MD, of Katharine Dormandy Haemophilia and Thrombosis Centre at Royal Free Hospital, University College London, and colleagues wrote.
The researchers called adeno-associated virus (AAV) gene therapy “a promising treatment approach for hemophilia B,” but it has yet to produce factor IX levels within the normal range after a single vector infusion.
The goal of treatment with verbrinacogene setparvovec — a liver-directed AAV gene therapy — is “sustained expression of factor IX in the normal range,” they wrote. “Predictable and stable factor expression in the normal range would be expected to provide protection from bleeding, even in situations that necessitate intensive factor replacement, such as serious trauma or surgery.”
Methodology
Chowdary and colleagues analyzed data of 10 men with moderate to severe hemophilia B and no evidence of inhibitors to factor IX.
The analysis included results of the multicenter phase 1/phase 2 B-AMAZE trial plus preliminary results of a long-term follow-up study.
Study participants received one of four dose levels of verbrinacogene setparvovec in vector genomes (vg) per kilogram of body weight (3.84 × 1011 vg, 6.4 × 1011 vg, 8.32 × 1011 vg or 1.28 × 1012 vg), plus prophylactic immunosuppression using prednisolone with or without tacrolimus.
Safety and efficacy served as the study’s primary endpoints, with efficacy being measured by factor IX levels at 26 weeks after infusion with verbrinacogene setparvovec. Secondary endpoints included annualized bleeding rate, consumption of factor IX concentrate, development of factor IX inhibitors and clearance of viral genomes.
Key findings
The investigators noted that all 10 men had a dose-dependent increase in factor IX levels after a single infusion of verbrinacogene setparvovec.
At median follow-up of 27.2 months, all but one patient had sustained factor IX activity above normal.
As of the data cutoff date of Sept. 20, 2021, three men had factor IX levels ranging from 23% to 43%, five had normal levels ranging from 51% to 78% and one had a factor IX level of 260%.
Mean annualized bleeding rate decreased from 2.93 events per year (range, 0-7.33) at baseline to 0.71 events per year (range, 0-1.7) after receiving verbrinacogene setparvovec. Likewise, mean annual concentrated factor IX consumption per patient decreased from 226,026 IU per year (range, 83,263-423,333) to 9,723 IU per year (range, 0-95,532).
The researchers reported no deaths or patient withdrawals due to treatment-related toxicity during the analysis. Additionally, no patients developed inhibitors to factor IX as of the data cutoff point.
Investigators noted approximately 10% of severe treatment-related adverse events as being attributed to use of verbrinacogene setparvovec, with increases in liver aminotransferase levels being the most common. Nearly a quarter (24%) of treatment-related adverse events involved use of immunosuppressive therapies.
Clinical implications
Chowdary and colleagues said the results confirm that gene therapy can produce durable factor IX levels at or above normal levels.
Despite the success they observed, the investigators noted that the emergence of late episodes of increased liver aminotransferase levels that occurred in patients who required longer immunosuppressive treatment requires further attention and likely refinement of the treatment regimen in future studies.
“Normal factor IX levels can be achieved in patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of [verbrinacogene setparvovec],” Chowdary and colleagues wrote. “Our trial results support further evaluation of [verbrinacogene setparvovec] in clinical trials to confirm the dose and immunosuppressive regimen that are necessary for the maintenance of adequate hemostasis in patients with hemophilia B.”
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