For patients with severe or moderately severe hemophilia B, a single dose of etranacogene dezaparvovec gene therapy reduced bleeding rates and eliminated routine infusions associated with intravenous injections of factor IX (FIX) therapies. This is according to results from an indirect treatment comparison study published in Haemophilia, which compared the efficacy of etranacogene dezaparvovec to that of extended half-life FIX therapies.
“The current standard of care for people with moderate to severe hemophilia B includes life-long prophylactic infusions of FIX to temporarily replace or supplement low levels of blood-clotting factor,” explained corresponding author Songkai Yan, MS, of CSL Behring in King of Prussia, Pennsylvania. “While these therapies are effective, people receiving prophylaxis for hemophilia B must adhere to a strictly scheduled lifelong infusion regimen and may still experience spontaneous bleeding episodes, which could require additional FIX infusions.”
This indirect treatment comparison study compared outcomes from “patients using standard prophylactic infusions of FIX to those who have used etranacogene dezaparvovec, a gene therapy that was designed to be a long-lasting, single-infusion treatment,” Mr. Yan said.
Specifically, the study analyzed the efficacy of hemostatic protection for prophylaxis in patients with severe or moderately severe hemophilia B (FIX activity ≤2% of the normal value). Etranacogene dezaparvovec was compared to the following recombinant FIX replacement therapies with extended half-life: albutrepenonacog alfa (recombinant factor IX albumin fusion protein [rIX-FP]), eftrenonacog alfa (recombinant factor IX-Fc fusion protein [rFIXFc]), and nonacog beta pegol (N9-GP).
Data from the HOPE-B, PROLONG-9FP, B-LONG, and Paradigm 2 phase III trials were included. In HOPE-B, etranacogene dezaparvovec showed superior efficacy at 24 months in reducing bleeds versus at least a six-month lead-in period of prophylaxis with the FIX products, while PROLONG-9FP, B-LONG, and Paradigm 2 represented key sources of efficacy data for rIX-FP, rFIXFc, and N9-GP, respectively. After matching trial eligibility criteria and adjusting for key prognostic factors and treatment-effect modifiers, the researchers assessed annualized bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds, and FIX consumption.
Etranacogene dezaparvovec showed significantly lower bleeding rates versus all three FIX products. When compared with rIX-FP, the respective rate ratios for ABR, AsBR, and AjBR were 0.19, 0.08, and 0.09 (p<0.0001 for all). When etranacogene dezaparvovec was compared with rFIXFc, the respective rate ratios for ABR, AsBR, and AjBR were 0.14 (p<0.0001), 0.13 (p=0.0083), and 0.15 (p=0.0111). For the N9-GP comparison, the respective rate ratios for ABR and AsBR were 0.24 (p=0.0231) and 0.13 (p=0.0071); AjBR data for N9-GP were not available. Etranacogene dezaparvovec showed a significantly higher percentage of patients with no bleeds versus rIX-FP and rFIXFc, with odds ratios (OR) of 17.60 (p<0.0001) and 5.65 (p=0.0037), respectively, and a numerically higher percentage versus N9-GP, though not statistically significant (OR=1.53; p=0.5123).
“Etranacogene dezaparvovec also demonstrated significantly lower FIX consumption than rIX-FP and rFIXFc (N9-GP data not available for comparison) as a result of the discontinuation of routine prophylaxis with FIX,” Mr. Yan said.
The authors noted that etranacogene dezaparvovec is not indicated for all patients with hemophilia B, with the findings only applicable to those who met current gene therapy eligibility criteria. Because the HOPE-B data included patients with baseline adeno-associated virus neutralizing antibody (AAV Nab) titers below 700, further research on patients with higher titers may be needed. Another limitation of the study was that it was an indirect treatment comparison like all others that depends on the balance of all prognostic factors and treatment effect modifiers, which is difficult to verify. On the other hand, this study used the best available phase III trial data and robust statistical methods. A formal feasibility assessment was performed, and a systematic process involving clinical experts was conducted to rank order and prioritize factors for adjustment.
“Based on the findings from this study, etranacogene dezaparvovec improves protection against bleeding events and largely eliminates the need for frequent prophylactic infusions of FIX for patients with severe or moderately severe hemophilia B,” Mr. Yan said.
Any conflicts of interest declared by the authors can be found in the original article.
Klamroth R, Bonner A, Gomez K, et al. Indirect treatment comparisons of the gene therapy etranacogene dezaparvovec versus extended half-life factor IX therapies for severe or moderately severe haemophilia. Haemophilia [published online ahead of print, 2023 October 30]. doi: 10.1111/hae.14882.