Mancuso Maria Elisa, Eriksson Daniel, Falk Aletta, Hakimi Zalmai, Wojciechowski Piotr, Wdowiak Marlena, Klamroth Robert
Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
Humanitas University, Pieve Emanuele, Milan, Italy.
J Blood Med. 2023 Jul 27;14:427-434. doi: 10.2147/JBM.S389094. eCollection 2023.
For patients with hemophilia B, extended half-life factor IX (FIX) products are available for prophylaxis and for treating bleeds. Different methods are used to extend the half-lives of recombinant FIX Fc fusion protein (rFIXFc) and nonacog beta pegol (N9-GP). This affects their biodistribution and plasma FIX levels, although differences do not always correlate with clinical outcomes. A matching-adjusted indirect comparison (MAIC) of prophylaxis with rFIXFc and N9-GP was performed, based on licensed dosing in the European Union.
Combined rFIXFc data from the weekly and individualized interval prophylaxis arms of the B-LONG clinical trial, and N9-GP data from the 40 IU/kg once-weekly prophylaxis arm of PARADIGM 2 were used in a MAIC. Individual patient data for rFIXFc (n=87) were matched to aggregated data for N9-GP (n=29). Estimated annualized bleeding rates (ABRs) for rFIXFc were recalculated using a Poisson regression model with adjustment for over-dispersion, and compared with ABRs reported for N9-GP, using incidence rate ratios (IRRs) with 95% confidence interval (CI).
There was no evidence of significant differences in estimated ABRs between prophylaxis with rFIXFc and N9-GP. Analysis of pooled rFIXFc weekly and interval-adjusted dosing compared with N9-GP 40 IU/kg once weekly produced estimated ABRs of 2.59 versus 2.51 (IRR 1.03; 95% CI 0.56-1.89), as well as 1.34 versus 1.22 (IRR 1.10; 95% CI 0.42-2.91) and 1.13 versus 1.29 (IRR 0.88; 95% CI 0.47-1.63) for overall, spontaneous, and traumatic bleeding events, respectively.
The study did not reveal any significant differences in the efficacy of rFIXFc and N9-GP prophylaxis. Given differences in trough levels (rFIXFc dosing was targeted to achieve a trough 1-3 IU/dL above baseline versus a reported estimated N9-GP mean trough of 27.3 IU/dL), interpreting plasma FIX levels as potential surrogate efficacy markers requires consideration of compound-specific pharmacokinetic profiles.
对于乙型血友病患者，延长半衰期的凝血因子IX（FIX）产品可用于预防和治疗出血。不同方法用于延长重组FIX Fc融合蛋白（rFIXFc）和非阿考糖β聚乙二醇（N9-GP）的半衰期。这会影响它们的生物分布和血浆FIX水平，尽管差异并不总是与临床结果相关。基于欧盟批准的给药方案，对rFIXFc和N9-GP的预防进行了匹配调整间接比较（MAIC）。
将B-LONG临床试验中每周和个体化间隔预防组的rFIXFc合并数据，以及PARADIGM 2中40 IU/kg每周一次预防组的N9-GP数据用于MAIC。rFIXFc的个体患者数据（n = 87）与N9-GP的汇总数据（n = 29）进行匹配。使用泊松回归模型对rFIXFc的估计年化出血率（ABR）进行重新计算，并对过度离散进行调整，然后与N9-GP报告的ABR进行比较，使用95%置信区间（CI）的发病率比（IRR）。
没有证据表明rFIXFc和N9-GP预防的估计ABR存在显著差异。将rFIXFc每周和间隔调整剂量的汇总分析与N9-GP每周40 IU/kg进行比较，总体、自发性和创伤性出血事件的估计ABR分别为2.59对2.51（IRR 1.03；95% CI 0.56 - 1.89）、1.34对1.22（IRR 1.10；95% CI 0.42 - 2.91）和1.13对1.29（IRR 0.88；95% CI 0.47 - 1.63）。
该研究未发现rFIXFc和N9-GP预防效果有任何显著差异。鉴于谷值水平的差异（rFIXFc给药目标是使谷值比基线高1 - 3 IU/dL，而报告的N9-GP估计平均谷值为27.3 IU/dL），将血浆FIX水平解释为潜在的替代疗效标志物时需要考虑化合物特异性药代动力学特征。
