Mozaffar Tahseen, Riou França Lionel, Msihid Jérôme, Shukla Pragya, Proskorovsky Irina, Zhou Tianyue, Periquet Magali, An Haack Kristina, Pollissard Laurence, Straub Volker
Division of Neuromuscular Disorders, Department of Neurology, University of California, Irvine, CA, United States.
Sanofi, Gentilly, France.
Mol Genet Metab Rep. 2024 Jun 26;40:101109. doi: 10.1016/j.ymgmr.2024.101109. eCollection 2024 Sep.
The efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on forced vital capacity percent predicted (FVCpp) in patients with late-onset Pompe disease (LOPD) has been assessed in the Phase 3 COMET trial (NCT02782741). Due to the rarity of LOPD and thus small sample size in COMET, additional data were analyzed to gain further insights into the efficacy of AVA versus ALG.
Data from treatment-naive patients with LOPD were pooled from COMET and Phase 1/2 NEO1/NEO-EXT (NCT01898364/NCT02032524) trials for patients treated with AVA, and Phase 3 LOTS trial (NCT00158600) for patients treated with ALG. Regression analyses using mixed models with repeated measures consistent with those pre-specified in COMET were performed post-hoc. Analyses were adjusted for trials and differences in baseline characteristics. Four models were developed: Model 1 considered all trials; Model 2 included Phase 3 trials; Model 3 included Phase 3 trials and was adjusted for baseline ventilation use; Model 4 included COMET and NEO1/NEO-EXT (i.e., AVA trials only).
Overall, 100 randomized patients from COMET (AVA, = 51, ALG, = 49), 60 from LOTS (ALG arm only), and three patients from NEO1/NEO-EXT (who received open-label AVA only) were considered for analysis. Mean age at enrollment was similar across trials (45.3-50.3 years); however, patients from LOTS had a longer mean duration of disease versus COMET and NEO1/NEO-EXT trials (9.0 years and 0.5-2.2 years, respectively) and younger mean age at diagnosis (36.2 years and 44.7-48.6 years, respectively). Least squares mean (95% confidence interval) improvement from baseline in FVCpp at Week 49-52 for AVA versus ALG was 2.43 (-0.13; 4.99) for COMET ( = 98); 2.31 (0.06; 4.57) for Model 1 ( = 160); 2.43 (0.21; 4.65) for Model 2 ( = 157); 2.80 (0.54; 5.05) for Model 3 ( = 154); and 2.27 (-0.30; 4.45) for Model 4 ( = 101).
Models 1 to 3, which had an increased sample size versus COMET, demonstrated a nominally significant effect on FVCpp favoring AVA versus ALG after 1 year of treatment, consistent with results from COMET.
在3期COMET试验（NCT02782741）中评估了阿伐糖苷酶α（AVA）与阿糖苷酶α（ALG）对比，对晚发型庞贝病（LOPD）患者预计用力肺活量百分比（FVCpp）的疗效。由于LOPD罕见，因此COMET试验样本量较小，故分析了更多数据，以进一步深入了解AVA与ALG的疗效。
将来自未接受过治疗的LOPD患者的数据进行汇总，这些数据来自COMET试验以及1/2期NEO1/NEO-EXT试验（NCT01898364/NCT02032524）中接受AVA治疗的患者，以及3期LOTS试验（NCT00158600）中接受ALG治疗的患者。采用与COMET预先指定的方法一致的重复测量混合模型进行事后回归分析。分析针对试验和基线特征差异进行了调整。建立了四个模型：模型1纳入所有试验；模型2纳入3期试验；模型3纳入3期试验并针对基线通气使用情况进行了调整；模型4纳入COMET和NEO1/NEO-EXT试验（即仅AVA试验）。
总体而言，分析纳入了COMET试验中的10名随机分组患者（AVA组51例，ALG组49例）、LOTS试验中的60名患者（仅ALG组）以及NEO1/NEO-EXT试验中的3名患者（仅接受开放标签AVA治疗）。各试验入组时的平均年龄相似（45.3 - 50.3岁）；然而，LOTS试验的患者疾病平均病程长于COMET试验和NEO1/NEO-EXT试验（分别为9.0年和0.5 - 2.2年），诊断时的平均年龄也更年轻（分别为36.2岁和44.7 - 48.6岁）。在第49 - 52周时，AVA与ALG相比，FVCpp自基线的最小二乘均值（95%置信区间）改善情况如下：COMET试验为2.43（-0.13；4.99）（n = 98）；模型1为2.31（0.06；4.57）（n = 160）；模型2为2.43（0.21；4.65）（n = 157）；模型3为2.80（0.54；5.05）（n = 154）；模型4为2.27（-0.30；4.4）（n = 101）。
与COMET试验相比，样本量增加的模型1至3显示，治疗1年后，FVCpp方面AVA对比ALG有名义上的显著疗效，这与COMET试验结果一致。
