Carter Chris, Boggs Tracy, Case Laura E, Kishnani Priya
Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United States.
Department of Rehabilitation Services, Duke University Health System, Durham, NC, United States.
Front Genet. 2024 Jan 19;15:1309146. doi: 10.3389/fgene.2024.1309146. eCollection 2024.
Pompe disease is an inherited, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase and accumulation of glycogen in tissues, resulting in cellular dysfunction, muscle damage, and functional disabilities. Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme) has led to better outcomes, but many patients have plateaued or declined despite treatment. The second-generation ERT avalglucosidase alfa (Nexviazyme) was designed to have enhanced cellular uptake via the conjugation of additional bis-mannose-6-phosphate residues. There have been trials comparing the efficacy of alglucosidase and avalglucosidase, but there remains a need for more real-world data on patients who switched from alglucosidase to avalglucosidase. A chart review was conducted on = 15 patients with late-onset Pompe disease followed at a single center who switched from alglucosidase to avalglucosidase and continued for at least 6 months. A total of = 8/15 patients received alglucosidase for more than 3 years prior to switching, and = 7/15 received it for more than 5 years prior to switching. There were statistically significant improvements in CK, Hex4, and AST with mean differences of -104.8 U/L, -3.0 mmol/molCr, and -14.7 U/L, respectively, post-switch. 6-Minute Walk Test; comfortable gait speed; Gait, Stairs, Gower, Chair; and Quick Motor Function Test scores improved or stabilized in most patients post-switch ( = 8/12, = 11/12, = 9/12, =7/11, respectively). Of = 7 patients with pulmonary function testing, = 4/7 had improved upright FVC. Patient-reported outcomes revealed improvements in dyspnea ( = 4/4), physical function ( = 3/4), fatigue ( = 2/3), and lower back pain ( = 3/3). Avalglucosidase was well tolerated without infusion-associated reactions, and all = 7 patients on home infusions continued receiving ERT at home. Anti-drug antibodies were seen in = 9/10 of patients on alglucosidase and = 8/13 of those on avalglucosidase, with titers below 12,800 in a majority of patients. We also present the first outcome data for a patient with LOPD who is non-ambulatory and a full-time wheelchair user; she demonstrated meaningful improvements in quality of life and motor function with the switch. In summary, improved outcomes were seen in most patients, with a subset whose decline persisted. This study presents evidence that switching from alglucosidase to avalglucosidase may be associated with improved outcomes in certain patients with LOPD.
庞贝病是一种遗传性进行性神经肌肉疾病，由溶酶体酸性α-葡萄糖苷酶缺乏和糖原在组织中蓄积引起，导致细胞功能障碍、肌肉损伤和功能残疾。用阿糖苷酶α（美而赞/鲁酶）进行酶替代疗法已取得更好的疗效，但许多患者尽管接受了治疗，病情仍趋于平稳或恶化。第二代酶替代疗法阿伐糖苷酶α（耐昔妥珠单抗）通过额外的双甘露糖-6-磷酸残基共轭设计，以增强细胞摄取。已经有试验比较了阿糖苷酶和阿伐糖苷酶的疗效，但对于从阿糖苷酶转换为阿伐糖苷酶的患者，仍需要更多的真实世界数据。对在单一中心随访的15例晚发型庞贝病患者进行了图表回顾，这些患者从阿糖苷酶转换为阿伐糖苷酶并持续治疗至少6个月。共有8/15例患者在转换前接受阿糖苷酶治疗超过3年，7/15例患者在转换前接受治疗超过5年。转换后，肌酸激酶（CK）、己糖胺酶4（Hex4）和天冬氨酸转氨酶（AST）有统计学意义的改善，平均差异分别为-104.8 U/L、-3.0 mmol/mol肌酐和-14.7 U/L。6分钟步行试验、舒适步态速度、步态、楼梯、从仰卧到站立动作、椅子起立试验以及快速运动功能测试评分在大多数患者转换后得到改善或稳定（分别为8/12、11/12、9/12、7/11）。在7例进行肺功能测试的患者中，4/7例患者的直立用力肺活量（FVC）有所改善。患者报告的结果显示呼吸困难（4/4）、身体功能（3/4）、疲劳（2/3）和下背痛（3/3）有所改善。阿伐糖苷酶耐受性良好，无输液相关反应，所有7例接受家庭输液的患者继续在家接受酶替代疗法。在接受阿糖苷酶治疗的患者中，9/10例出现抗药抗体，在接受阿伐糖苷酶治疗的患者中为8/13例，大多数患者的抗体滴度低于12,800。我们还展示了首例非卧床且全职使用轮椅的晚发型庞贝病患者的结果数据；转换治疗后，她的生活质量和运动功能有了显著改善。总之，大多数患者的结果有所改善，但仍有一部分患者病情持续恶化。这项研究表明，对于某些晚发型庞贝病患者，从阿糖苷酶转换为阿伐糖苷酶可能与改善结果相关。
