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Outcomes of a pediatric patient with late-onset Pompe disease switching from high‑dose alglucosidase alfa to standard-dose cipaglucosidase alfa plus miglustat

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Enzyme Replacement Therapy
  • Secondary Categories:
    • Enzyme Replacement Therapy
Introduction
The first disease-specific treatment for late-onset Pompe disease (LOPD) was a recombinant human GAA (rhGAA), alglucosidase alfa (alg). Despite initial efficacy, many patients experience a sustained decline in outcomes over time with standard-dose alg (20 mg/kg biweekly). High-dose, high-frequency (HDHF) alg (40 mg/kg weekly) is a common therapeutic strategy to try to improve clinical outcomes in these patients. Cipaglucosidase alfa plus miglustat (cipa+mig) is a next-generation, two-component therapy for LOPD, comprising cipaglucosidase alfa, a bis-mannose-6-phosphate-enriched rhGAA, in conjunction with an oral enzyme stabilizer, miglustat. Clinical trials investigating the efficacy and safety of cipa+mig in adults with LOPD previously only included treatment-naïve patients or patients treated with standard-dose alg. Therefore, data are limited for patients switching from HDHF alg to standard‑dose cipa+mig (20 mg/kg + 260 mg biweekly). Here we present the outcomes of one pediatric LOPD patient who switched from HDHF alg to standard-dose cipa+mig in the open-label Phase III pediatric study ATB200-04 (NCT03911505).

Case Presentation
Male patient, currently 19 years old (yo), initially presented at 5 months old with developmental concerns including no head control and no weight bearing on legs. At 14 months old the patient had never borne weight on his legs, prompting further investigation.

Diagnostic Workup
A neurology evaluation was performed alongside a muscle biopsy and histology report with suspicions of Pompe disease. Dried blood spot and skin biopsy both revealed low GAA activity and patient was diagnosed with Pompe disease. Diagnosis was supported by molecular testing at 7 yo, indicating two heterozygous GAA variants including an IVS variant.

Treatment and Management
The patient was initially started on standard-dose alg at diagnosis; after several dose adjustments, the patient started HDHF alg at 9 yo. In addition, the patient had orthopedic surgery at 5, 8 and 11 yo. After 5.75 years of HDHF alg (age 15 yo), the patient remained ambulatory, with a slow and labored gait, and required support to stand up from the floor. He also experienced progressive scoliosis. The patient was enrolled in the open-label Phase III pediatric study ATB200-04 and switched to standard-dose cipa+mig. In ATB200-04, the patient was exposure-matched to adults (ATB200-02, NCT02675465; PROPEL, NCT03729362) at day 1 and weeks 26 and 52, and remained on standard-dose cipa+mig.

Outcome and Follow-Up
At 156 weeks, 4-stair climb, chair test, and 10-meter walk improved over baseline (baseline vs week 156 4-stair climb: 4.1 vs 2.8 s; chair: 2.1 vs 1.5 s; 10-meter walk: 8.5 vs 7.3 s). There were improvements from baseline to week 156 in 6-minute walk distance (6MWD; 287.9 vs 336.6 m) and timed-up-and-go (11.7 vs 10.7 s). Percent predicted forced vital capacity (% FVC) remained relatively stable from baseline up to week 156 (93.1% vs 90.9%). Both Subject’s and Physician’s Global Impression of Change scores reported stability or improvement versus baseline at every visit. Urine hexose tetrasaccharide (hex4) decreased versus baseline from week 6 onwards and anti-drug antibodies remained stable. Cipa+mig was well tolerated, with safety outcomes similar to those previously reported in adult patients; no additional safety concerns were noted. At 18 yo the patient transitioned from ATB200-04 to standard-dose commercial cipa+mig. In his latest evaluation 9 months later, improvements were maintained in captured outcomes (6MWD: 359.6 m; % FVC: 93%).

Discussion
This report offers potential evidence for the efficacy and safety of cipa+mig treatment in an under-studied LOPD subpopulation: patients switching from long-term HDHF alg. The pediatric study ATB200-04 is still ongoing, and its results will further contribute to determine cipa+mig profile in a broader range of LOPD patients.

Conclusion
This patient showed sustained, long-term improvements in multiple measures following the switch from HDHF alg to standard-dose cipa+mig. Supported by Amicus Therapeutics, Inc.

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