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(2021)Objective
To assess the safety and efficacy of cipaglucosidase alfa plus miglustat (novel two-component therapy) versus alglucosidase alfa plus placebo for treatment of late-onset Pompe disease
Study Summary
• FVC decline was nominally significantly less with cipaglucosidase alfa plus miglustat (-0.9% vs -4.0%; between-group difference 3.0%, nominal p=0.023)
• ERT-experienced patients showed nominally significant 6MWD improvement (+16.9 m vs 0.0 m, nominal p=0.047) and FVC stabilization (+0.1% vs -4.0%, nominal p=0.0061)
Intervention
Cipaglucosidase alfa 20 mg/kg IV plus oral miglustat (195 mg for body weight 40 to <50 kg, 260 mg for ≥50 kg) vs alglucosidase alfa 20 mg/kg IV plus oral placebo, every 2 weeks for 52 weeks
Inclusion Criteria
Adults ≥18 years with body weight ≥40 kg and late-onset Pompe disease (confirmed by GAA enzyme deficiency or GAA genotyping); either ERT-experienced (alglucosidase alfa 20 mg/kg every 2 weeks for ≥2 years) or ERT-naive; sitting FVC ≥30% predicted; two valid 6-min walk tests (both ≥75 m and ≤90% predicted, with lower value ≥80% of the higher)
Study Design
Arms: Cipaglucosidase alfa + miglustat, Alglucosidase alfa + placebo
Patients per Arm: 125 randomized 2:1 — cipaglucosidase alfa + miglustat: 85 (ITT n=85); alglucosidase alfa + placebo: 40 randomized (ITT n=38; 2 excluded for absent genotype confirmation)
Outcome
• First key secondary: FVC -0.9% vs -4.0% (difference 3.0%, nominal p=0.023 — nominally significant)
• Biomarkers: Creatine kinase -130.5 vs +60.2 U/L (nominal p<0.0001); urinary Hex4 -1.9 vs +1.2 (nominal p<0.0001)
Bottom Line
Cipaglucosidase alfa plus miglustat did not achieve statistical superiority over standard of care for the primary endpoint of 6-min walk distance, but showed nominally significant improvement in FVC and clinically meaningful benefits particularly in ERT-experienced patients, who showed nominally significant improvements in both motor and respiratory outcomes.
Major Points
- Primary endpoint not met: 6MWD improved 20.8 m vs 7.2 m (difference 13.6 m, p=0.097 MMRM; p=0.071 non-parametric ANCOVA)
- FVC decline was nominally significantly less with cipaglucosidase alfa plus miglustat (-0.9% vs -4.0%; difference 3.0%, nominal p=0.023)
- ERT-experienced patients (n=95) showed nominally significant 6MWD improvement (+16.9 m vs 0.0 m, nominal p=0.047) and FVC stabilization (+0.1% vs -4.0%, nominal p=0.0061)
- Nominally significant reductions in biomarkers: creatine kinase (-130.5 vs +60.2 U/L, nominal p<0.0001) and urinary Hex4 (-1.9 vs +1.2, nominal p<0.0001)
- ERT-naive patients showed similar responses in both groups, confounded by small sample size and near-normal baseline FVC
- Safety profile was similar between groups; most common TEAEs were falls, headache, nasopharyngitis
- Largest randomized controlled trial in any lysosomal disorder and only study to include ERT-experienced patients at licensed standard dose
- Approximately two-thirds of enrolled patients were ERT-experienced with mean ~7.3 years prior treatment
Study Design
- Study Type
- Randomized, double-blind, parallel-group, phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind: patients, sponsor, investigators, site personnel, and contracted research organizations were masked. Randomization (2:1) using interactive response technology software stratified by baseline 6MWD (75 to <150 m, 150 to <400 m, or ≥400 m) and previous ERT status (ERT-naive or ERT-experienced)
- Sample Size
- 125 randomized (85 cipaglucosidase alfa + miglustat, 40 alglucosidase alfa + placebo); 123 in ITT population (2 controls excluded for absent genotype confirmation)
- Follow-up
- 52 weeks
- Centers
- 62
- Countries
- Argentina, Austria, Australia, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Denmark, France, Germany, Greece, Hungary, Italy, Japan, Netherlands, New Zealand, Poland, Slovenia, Spain, South Korea, Sweden, Taiwan, UK, USA
Primary Outcome
Definition: Change from baseline to week 52 in 6-min walk distance (6MWD)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| +7.2 m (SE 6.6) | +20.8 m (SE 4.6) | - (-2.8 to 29.9 (between-group difference)) | 0.097 (MMRM); 0.071 (non-parametric ANCOVA) |
Limitations & Criticisms
- Primary endpoint did not reach statistical significance
- Unequal randomization (2:1) resulted in smaller control group
- ERT-naive cohort was small (n=27), limiting interpretation of subgroup findings
- Unexpected large response in ERT-naive alglucosidase alfa group (38.3 m 6MWD improvement) may have contributed to failure of primary endpoint
- ERT-naive patients had near-normal baseline FVC (~80%), limiting ability to detect improvement
- Only single dose level of treatments evaluated
- Heterogeneous disease population with wide spectrum of manifestations
- One patient excluded from efficacy analyses for suspected deliberate underperformance at baseline
- COVID-19 pandemic affected some study visits
Citation
Lancet Neurol 2021; 20: 1027-37