PROPEL
Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial
Year of Publication: 2021
Authors: Benedikt Schoser, Mark Roberts, Barry J Byrne, ..., PROPEL Study Group
Journal: The Lancet Neurology
Citation: Lancet Neurol 2021; 20: 1027-37
Link: https://doi.org/10.1016/S1474-4422(21)00331-8
PDF: https://pure.eur.nl/ws/files/185503716/S...t_Neur_2021.pdf
PDF: Clinical Question
Is cipaglucosidase alfa plus miglustat (a novel two-component enzyme replacement therapy) superior to alglucosidase alfa plus placebo for improving walking distance and respiratory function in late-onset Pompe disease?
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 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)
- FVC decline was nominally significantly less with cipaglucosidase alfa plus miglustat (-0.9% vs -4.0%; difference 3.0%, p=0.023)
- ERT-experienced patients (n=95) showed significant 6MWD improvement (+16.9 m vs 0.0 m, p=0.047) and FVC stabilization (+0.1% vs -4.0%, p=0.0061)
- Significant reductions in biomarkers: creatine kinase (-130.5 vs +60.2 U/L, p<0.0001) and urinary Hex4 (-1.9 vs +1.2, 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
Design
Study Type: Randomized, double-blind, parallel-group, phase 3 trial
Randomization: 1
Blinding: Double-blind: patients, sponsor, investigators, site personnel, and contracted research organizations were masked. Randomization using interactive response technology software stratified by 6MWD and previous ERT status
Enrollment Period: December 3, 2018 to November 26, 2019
Follow-up Duration: 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
Sample Size: 123
Analysis: Intention-to-treat. Primary endpoint by mixed-effect model for repeated measures (MMRM). Key secondary endpoints by ANCOVA with hierarchical testing procedure. One-sided significance level of 0.025. Prespecified subgroup analyses by ERT status. SAS version 9.4.
Inclusion Criteria
- Age >=18 years
- Body weight >=40 kg
- Diagnosis of late-onset Pompe disease confirmed by GAA enzyme deficiency or GAA genotyping
- ERT-experienced (alglucosidase alfa 20 mg/kg every 2 weeks for >=2 years) or ERT-naive
- Sitting FVC >=30% of predicted value
- Two valid 6-min walk tests (both >=75 m and <=90% predicted; lower value >=80% of higher value)
Exclusion Criteria
- Investigational therapy within 30 days or 5 half-lives before day 1
- Prior gene therapy for Pompe disease
- Ventilation support for >6 hours per day while awake
- Prohibited medications (miglitol, miglustat, acarbose, voglibose) within 30 days
- Hypersensitivity to excipients in study drugs
- Medical condition posing undue safety risk or compromising compliance
Baseline Characteristics
| Characteristic | Cipaglucosidase alfa + miglustat | Alglucosidase alfa + placebo |
|---|---|---|
| N | 85 | 38 |
| Age - years (mean, SD) | 47.6 (13.3) | 45.1 (13.3) |
| Age at diagnosis - years (mean, SD) | 39.9 (13.8) | 36.9 (15.3) |
| Sex - Female | 49 (58%) | 18 (47%) |
| Sex - Male | 36 (42%) | 20 (53%) |
| Race - White | 74 (87%) | 30 (79%) |
| Race - Asian | 5 (6%) | 5 (13%) |
| Use of walking aid | 17 (20%) | 11 (29%) |
| 6MWD - m (mean, SD) | 357.9 (111.8) | 351 (121.3) |
| Sitting FVC - % predicted (mean, SD) | 70.7% (19.6) | 69.7% (21.5) |
| ERT-experienced | 65 (76%) | 30 (79%) |
| ERT duration - years (mean, SD) | 7.5 (3.4) | 7.1 (3.6) |
| ERT-naive | 20 (24%) | 8 (21%) |
| c.-32-13T>G mutation | 76 (89%) | 32 (84%) |
Arms
| Field | Control | Cipaglucosidase alfa + miglustat |
|---|---|---|
| Intervention | Alglucosidase alfa 20 mg/kg IV plus oral placebo (matched to miglustat) every 2 weeks for 52 weeks. Placebo given approximately 1 hour before infusion. | Cipaglucosidase alfa 20 mg/kg IV plus oral miglustat (195 mg for 40-<50 kg, 260 mg for >=50 kg) every 2 weeks for 52 weeks. Miglustat given approximately 1 hour before infusion. |
| Duration | 52 weeks | 52 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change from baseline to week 52 in 6-min walk distance (6MWD) | Primary | +7.2 m (SE 6.6) | +20.8 m (SE 4.6) | 0.097 (MMRM); 0.071 (non-parametric ANCOVA) | |
| Change from baseline to week 52 in sitting FVC (% predicted) | Secondary | -4.0% (SE 0.8) | -0.9% (SE 0.7) | 0.023 (nominally significant) | |
| Change in lower extremity MMT score | Secondary | +0.9 (SE 0.4) | +1.6 (SE 0.4) | ||
| Change in GSGC total score | Secondary | +0.8 (SE 0.3) | -0.5 (SE 0.3) | ||
| ERT-experienced: 6MWD change at week 52 | Secondary | 0.0 m (SE 7.2) | +16.9 m (SE 5.0) | 0.047 (nominal) | |
| ERT-experienced: FVC change at week 52 | Secondary | -4.0% (SE 0.9) | +0.1% (SE 0.7) | 0.0061 (nominal) | |
| Serum creatine kinase change (U/L) | Secondary | +60.2 (SE 26.2) | -130.5 (SE 25.1) | <0.0001 | |
| Urinary Hex4 change (mmol/mol creatinine) | Secondary | +1.2 (SE 0.7) | -1.9 (SE 0.3) | <0.0001 | |
| Any treatment-emergent adverse event | Adverse | 37 (97%) | 81 (95%) | ||
| Fall | Adverse | 15 (39%) | 25 (29%) | ||
| Headache | Adverse | 9 (24%) | 20 (24%) | ||
| Nasopharyngitis | Adverse | 3 (8%) | 19 (22%) | ||
| Myalgia | Adverse | 5 (13%) | 14 (16%) | ||
| Serious adverse events | Adverse | 1 (3%) | 8 (9%) | ||
| Infusion-associated reactions | Adverse | 10 (26%) | 21 (25%) | ||
| Treatment discontinuation due to AE | Adverse | 1 (3%) | 3 (4%) | ||
| Deaths | Adverse | 0 | 0 |
Subgroup Analysis
ERT-experienced patients (n=95) showed greater benefit: 6MWD +16.9 m vs 0.0 m (nominal p=0.047), FVC +0.1% vs -4.0% (nominal p=0.0061). ERT-naive patients (n=27) showed similar responses in both groups with no significant differences, likely confounded by small sample size and near-normal baseline FVC (~80%). Post-hoc analyses by baseline 6MWD (<300 m vs >=300 m) and FVC (<55% vs >=55%) showed consistent benefits favoring cipaglucosidase alfa plus miglustat in overall and ERT-experienced populations.
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
Funding
Amicus Therapeutics
Based on: PROPEL (The Lancet Neurology, 2021)
Authors: Benedikt Schoser, Mark Roberts, Barry J Byrne, ..., PROPEL Study Group
Citation: Lancet Neurol 2021; 20: 1027-37
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