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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

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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

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

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	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

Content summarized and formatted by NeuroTrials.ai.

PROPEL

(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

• Primary endpoint not met: 6MWD improved 20.8 m vs 7.2 m but did not reach statistical superiority (p=0.097)
• FVC decline was significantly less with cipaglucosidase alfa (-0.9% vs -4.0%; between-group difference 3.0%, p=0.023)
• ERT-experienced patients showed significant 6MWD improvement (+16.9 m vs 0.0 m, p=0.047)

Intervention

Cipaglucosidase alfa 20 mg/kg IV plus miglustat 260 mg oral vs alglucosidase alfa 20 mg/kg IV plus oral placebo every 2 weeks for 52 weeks

Inclusion Criteria

Adults >=18 years with late-onset Pompe disease (GAA enzyme deficiency or genotyping confirmed), sitting FVC >=30% predicted, valid 6MWT (>=75 m and <=90% predicted), ERT-experienced (>=2 years) or ERT-naive

Study Design

Arms: Cipaglucosidase alfa + miglustat, Alglucosidase alfa + placebo

Patients per Arm: 85 (cipaglucosidase alfa + miglustat), 38 (alglucosidase alfa + placebo)

Outcome

• Primary: 6MWD change +20.8 m vs +7.2 m (difference 13.6 m, 95% CI -2.8 to 29.9, p=0.097 - not significant)
• First key secondary: FVC -0.9% vs -4.0% (difference 3.0%, p=0.023 - nominally significant)
• Biomarkers: Creatine kinase -130.5 vs +60.2 U/L (p<0.0001)

Bottom Line

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

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 using interactive response technology software stratified by 6MWD and previous ERT status
Sample Size: 123
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

View Original Publication →

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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