Despite this, benefits may be clinically meaningful

Two phase III studies of enzyme replacement therapies (ERT) for late-onset Pompe disease, published simultaneously in Lancet Neurology, showed next-generation treatments were not superior to current standard of care.

Despite optimistic expectations given promising earlier research and a proven treatment pathway with modifiable defects, COMET, which evaluated avalglucosidase alfa, showed non-inferiority but not superiority on a primary respiratory outcome. PROPEL, which evaluated cipaglucosidase alfa plus a half-life-extending chaperone molecule, miglustat, also failed to show superiority on its primary outcome of timed walk test.

Both study treatments were compared with alglucosidase alfa, the current standard of care of late-onset (>1 year of age) Pompe disease.

“In mice, both new drugs (particularly cipaglucosidase alfa plus miglustat) greatly outperformed the standard of care in all measured outcomes,” notes Rosa Puertollano, PhD, and Nina Raben, MD, PhD, both of the National Institutes of Health in Bethesda, Maryland, in an editorial accompanying the trial data.

The phase I/II trial of avalglucosidase alfa and its extension showed sustained benefit in respiratory and motor function for up to 5.5 years, while phase I/II results for cipaglucosidase alfa showed a marked increase in walking distance beyond two years with increase in forced vital capacity (FVC), the editorialists noted.

“Given positive results from preclinical studies and the phase I/II trials, the results of COMET and PROPEL are somewhat disappointing,” Puertollano and Raben observed. “Although the discrepancy with the preclinical studies is easily explained—animal studies were performed in an inbred strain of clinically presymptomatic mice—it is difficult to account for the incongruity with the phase I/II trial results.”

Despite this, “the preponderance of evidence favoring the new drugs over the standard of care across multiple outcomes, particularly pulmonary function, suggests that the benefits of these new treatments are clinically meaningful,” they wrote. “Although neither avalglucosidase alfa nor cipaglucosidase alfa plus miglustat will cure late-onset Pompe disease, the new therapies might delay the onset of disability and respiratory failure.”

Pompe disease is rare, autosomal recessive, and results from α-glucosidase (GAA) gene variants leading to complete or partial loss of enzyme activity for glycogen breakdown. Glycogen accumulation particularly affects heart and skeletal muscle, and those with untreated infantile onset disease show symptoms in days to weeks and die within a year due to heart or respiratory issues. Late onset disease manifests after age 1, with slower progression.

A paucity of M6P ligands on recombinant human alglucosidase alfa limits its binding to endosomal M6P receptors, entry to the lysosome, and breakdown of glycogen. While phase III data published in 2010 for this form of alglucosidase alfa showed stable pulmonary function and improvement in walking distance, further improvements were sought by boosting M6P ligands, either by conjugating synthetic oligosaccharides containing M6P ligand to the enzyme (avalglucosidase alfa) or re-design of the enzyme (cipaglucosidase alfa).

COMET (avalglucosidase alfa)

COMET, which ran from November 2016 to March 2019, was a non-inferiority trial with a margin of 1.1% that compared ERT-naive patients treated with avalglucosidase alfa (n=51) and alglucosidase alfa (n=49) on a primary outcome of upright FVC change over 49 weeks. Participants were age 3 or older, had confirmed Pompe disease, could walk 40 meters without assistance, and had baseline FVC values of 30%-80% predicted.

The study found least-squares mean improvement in upright FVC% predicted of 2.89% versus 0.46% for avalglucosidase and alglucosidase, respectively, with noninferiority on FVC (between group difference 2.43%, 95% CI -0.13 to 4.99). Numerical improvement was also seen in distance covered on a walking test (difference 30.01 m).

“We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported,” wrote Jordi Diaz-Manera, MD, of Newcastle University in England, and co-authors.

“Non-inferiority was shown because the lower bound of the 95% CI for the difference [in FVC] far exceeded the predefined non-inferiority margin but did not exclude 0 (P=0.0074),” they added. “Superiority was not reached.”

The FDA approved avalglucosidase alfa for late-onset Pompe disease in August 2021. An open-label extension study is ongoing.

PROPEL (cipaglucosidase alfa plus miglustat)

PROPEL ran from December 2018 to November 2019 and compared cipaglucosidase alfa plus miglustat (n=85) versus alglucosidase alfa (n=38) on a primary outcome of 6-minute walk distance from baseline to week 52 in patients 18 and older with confirmed Pompe disease. Cipaglucosidase and alglucosidase were assigned to both ERT-naive (n=20 and 8, respectively) and ERT-experienced (n=65 and 30, respectively) participants.

The ERT-experienced group, which switched treatment to cipaglucosidase from alglucosidase alfa, had improved walk distances and stable FVC, while those who continued alglucosidase alfa showed no walking distance improvement and a decrease in FVC.

In the ERT-naive group, both treatments resulted in improved walking distance (mean change 38.3 m versus 33.4 m for cipaglucosidase versus alglucosidase, respectively, P=0.60 for treatment group difference) and decline in FVC (mean change −3.6% versus −4.1%, respectively, P=0.57 for treatment group difference).

Combined data for ERT-experienced and ERT-naive participants showed no difference in walking distance (between treatment group difference 13.6 m, 95% CI −2.8 to 29.9, P=0.071), though a benefit for cipaglucosidase on FVC was seen (between treatment group difference 3.0%, P=0.023). Safety outcomes were similar for the treatment groups.

“Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-minute walk distance in our overall population,” noted Benedikt Schoser, MD, of the Ludwig-Maximilians-Universität in Munich, Germany, and co-authors.

“Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than two years, as suggested by our secondary and subgroup analyses,” they added.

The researchers identified the smaller sample size of the ERT-naive cohort as a potential limitation.

  1. Two phase III studies of enzyme replacement therapies (ERT) for late-onset Pompe disease showed next-generation treatments were not superior to current standard of care.

  2. Despite this, the benefits of these new treatments, especially in pulmonary function, may be clinically meaningful.

Paul Smyth, MD, Contributing Writer, BreakingMED™

COMET was funded by Sanofi Genzyme. Diaz-Manera has served as a consultant or speaker for Sanofi Genzyme, Lupin, Sarepta, and PTC Therapeutics, and received research support from Boehringer Ingelheim and Sanofi Genzyme.

PROPEL was funded by Amicus Therapeutics. Schoser reported grant funding to his institution and consulting fees from Amicus Therapeutics; he has served as an advisory board member for Sanofi Genzyme, Lupin, Spark Therapeutics, and Astellas Therapeutics, as a consultant for Alexion, Argenx, and UCB Pharma, and as a speaker for Kedrion.

Puertollano and Raben reported research funding as part of a cooperative research and development agreement between the National Heart, Lung, and Blood Institute and Amicus Therapeutics.

Cat ID: 130

Topic ID: 82,130,730,130,192,925