Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial

SPS commentary:

Thus is one of 2 RCTs in reported in The Lancet Neurology comparing the safety and efficacy of next-generation enzyme replacement therapy (ERT) against alglucosidase alfa, the current standard of care for patients with late-onset Pompe disease, a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen.

In the PROPEL trial (n=125), use of cipaglucosidase alfa with miglustat, an enzyme stabiliser, did not achieve statistical superiority to alglucosidase alfa for improving 6-min walk distance in overall population at week 52.

According to a commentary, given the positive results from preclinical studies and the phase 1/2 trials, the results of COMET and PROPEL are somewhat disappointing. Nevertheless, the preponderance of evidence favouring 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. It notes that 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. It adds that it is premature to speculate how these two new drugs compare with each other, but it is hard to overestimate the importance of improvement—albeit modest—in ERT-experienced patients who would typically be showing a decline after several years on standard of care, and only long-term extension studies could reveal which of the two new treatments is significantly (or at least marginally) superior.