Avalglucosidase Alfa (Nexviazyme)

Avalglucosidase alfa is a second-generation enzyme-replacement drug for late-onset Pompe disease, engineered from the same underlying enzyme as alglucosidase alfa but re-designed to carry substantially more of the sugar tag muscle cells use to pull the enzyme in. Approved by the FDA in 2021 based on a head-to-head trial against the original enzyme rather than a placebo, it's the second distinct Pompe enzyme molecule to reach market — and as this page was reviewed, its maker was preparing to ask the FDA to extend its US approval to infants for the first time, five years after Europe already cleared it for that use.

A second-generation Pompe enzyme, engineered for better uptake

This site's alglucosidase alfa page describes Pompe disease — a rare inherited disorder in which deficient acid alpha-glucosidase (GAA) activity lets glycogen accumulate inside muscle cells, most dangerously the heart and breathing muscles — and Myozyme/Lumizyme's role as the first disease-specific treatment, approved in 2006. Getting enough infused enzyme into muscle cells has always been the central limitation of Pompe enzyme-replacement therapy: the drug has to bind a receptor on the cell surface, the cation-independent mannose-6-phosphate receptor (CI-MPR), which recognizes a specific phosphorylated sugar tag on the enzyme and pulls it inside. Sanofi/Genzyme's second attempt at the same underlying enzyme, avalglucosidase alfa, was deliberately glycoengineered to carry substantially more of that bis-mannose-6-phosphate tag per molecule than alglucosidase alfa carries — published estimates of the exact fold-increase vary depending on measurement method, but consistently describe a large gain — aiming for better receptor binding and cellular uptake rather than any change to what the enzyme does once inside the cell. The FDA approved it on 6 August 2021 (BLA 761194) under the brand name Nexviazyme, specifically for late-onset Pompe disease in patients 1 year of age and older — becoming the second distinct Pompe enzyme molecule to reach the US market, three years before cipaglucosidase alfa became the fourth approved Pompe product.

COMET: a head-to-head trial against the original enzyme

Because alglucosidase alfa was already an approved, effective treatment by the time avalglucosidase alfa reached late-stage testing, its pivotal trial compared the two enzymes directly rather than testing avalglucosidase alfa against placebo. The phase 3 COMET trial enrolled 100 treatment-naive adults and adolescents (age 3 and older) with late-onset Pompe disease across 55 sites in 20 countries, randomizing 51 to avalglucosidase alfa and 49 to alglucosidase alfa, both dosed at 20 mg/kg every two weeks for 49 weeks. The primary endpoint was change in upright forced vital capacity (FVC) percent-predicted, a measure of respiratory muscle strength: avalglucosidase alfa met the trial's pre-specified non-inferiority criterion against alglucosidase alfa (p=0.0074), and the pre-specified test for superiority came close but fell just short of the conventional 0.05 threshold (p=0.0626), with a roughly 2.4-percentage-point greater improvement at week 49 (95% CI, -0.13 to 4.99 — a confidence interval that itself crosses zero, consistent with superiority falling just short of significance) and roughly 70% of avalglucosidase alfa patients showing any FVC improvement versus 47% on alglucosidase alfa (Diaz-Manera J, Kishnani PS, Kushlaf H, et al., "Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial," Lancet Neurol 2021;20(12):1012-1026, PMID 34800399, DOI: 10.1016/S1474-4422(21)00241-6).¹ On the secondary six-minute walk distance endpoint, avalglucosidase alfa patients improved by a mean 32.2 meters against 2.2 meters on alglucosidase alfa — a roughly 30-meter between-group gap — though this endpoint wasn't part of the trial's formal statistical hierarchy, so that difference is presented as supportive rather than independently confirmed evidence.

Approved on priority review, not on a completed confirmatory record

In November 2020, the FDA granted the avalglucosidase alfa application Breakthrough Therapy, Priority Review and Fast Track designations, based on the COMET data described above together with early results from a separate infantile-onset study. The FDA approved Nexviazyme on 6 August 2021, roughly nine months later — a fast review by ordinary standards, though the underlying COMET trial's long-term, open-label extension phase (in which every participant, including those originally randomized to alglucosidase alfa, crosses over to avalglucosidase alfa) was still ongoing at the time of approval and continued generating data for several years afterward, including published 97-week, 145-week and longer-term follow-up analyses. The European Commission separately approved the same enzyme, marketed there as Nexviadyme, on 28 June 2022 — covering both late-onset and infantile-onset Pompe disease in a single approval, a broader initial indication than avalglucosidase alfa received in the US.

Reaching for infants: Baby-COMET and a 2026 filing

Unlike the European approval, the FDA's original 2021 clearance of Nexviazyme covers only late-onset Pompe disease; a separate US approval for infantile-onset disease, the more severe and rapidly fatal form this site's alglucosidase alfa page describes, has not yet followed. Sanofi has run two supporting studies aimed at closing that gap: Mini-COMET, an earlier open-label study in children already on alglucosidase alfa who switched to avalglucosidase alfa, and Baby-COMET, a phase 3 trial in treatment-naive infants with infantile-onset disease. In June 2026, Sanofi reported that Baby-COMET met all of its primary and secondary endpoints with no serious treatment-related adverse events, and said it planned to submit a supplemental Biologics License Application to the FDA in the second half of 2026 seeking approval for infants younger than six months — meaning that, as of this review, avalglucosidase alfa's US label still does not cover the youngest and most severely affected Pompe patients, roughly five years after Europe's single approval already did.

Current status

Nexviazyme remains FDA-approved and currently marketed by Sanofi (through its Genzyme division) for late-onset Pompe disease in patients 1 year and older, alongside the original alglucosidase alfa (Myozyme/Lumizyme) and cipaglucosidase alfa plus miglustat (Pombiliti and Opfolda) described on this site's other Pompe pages. Its label carries a boxed warning for hypersensitivity reactions including anaphylaxis, infusion-associated reactions, and a risk of acute cardiorespiratory failure in susceptible patients, consistent with the pattern across infused enzyme-replacement drugs on this site. Sanofi has reported Nexviazyme/Nexviadyme sales growing at double-digit rates through 2025 (roughly €387 million combined US/EU sales in the first half of the year), commercial momentum that, combined with the pending infantile-onset filing described above, suggests avalglucosidase alfa's role is still expanding rather than settled five years after its original approval.