AT-GAA (cipaglucosidase alfa/miglustat) is an investigational therapy comprising 2 components that was developed by Amicus Therapeutics for the management of late-onset Pompe disease (LOPD).1 Pompe disease is a rare inherited lysosomal disease characterized by a deficiency of glycogen-degrading lysosomal acid alpha-glucosidase (GAA).2,3 Individuals with Pompe disease present with a partial or total loss of GAA activity, which results in the accumulation of glycogen within the lysosomes of the cells of several tissues, especially the heart and skeletal muscles.2,3 The accumulation of glycogen is believed to be responsible for the symptoms of Pompe disease, which include severe and progressive muscle weakness and loss of motor function.3,4 

Read about Pompe disease symptoms

The introduction of enzyme replacement therapy (ERT) has altered the natural course of Pompe disease.2 ERT with recombinant GAA was the first treatment approved for the disease, although some patients do not respond to the treatment and the benefits are not sustained in others.1 ERT in LOPD achieves positive outcomes and can help delay disease progression for up to 2 years after the initiation of treatment; however, skeletal muscle and respiratory function are still affected over time.2 

AT-GAA in Pompe disease 

AT-GAA has been developed with CHART (Chaperone-Advanced Replacement Therapy), a chaperone-ERT combination platform.5 The therapy consists of cipaglucosidase alfa (ATB200), which is a recombinant human acid alpha-glucosidase (rhGAA) enzyme, and miglustat (AT2221). Cipaglucosidase alfa has been designed with optimized carbohydrate structures (bis-phosphorylated mannose-6 phosphate [bis-M6P] glycans) that enhance drug uptake by cells. Miglustat is a small-molecule pharmacological chaperone, developed by Actelion Pharmaceuticals, that is currently approved for the treatment of type I Gaucher disease and Niemann-Pick disease type C.3 The chaperone binds to the cipaglucosidase alfa enzyme and improves its pharmacological properties by stabilizing its structure.1,3,4,6 

AT-GAA in Preclinical Studies and Clinical Trials

In preclinical studies, AT-GAA was superior to alpha-glucosidase, leading to higher levels of GAA in its mature form, decreasing glycogen levels in muscle, and increasing muscle strength.3,6 Additionally, AT-GAA was shown to decrease autophagic buildup in diseased muscles.3

AT-GAA was evaluated in a first-in-human phase1/2 clinical trial, ATB200-02 (NCT02675465).7,8 This international, open-label, multicenter trial was designed to test the safety, tolerability, and pharmacokinetics of intravenously administered ATB200 and orally administered AT2221 in adults with Pompe disease.7,8 

Treatment-naïve patients and patients receiving ERT were included in the study, which comprised 3 stages in which single ascending doses of ATB200 and single and multiple ascending dose combinations of ATB200 and AT2221 were evaluated.7 The trial reported sustained and durable improvements in clinical response that were observed for up to 36 months.9 The US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to AT-GAA for the treatment of LOPD on the basis of results from this phase 1/2 clinical trial.4

Read the latest news about AT-GAA:

The PROPEL clinical trial (NCT03729362) was a randomized, double-blind, parallel-group, multicenter phase 3 study that evaluated the efficacy and safety of AT-GAA in 123 patients with LOPD.1,10,11 The patients enrolled in this trial were aged 18 years and older who had either received ERT for at least 2 years or never received ERT.1 The experimental treatment was compared with alglucosidase alfa plus placebo. Patients were randomized 2:1 to receive intravenous cipaglucosidase alfa at 20 mg/kg plus oral miglustat or intravenous alglucosidase alfa at 20 mg/kg plus oral placebo once every 2 weeks for 52 weeks.1 In the AT-GAA group, 65 of the participants had previously received ERT; in the alglucosidase group, 30 had previously received ERT. Changes in 6-minute walk distance (6MWD) and percentage of predicted forced vital capacity (FVC) from baseline to week 52 were evaluated.1 

In the results of PROPEL, the combination of cipaglucosidase alfa plus miglustat led to clinical improvements on the 6MWD in comparison with alglucosidase. The difference, however, was not statistically different. A statistically significant improvement in the FVC was observed in the AT-GAA group. Biomarkers such as creatine kinase were also significantly improved in the AT-GAA group.1 The safety profiles of AT-GAA and alglucosidase were similar. During the trial, 118 (96%) of the 123 participants experienced at least one treatment-emergent adverse event. In the 8 patients who received AT-GAA, 12 serious adverse events were reported, but only anaphylaxis was related to the experimental treatment.1

The FDA is currently evaluating the Biologics License Application (BLA) submitted for cipaglucosidase alfa and the New Drug Application (NDA) submitted for miglustat. The Prescription Drug User Fee Act (PDUFA), previously set for May 29, 2022, for the NDA and July 29, 2022, for the BLA, have recently been extended for 90 days by the FDA, with final decisions expected by the fall of 2022. A decision regarding AT-GAA approval in the European Union is also expected in late 2022.4,6 

Another open-label, multicenter phase 3 clinical trial (NCT03911505) is currently recruiting and aims to evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of AT-GAA in ERT-experienced and -naïve pediatric participants with Pompe disease.12 The Rossella phase 3 trial (NCT04808505) will also evaluate the experimental therapy in children with infantile-onset Pompe disease (IOPD) and is currently recruiting.13


1. Schoser B, Roberts M, Byrne BJ, P et al. 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. Lancet Neurol. 2021;20(12):1027-1037. doi:10.1016/S1474-4422(21)00331-8

2. Meena NK, Ralston E, Raben N, Puertollano R. Enzyme replacement therapy can reverse pathogenic cascade in Pompe disease. Mol Ther Methods Clin Dev. 2020;18:199-214. doi:10.1016/j.omtm.2020.05.026

3. Xu S, Lun Y, Frascella M, et al. Improved efficacy of a next-generation ERT in murine Pompe disease. JCI Insight. 2019;4(5):e125358. doi:10.1172/jci.insight.125358

4. U.S. FDA accepts filings for Amicus’ AT-GAA for the treatment of Pompe disease. News release. Amicus Therapeutics; September 29, 221.

5. Amicus Therapeutics introduces proprietary “CHART” platform technology. News release. Amicus Therapeutics; March 4, 2013.

6. Amicus Therapeutics receives notification of PDUFA date extensions for AT-GAA. News release; May 10, 2022.

7. First-in-human study to evaluate safety, tolerability, and PK of intravenous ATB200 alone and when co-administered with oral AT2221. February 5, 2016. Updated June 13, 2022.

8. POMPE [ATB200-02]. Amicus Therapeutics. Accessed September 8, 2022.

9. Long-term follow-up of cipaglucosidase alfa/miglustat in ambulatory patients with Pompe disease: an open-label phase I/II study (ATB200-02). Poster presented at: 2022 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, Nashville, TN; March 13-16, 2022.

10. PROPEL study – a study comparing ATB200/AT2221 with alglucosidase/placebo in adult subjects with LOPD. November 2, 2018. Updated October 13, 2021.

11. PROPEL. Amicus Therapeutics. Accessed September 8, 2022.

12. ZIP Study-OL study of safety, PK, efficacy, PD, immunogenicity of ATB200/AT2221 in pediatrics aged 0 to < 18 y.o. w/LOPD. April 11, 2019. Updated July 18, 2022.

13. Rossella: a study to evaluate the safety, PK, efficacy, PD and immunogenicity of cipaglucosidase alfa/miglustat in IOPD subjects aged 0 to <18. March 22, 2021. Updated January 24, 2022.

Reviewed by Kyle Habet, MD, on 9/28/2022.