A Study Comparing ATB200/AT2221 With Alglucosidase Alfa/Placebo in Adult Subjects With Late-onset Pompe Disease

This is a double-blind, randomized, multicenter, international study of ATB200/AT2221 in adult subjects with late-onset Pompe disease (LOPD) who have received enzyme replacement therapy with alglucosidase alfa (ie, ERT-experienced) or who have never received ERT (ie, ERT naïve) compared with alglucosidase alfa/placebo.

The study will consist of a screening period up to 30 days, a 12-month treatment period, and a 30 day safety follow-up period. Subjects who complete this study will have the option to participate in an open label extension study to receive ATB200/AT2221 under a separate protocol.

Enzyme replacement therapy-experienced subjects will continue to take alglucosidase alfa during the screening period; treatment with alglucosidase alfa will then be replaced by study drug (ATB200/AT2221 or alglucosidase alfa/placebo) on the same schedule without interruption (ie, every 2 weeks).

Infusion visits will be scheduled every 2 weeks throughout the study; assessments (eg, clinical laboratory tests) for initial safety monitoring will be performed at these visits for the first 6 weeks of the study. Study visits that include efficacy, safety, and other assessments will be scheduled approximately every 3 months and may occur over 2 days, provided all study assessments and procedures (with the exception of pharmacokinetic \[PK\] sample collection) are performed before administration of study drug.

Efficacy assessments (ie, functional assessments) include evaluation of ambulatory function (6MWT), motor function tests (Gait, Stair, Gowers' maneuver, and Chair \[GSGC\] test and Timed Up and Go \[TUG\] test), muscle strength (manual muscle testing and quantitative muscle testing), and pulmonary function tests (forced vital capacity \[FVC\], slow vital capacity \[SVC\], maximal inspiratory pressure \[MIP\], maximal expiratory pressure \[MEP\], and sniff nasal inspiratory pressure \[SNIP\]). Patient reported outcomes (Rasch-built Pompe-specific Activity \[R PAct\] Scale, EuroQol 5 Dimensions 5 Levels Instrument \[EQ-5D-5L\], Patient-Reported Outcomes Measurement Information System \[PROMIS®\] instruments for physical function, fatigue, dyspnea, and upper extremity, and Subject's Global Impression of Change). The Physician's Global Impression of Change will also be performed.

Pharmacodynamic assessments include measurement of biomarkers of muscle injury (creatine kinase \[CK\]) and disease substrate (urinary hexose tetrasaccharide \[Hex4\]). Blood samples will be collected for determination of total GAA protein levels and AT2221 concentrations in plasma for a population PK analysis. Safety assessments include monitoring of adverse events (AEs), including infusion associated reactions (IARs), clinical laboratory tests (chemistry, hematology, and urinalysis), vital signs, physical examinations including weight, electrocardiograms (ECGs), and immunogenicity. Concomitant medications and nondrug therapies will also be recorded.