Researchers observed improvements in motor and respiratory function and biomarkers in the investigational treatment group.
Tahseen Mozaffar, MD, FAAN
Data from the recent phase 3, double-blind, parallel-group PROPEL trial (NCT03729362) suggest that investigational treatment AT-GAA improved motor and respiratory functions in Pompe disease compared to approved enzyme-replacement therapy (ERT).
These findings were presented at the Muscular Dystrophy Association’s (MDA) Scientific and Clinical Conference 2021, March 15-18, by Tahseen Mozaffar, MD, FAAN, interim chair of neurology, and director, UC Irvine-MDA ALS and Neuromuscular Center and UC Irvine Neuromuscular Program, University of California, Irvine.
“Alglucosidase alfa, which is a recombinant human GAA (rhGAA), is the currently the only approved treatment that has been shown to improve prognosis in patients with infantile onset Pompe disease, as well as late onset. AT-GAA, which is an investigational two component, therapy, comprising of cipaglucosidase alfa, which is administrated in conjunction with miglustat, so it's an adjunctive therapy,” Mozaffar said during his presentation.
AT-GAA cipaglucosidase alfa is a novel rhGAA with enhanced glycosylation for improved uptake and processing, and miglustat is an enzyme stabilizer. Mofazzar and colleagues sought to compare AT-GAA to alglucosidase alfa/placebo in adults with late-onset Pompe disease (LOPD).
They randomized ERT-experienced and -naïve patients 2:1 to co-administration of intravenous cipaglucosidase miglustat or alglucosidase alfa/placebo every 2 weeks, at 20-mg/kg dosages for each group. They sought to identify the mean change in 6-minute walk distance (6MWD) and percent predicted forced vital capacity (FVC; sitting) from baseline to week 52. They also assessed lower extremities manual muscle test (MMT); gait, stairs, Gower, chair test (GSGC); and Patient-Reported Outcomes Measurement Information System (PROMIS)-physical function and -fatigue.
Mozaffar and colleagues analyzed data from 123 patients in 62 sites across 24 countries, 85 patients treated with AT-GAA and 38 with alglucosidase. Patients had a mean age of 46.8 years (standard deviation [SD], 13.3) and about half were men (n = 56; 45.5%).
In the AT-GAA group, 65 participants were ERT-experienced and 20 were ERT-naïve. In the alglucosidase group, 30 were ERT-experienced and 8 were ERT-naïve. Baseline characteristics, such as score on 6MWD and MMT, were similar between groups.
The researchers found that, at week 52, participants in the AT-GAA group showed clinical improvement on 6MWD (mean change, 20.8 meters [SD, 7.2]) compared to alglucosidase approved therapy (mean change, 7.6 meters [SD, 6.6]; P = .072) but this did not reach statistical significance. A statistically significant improvement in FVC was seen in the AT-GAA group (–0.9 change [SD, 0.7]) compared to the alglucosidase group (–4.0 change [SD, 0.8]; P = .023).
Mozaffar and colleagues also saw clinically significant improvements in GSGC and promising trends in lower MMT, PROMIS-physical function, and fatigue in the AT-GAA group versus alglucosidase group.
Biomarkers assessed also showed significant improvements with the AT-GAA group versus alglucosidase, with creatine kinase showing a 22.4% reduction versus a 15.6% gain in the alglucosidase group (P <.05) and urine hexose tetrasaccharide showing a 31.5% reduction versus 11.0% gain (P <.001). Overall, 16 of 17 biomarkers assessed favored the AT-GAA group in both ERT-naïve and -experienced patients.
Safety profiles were similar between AT-GAA and alglucosidase groups, with 81 (95.3%) treatment-related adverse events (TEAEs) in the AT-GAA group and 37 (97.4%) in the alglucosidase group. Of these TEAEs, 26 (30.6%) in the AT-GAA group and 14 (36.8%) in the alglucosidase group were potentially related to treatment.
Eight (9.4%) serious TEAEs, 1 (1.2%) potentially related to treatment, were reported in the AT-GAA group while 1 serious TEAE unrelated to treatment was reported in the alglucosidase group. Three TEAEs led to study withdrawal, 2 (2.4%) in the AT-GAA group and 1 (2.6%) in the alglucosidase group, and none led to death.
“In conclusion, in the overall study population of ERT-naïve and ERT-experienced patients, AT-GAA showed clinically meaningful improvements in motor and respiratory functions and biomarkers, compared with alglucosidase alfa. Amongst the ERT-experienced patients, those randomized to AT-GAA showed clinically meaningful improvements on motor and respiratory functions, as well as biomarkers, compared to patients on the standard care,” Mozaffar concluded his presentation.
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